WO2021243596A1

WO2021243596A1 - Aminopyrimidine compounds, preparation methods and uses thereof

Info

Publication number: WO2021243596A1
Application number: PCT/CN2020/094103
Authority: WO
Inventors: Xing DAI; Yaolin Wang; Yueheng Jiang; Yanqin Liu; Haotao NIU; Hong Yang; Zixing HAN; Zhenwu Wang; Liangshan TAO; Zhe SHI; Jifang WENG
Original assignee: InventisBio Co., Ltd.
Priority date: 2020-06-03
Filing date: 2020-06-03
Publication date: 2021-12-09
Also published as: WO2021244560A1

Abstract

Provided herein are novel compounds, for example, compounds having a Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof. Also provided herein are methods of preparing the compounds and methods of using the compounds, for example, for treating various cancer described herein, such as lung cancer (e.g., non-small cell lung cancer).

Description

AMINOPYRIMIDINE COMPOUNDS, PREPARATION METHODS AND USES THEREOF

BACKGROUND OF THE DISCLOSURE

Field of the Disclosure

In various embodiments, the present disclosure generally relates to novel aminopyrimidine compounds, compositions of the same, methods of preparing and methods of using the same, e.g., for treating a number of diseases or disorders, such as lung cancers.

Background

Epidermal growth factor receptor (EGFR) is a receptor tyrosine protein kinase, and a transmembrane protein in the ErbB receptor family.

EGFR regulates proliferation, survival, adhesion, migration and differentiation of cells, which is hyperactivated or sustained in a variety of tumor cells, such as lung cancer cells, breast cancer cells, prostate cancer cells and the like. Abnormal activation of EGFR plays a key role in tumor transformation and growth. Blocking activation of EGFR has been clinically proven as one of the effective targeted therapies for treating cancer. EGFR has been found to be highly mutated in NSCLC (non-small cell lung cancer) patients, which makes EGFR and its family members candidates for targeted therapy. Gefitinib and erlotinib are the first generation of small molecule inhibitors of EGFR, which are primarily used as drugs for treating advanced NSCLC. Clinical studies showed that EGFR is mutatd in 15%of Caucasian patients with NSCLC and 35%-50%of Asian NSCLC patients. Analyses also show that the response rate to EGFR-tyrosine kinase inhibitor (TKI) such as gefitinib or erlotinib in most NSCLC patients with EGFR activated mutants was significantly higher than that in NSCLC patients with only wild type EGFR.

Approximately 10-12%of EGFR mutated NSCLC tumors have an in-frame insertion within exon 20 of EGFR (Arcila et al, 2012) . In addition, 90%of human epidermal growth factor receptor 2 (HER2) mutations in NSCLC are exon 20 mutations (Mazieres et al, 2013) . EGFR and HER2 kinase inhibitors such as gefitinib, erlotinib, osimertinib, lapatinib, etc. have limited activity in patients with EGFR and/or HER2 exon 20 mutant tumors.

There is a huge unmet medical need for therapeutic treatment of cancer patients with EGFR and/or HER2 mutations such as exon 20 mutations.

BRIEF SUMMARY

In various embodiments, the present disclosure provides novel compounds, pharmaceutical compositions, methods of preparing and using the same. Typically, the compounds herein are inhibitors of EGFR and/or HER2 mutant proteins, such as those with mutations in the exon 20 domain as described herein. The compounds and compositions herein are useful for treating various diseases or disorders, including cancer associated with EGFR and/or HER2 mutations in the exon 20 domain.

In various embodiments, the present disclosure provides a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof:

wherein the variables X, L, R ¹, R ², R ³, A, G ¹, G ², R ^5A, R ^5B, and R ⁶ are defined herein. In some embodiments, the compounds of Formula I can have a subformulae of I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, or I-2B as defined herein. In some embodiments, the compounds of Formula II can have a subformulae of II-1, II-2, II-3, II-1A, II-2A, or II-3A as defined herein. In some embodiments, the compounds of Formula III can have a subformulae of III-1 as defined herein. In some embodiments, the present disclosure also provides specific compound Nos. 1-77, or a pharmaceutically acceptable salt thereof.

Certain embodiments are directed to a pharmaceutical composition comprising one or more of the compounds of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-77, or a pharmaceutically acceptable salt thereof) and optionally a pharmaceutically acceptable excipient. The pharmaceutical composition described herein can be formulated for different routes of administration, such as oral administration, parenteral administration, or inhalation etc.

Certain embodiments are directed to a method of treating a disease or disorder, such as a cancer described herein. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-77, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, a method of treating cancer, e.g., a cancer associated with EGFR and/or HER2 mutant protein which has an exon 20 mutation, in a subject in need thereof, is provided. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure or a therapeutically effective amount of a pharmaceutical composition described herein. In various embodiments, the cancer can be any one or more selected from lung cancer (e.g., non-small cell lung cancer) , breast cancer, stomach cancer, colorectal cancer, pancreatic cancer, prostate cancer, myeloma, head and neck cancer, ovarian cancer, uterine cancer, esophageal cancer, and metastatic cell carcinoma. In some embodiments, the cancer is associated with a mutation in the exon 20 domain of EGFR selected from A763insFQEA, V769insASV, D770insSVD, or H773insNPH, or T790M. In some embodiments, the cancer is associated with an NPH insertion in the exon 20 domain of EGFR, H773insNPH. In some embodiments, the cancer is associated with a T790M mutation in the exon 20 domain of EGFR concurrent with an exon 19 deletion mutation and/or an exon 21 point mutation (e.g., L858R) . In some embodiments, the cancer is associated with an YVMA insertion mutation in the exon 20 domain of HER2. The administering is not limited to any particular route of administration. For example, in some embodiments, the administering can be orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. The compounds of the present disclosure can be used as a monotherapy or in a combination therapy. In some embodiments, the combination therapy includes treating the subject with a chemotherapeutic agent, therapeutic antibody, radiation, cell therapy, or immunotherapy.

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

DETAILED DESCRIPTION

In various embodiments, provided herein are novel compounds, pharmaceutical compositions, methods of preparation and methods of use. It was discovered that the compounds of the present disclosure can have potent inhibition on EGFR mutant proteins with mutations in the exon 20 domain, such as with an insertion mutation. The compounds of the present disclosure can selectively inhibit mutant EGFR with mutations in the exon 20 domain over wild type EGFR.

Compounds

Some embodiments of the present disclosure are directed to novel compounds.

In some embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein:

A is a fused bicyclic heteroaryl group substituted with a substituent having a –SO ₂- or –C (=O) - group and optionally further substituted, preferably, A is A-I or A-II,

wherein:

each of J ¹, J ³, J ⁴, and J ⁹ is independently C or N,

J ² is CR ⁵ or N,

each of J ⁵, J ⁶, J ⁷, and J ⁸ is independently CR ⁶ or N,

provided that the bicyclic ring of J ¹-J ⁹ is a heteroaryl ring;

R ⁴ is an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted amino group;

R ⁵ is hydrogen, halogen, -CN, -OH, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl; or when both J ¹ and J ³ are N, R ⁵ can also be an oxo group; R ⁶ at each occurrence is independently hydrogen, halogen, -CN, -OH, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, an optionally substituted C _1-6 alkoxy, an optionally substituted C _3-6 cycloalkoxy, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl; and

R ⁷ is OH, an optionally substituted C _1-6 alkoxy, or an optionally substituted amino group, provided that when J ³ is N, R ⁷ is not OH;

wherein:

R ¹ is –L ¹-R ¹⁰, wherein L ¹ is absent, an optionally substituted C _1-6 alkylene, optionally substituted C _2-6 alkenylene, optionally substituted C _2-6 alkynylene, optionally substituted C _1-6 heteroalkylene, -C (=O) -O-, -C (=O) -NH-, -C (=O) -N (C _1-6 alkyl) -, -S (O) ₂-O-, -S (O) ₂-NH-, -S (O) ₂-N (C _1-6 alkyl) -, -P (=O) (C _1-6 alkyl) -, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenylene, or optionally substituted 5 or 6 membered heteroarylene, and R ¹⁰ is hydrogen, halogen, -CN, -C (=O) -O- (C _1-6 alkyl) , -C (=O) -NH- (C _1-6 alkyl) , -C (=O) -N (C _1-6 alkyl) (C _1-6 alkyl) , -S (O) ₂-O- (C _1-6 alkyl) , -S (O) ₂-NH- (C _1-6 alkyl) , -S (O) ₂-N (C _1-6 alkyl) (C _1-6 alkyl) , optionally substituted C _1- ₆ alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl;

R ² is hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or an oxygen protecting group;

X is O, NR ²⁰, or an optionally substituted 4 to 7 membered heterocyclic ring, wherein R ²⁰ is hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group;

L is absent or an optionally substituted C _1-6 alkylene, optionally substituted C _1-6 heteroalkylene, optionally substituted C _3-6 carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring;

R ³ is hydrogen, -NR ²¹R ²², or an optionally substituted 4 to 7 membered heterocyclyl, wherein R ²¹ and R ²² are independently hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group.

Various fused bicyclic heteroaryls are suitable for use as A in Formula I. In some embodiments, A is a fused 5, 6-or 6, 6-bicyclic heteroaryl with a substituent having a –SO ₂- or –C (=O) - group, such as a –SO ₂-R ⁴ or –C (=O) -R ⁷ group and optionally further substituted, wherein R ⁴ and R ⁷ are defined herein.

Preferably, A in Formula I is A-1 or A-II,

wherein J ¹-J ⁹, R ⁴, and R ⁷ can be any of those defined herein in any combination. In some embodiments, J ³ is N. In some embodiments, J ³ is C. In some embodiments, J ¹ is N. In some embodiments, J ¹ is C. In some embodiments, J ² is N. In some embodiments, J ² is CR ⁵. Typically, J ⁴ and J ⁹ are both C. In some embodiments, one of J ⁴ and J ⁹ is N and the other of J ⁴ and J ⁹ is C.

In some embodiments, A in Formula I is selected from A-1 to A-18:

wherein R ⁴, R ⁵, R ⁶, and R ⁷ can be any of those defined herein in any combination. In some embodiments, A in Formula I is A-1. In some embodiments, A in Formula I is A-2. In some embodiments, A in Formula I is A-3. In some embodiments, A in Formula I is A-4. In some embodiments, A in Formula I is A-5. In some embodiments, A in Formula I is A-6. In some embodiments, A in Formula I is A-7. In some embodiments, A in Formula I is A-8. In some embodiments, A in Formula I is A-9. In some embodiments, A in Formula I is A-10. In some embodiments, A in Formula I is A-11. In some embodiments, A in Formula I is A-12. In some embodiments, A in Formula I is A-13. In some embodiments, A in Formula I is A-14. In some embodiments, A in Formula I is A-15. In some embodiments, A in Formula I is A-16. In some embodiments, A in Formula I is A-17. In some embodiments, A in Formula I is A-18.

In some embodiments, A in Formula I comprises a –SO ₂-R ⁴ group. For example, A is a fused 5, 6-bicyclic heteroaryl group represented by A-I,

as defined herein, such as A-1 to A-4 (i.e., A-1, A-2, A-3, or A-4) , or A-9 to A-13 (i.e., A-9, A-10, A-11, A-12, or A-13) .

For example, in some embodiments, the compound of Formula I can be a compound of Formula I-1:

wherein R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, X, and L can be any of those defined herein in any combination.

In some embodiments, the compound of Formula I can be a compound of Formula I-2:

wherein R ¹, R ², R ³, R ⁴, R ⁶, X, and L can be any of those defined herein in any combination.

In some embodiments, the compound of Formula I can be a compound of Formula I-1A, I-1B, or I-2A:

In some embodiments, the compound of Formula I can be a compound of Formula I-1C:

wherein R ¹, R ², R ³, R ⁴, X, and L can be any of those defined herein in any combination.

In some embodiments, the compound of Formula I can be a compound of Formula I-1D or 1E:

In some embodiments, the compound of Formula I can be a compound of Formula I-1F or 1G:

Various groups are suitable as R ⁴. For example, in some embodiments, when present, R ⁴ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, or Formula I-1H, or I-2B described below) or A-1 to A-4 or A-9 to A-13 is an optionally substituted C _1-6 alkyl, such as unsubstituted C _1-6 alkyl (e.g., methyl, ethyl, or isopropyl) or a C _1-6 alkyl substituted with 1-3 substituents independently selected from F, Cl, -CN, C _1-6 alkyl, C _1-6 alkyl substituted with 1-3 fluorine, C _1-6 alkoxy, C _1-6 alkoxy substituted with 1-3 fluorine, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) (C _1-6 alkyl) , cyclopropyl, cyclobutyl, optionally substituted 4-7 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from O, N, and S, optionally substituted phenyl, and optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, N, and S. In some embodiments, R ⁴ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B) or A-1 to A-4 or A-9 to A-13 can be an optionally substituted C _1-4 alkyl, such as an unsubstituted C _1-4 alkyl such as methyl, ethyl, or isopropyl. In some embodiments, R ⁴ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B) or A-1 to A-4 or A-9 to A-13 can be a C _1-4 alkyl substituted with 1-3 fluorine, such as CF ₃.

In some embodiments, R ⁴ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B) or A-1 to A-4 or A-9 to A-13 is an optionally substituted C _3-6 carbocyclic ring, such as unsubstituted C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) or C _3- ₆ cycloalkyl substituted with 1-3 substituents independently selected from F, Cl, -CN, C _1-6 alkyl, C _1-6 alkyl substituted with 1-3 fluorine, C _1-6 alkoxy, C _1-6 alkoxy substituted with 1-3 fluorine, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) (C _1-6 alkyl) , cyclopropyl, and cyclobutyl. For example, in some embodiments, R ⁴ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B) or A-1 to A-4 or A-9 to A-13 is a cyclopropyl or cyclobutyl, which is optionally substituted with 1-2 substituents selected from methyl and fluorine.

In some embodiments, R ⁴ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B) or A-1 to A-4 or A-9 to A-13 is an optionally substituted phenyl, such as substituted with 1-3 substituents independently selected from F, Cl, -CN, C _1-6 alkyl, C _1-6 alkyl substituted with 1-3 fluorine, C _1-6 alkoxy, C _1-6 alkoxy substituted with 1-3 fluorine, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) (C _1-6 alkyl) , cyclopropyl, and cyclobutyl. In some embodiments, R ⁴ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B) or A-1 to A-4 or A-9 to A-13 is an unsubstituted phenyl. In some embodiments, R ⁴ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B) or A-1 to A-4 or A-9 to A-13 is a phenyl substituted with 1-3 substituents independently selected from F, Cl, -CN, C _1-4 alkyl, CF ₃, methoxy, -OH, cyclopropyl, and cyclobutyl.

In some embodiments, R ⁴ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B) or A-1 to A-4 or A-9 to A-13 is an optionally substituted amino group. For example, in some embodiments, R ⁴ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B) or A-1 to A-4 or A-9 to A-13 is unsubstituted amino group –NH ₂. In some embodiments, R ⁴ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B) or A-1 to A-4 or A-9 to A-13 is a monosubstituted amino group, such as a monoalkylamine, such as -NH (C _1-6 alkyl) , monocycloalkylamine, such as –NH (C _3-6 cycloalkyl) , wherein the C _1-6 alkyl or C _3-6 cycloalkyl can be optionally substituted with a permissible substituent as described herein. In some embodiments, R ⁴ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B) or A-1 to A-4 or A-9 to A-13 is -NH (C _1-4 alkyl) , such as –NH (methyl) , -NH (ethyl) , or -NH (isopropyl) . In some embodiments, R ⁴ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B) or A-1 to A-4 or A-9 to A-13 is a disubstituted amino group, for example, a dialkylamine, such as -N (C _1-6 alkyl) (C _1-6 alkyl) . As used herein, for disubstituted amines such as -N (C _1-6 alkyl) (C _1-6 alkyl) , the two C _1-6 alkyl groups are independently selected, which can be the same or different. For example, -N (C _1-6 alkyl) (C _1-6 alkyl) includes without limitation both –N (CH ₃) ₂ and –N (CH ₃) (C ₂H ₅) . Other similar expressions should be understood similarly.

In any of the embodiments described herein, unless otherwise specified or contradictory from context, R ⁴ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1F, I-1H, or I-2B) or A-1 to A-4 or A-9 to A-13 can be methyl, ethyl, isopropyl, -CF ₃, cyclopropyl, phenyl, -NH ₂, or -NH-CH ₃.

In some embodiments, A in Formula I is A-I:

e.g., A-1 to A-4, or A-11 or A-13, wherein J ² is CR ⁵, and the other variables can be any of those defined herein in any combination. In some embodiments, when present, R ⁵ in Formula I (e.g., Formula I-1, I-1B, I-1D, I-1E, or I-1H) or A-1 to A-4, A-11 or A-13 is hydrogen, halogen, -CN, an optionally substituted C _1-6 alkyl or an optionally substituted C _3-6 cycloalkyl. In some preferred embodiments, R ⁵ in Formula I (e.g., Formula I-1, I-1B, I-1D, I-1E, or I-1H) or A-1 to A-4, A-11 or A-13 is hydrogen. In some embodiments, R ⁵ in Formula I (e.g., Formula I-1, I-1B, I-1D, I-1E, or I-1H) or A-1 to A-4, A-11 or A-13 is a C _1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH. For example, in some embodiments, R ⁵ in Formula I (e.g., Formula I-1, I-1B, I-1D, I-1E, or I-1H) or A-1 to A-4, A-11 or A-13 is an unsubstituted C _1-4 alkyl, such as methyl, ethyl, isopropyl, etc. In some embodiments, R ⁵ in Formula I (e.g., Formula I-1, I-1B, I-1D, I-1E, or I-1H) or A-1 to A-4, A-11 or A-13 is a C _1-4 alkyl substituted with fluorines, such as CF ₃, C _1-4 alkyl substituted with a cyclopropyl, such as cyclopropylmethyl, or hydroxyl-substituted C _1-4 alkyl such as hydroxyethyl, etc. In some embodiments, R ⁵ in Formula I (e.g., Formula I-1, I-1B, I-1D, I-1E, or I-1H) or A-1 to A-4, A-11 or A-13 is a C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups. In some embodiments, R ⁵ in Formula I (e.g., Formula I-1, I-1B, I-1D, I-1E, or I-1H) or A-1 to A-4, A-11 or A-13 can be cyclopropyl or cyclobutyl. Other suitable groups for R ⁵ include those described herein.

In some embodiments, A in Formula I is A-I,

e.g., A-1 to A-4, or A-9 to A-13, wherein each of J ⁵, J ⁶, J ⁷ and J ⁸ is CR ⁶ or N as defined herein, and other variables can be any of those defined herein in any combination. In some embodiments, when present, R ⁶ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1D, I-1E, I-1H, or I-2B) or any of A-1 to A-4 or A-9 to A-13 at each occurrence is independently hydrogen, F, Cl, -CN, C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _3-6 cycloalkyl optionally substituted with 1-3 fluorine, C _3-6 cycloalkoxy optionally substituted with 1-3 fluorine. In some embodiments, when applicable, 2, 3, or 4 of the R ⁶ groups are hydrogen, in other words, at least two of J ⁵, J ⁶, J ⁷ and J ⁸ are CH.

In some embodiments, A in Formula I comprises a –CO-R ⁷ group. For example, A is a fused 5, 6-bicyclic heteroaryl group represented by A-II:

e.g., A-5 to A-8 (i.e., A-5, A-6, A-7, or A-8) , or A-14 to A-18 (i.e., A-14, A-15, A-16, A-17, or A-18) wherein J ¹-J ⁹ and R ⁷ are defined herein. In some embodiments, J ³ is N. In some embodiments, J ³ is C. In some embodiments, J ¹ is N. In some embodiments, J ¹ is C. In some embodiments, J ² is N. In some embodiments, J ² is CR ⁵. Typically, J ⁴ and J ⁹ are both C. In some embodiments, one of J ⁴ and J ⁹ is N and the other of J ⁴ and J ⁹ is C.

In some embodiments, R ⁷ is an optionally substituted amino group. For example, in some embodiments, when present, R ⁷ in Formula I (e.g., those compounds having A-5 to A-8 or A-14 to A-18 as A) is unsubstituted amino group –NH ₂. In some embodiments, R ⁷ in Formula I (e.g., those compounds having A-5 to A-8 or A-14 to A-18 as A) is a monosubstituted amino group, such as a monoalkylamine, such as -NH (C _1-6 alkyl) , monocycloalkylamine, such as –NH(C _3-6 cycloalkyl) , wherein the C _1-6 alkyl or C _3-6 cycloalkyl can be optionally substituted with a permissible substituents as described herein. In some embodiments, R ⁷ in Formula I (e.g., those compounds having A-5 to A-8 or A-14 to A-18 as A) is -NH (C _1-4 alkyl) , such as –NH(methyl) , -NH (ethyl) , or -NH (isopropyl) . In some embodiments, R ⁷ in Formula I (e.g., those compounds having A-5 to A-8 or A-14 to A-18 as A) is a disubstituted amino group, for example, a dialkylamine, such as -N (C _1-6 alkyl) (C _1-6 alkyl) . In some embodiments, R ⁷ can also be an optionally substituted C _1-6 alkoxy group, such as methoxy, ethoxy, isopropoxy group.

In some embodiments, A in Formula I is A-II:

e.g., A-5, A-6, A-7, A-8, A-16 or A-18, wherein J ² is CR ⁵, and the other variables can be any of those defined herein in any combination. In some embodiments, when present, R ⁵ in Formula I (e.g., those compounds having A-5, A-6, A-7, A-8, A-16 or A-18 as A) is hydrogen, halogen, -CN, an optionally substituted C _1-6 alkyl or an optionally substituted C _3-6 cycloalkyl. In some preferred embodiments, R ⁵ in Formula I (e.g., those compounds having A-5, A-6, A-7, A-8, A-16 or A-18 as A) is hydrogen. In some embodiments, R ⁵ in Formula I (e.g., those compounds having A-5, A-6, A-7, A-8, A-16 or A-18 as A) is a C _1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH. For example, in some embodiments, R ⁵ in Formula I (e.g., those compounds having A-5, A-6, A-7, A-8, A-16 or A-18 as A) is an unsubstituted C _1-4 alkyl, such as methyl, ethyl, isopropyl, etc. In some embodiments, R ⁵ in Formula I (e.g., those compounds having A-5, A-6, A-7, A-8, A-16 or A-18 as A) is a C _1-4 alkyl substituted with fluorines, such as CF ₃, C _1-4 alkyl substituted with a cyclopropyl, such as cyclopropylmethyl, or hydroxyl-substituted C _1-4 alkyl such as hydroxyethyl, etc. In some embodiments, R ⁵ in Formula I (e.g., those compounds having A-5, A-6, A-7, A-8, A-16 or A-18 as A) is a C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups. In some embodiments, R ⁵ in Formula I (e.g., those compounds having A-5, A-6, A-7, A-8, A-16 or A-18 as A) can be cyclopropyl or cyclobutyl. Other suitable groups for R ⁵ include those described herein.

In some embodiments, A in Formula I is A-II:

e.g., A-5, A-6, A-7, A-8, or A-14 to A-18, wherein each of J ⁵, J ⁶, J ⁷ and J ⁸ is CR ⁶ or N as defined herein, and other variables can be any of those defined herein in any combination. In some embodiments, when present, R ⁶ in Formula I (e.g., those compounds having A-5 to A-8 or A-14 to A-18 as A) or any of A-5 to A-8 or A-14 to A-18, at each occurrence is independently hydrogen, F, Cl, -CN, C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _3-6 cycloalkyl optionally substituted with 1-3 fluorine, C _3-6 cycloalkoxy optionally substituted with 1-3 fluorine. In some embodiments, when applicable, 2, 3, or 4 of the R ⁶ groups are hydrogen, in other words, at least two of J ⁵, J ⁶, J ⁷ and J ⁸ in A-II are CH.

Various groups can be used as R ¹ in Formula I. In some embodiments, R ¹ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1E, I-1G, I-1H, or I-2B) is –L ¹-R ¹⁰, wherein L ¹ is absent, and R ¹⁰ is defined herein. In some embodiments, R ¹ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1E, I-1G, I-1H, or I-2B) is –L ¹-R ¹⁰, wherein L ¹ is – (CH ₂) _p-, -O-, -O- (CH ₂) _p-, -C (=O) -O-, -C (=O) -NH-, -C (=O) -N (C _1-6 alkyl) -, -S (O) ₂-O-, -S (O) ₂-NH-, -S (O) ₂-N (C _1-6 alkyl) -,

or 5 or 6 membered heteroarylene having 1-4 ring nitrogen atoms (examples of such heteroaryl groups are described herein) , wherein p is an integer of 1-4, and R ¹⁰ is defined herein. It should be understood that in the cases of unsymmetrical linkers such as -O- (CH ₂) _p-, -C (=O) -O-, -C (=O) -NH-, -C (=O) -N (C _1-6 alkyl) -, -S (O) ₂-O-, -S (O) ₂-NH-, -S (O) ₂-N (C _1-6 alkyl) -, either end can be attached to R ¹⁰. For example, in some embodiments, R ¹ can be -O- (CH ₂) _p-R ¹⁰ or R ¹⁰-O- (CH ₂) _p-, -C (=O) -NH-R ¹⁰ or R ¹⁰-C (=O) -NH-, etc. Similarly, when L ¹ is a 5 or 6 membered heteroarylene, it can link R ¹⁰ to the remaining structures via any two available attaching points, which can be through ring nitrogen atoms as valence permits. In some embodiments, R ¹ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1E, I-1G, I-1H, or I-2B) is –L ¹-R ¹⁰, wherein L ¹ is -O-, -C (=O) -O-, -C (=O) -NH-,

and R ¹⁰ is defined herein. In some embodiments, R ¹⁰ is hydrogen. In some embodiments, R ¹⁰ is -C (=O) -O- (C _1-6 alkyl) , wherein the C _1-6 alkyl is methyl, ethyl, isopropyl, etc. In some embodiments, R ¹⁰ is -C (=O) -NH- (C _1-6 alkyl) , wherein the C _1-6 alkyl is methyl, ethyl, isopropyl, etc. In some embodiments, R ¹⁰ is an optionally substituted C _1-6 alkyl, such as unsubstituted C _1-6 alkyl, e.g., a C _1-4 alkyl, methyl, ethyl, isopropyl, etc. or a C _1-6 alkyl optionally substituted with 1-3 fluorine, e.g., CF ₃. In some embodiments, R ¹⁰ is an optionally substituted C _3-6 carbocyclic ring, such as cyclopropyl or cyclobutyl. Other suitable R ¹⁰ groups are described herein.

Any of the R ¹⁰ groups can be combined with any of the L ¹ groups described herein to form a R ¹ group. For example, in some embodiments, L ¹ is – (CH ₂) _p-, -O-, -O- (CH ₂) _p-,

or 5 or 6 membered heteroarylene having 1-4 ring nitrogen atoms, and R ¹⁰ is hydrogen, optionally substituted C _1-6 alkyl, -C (=O) -O- (C _1-6 alkyl) , -C (=O) -NH- (C _1-6 alkyl) , optionally substituted C _3-6 carbocyclic ring, etc. In some embodiments, L ¹ is -C (=O) -O-, -C (=O) -NH-, -C (=O) -N (C _1-6 alkyl) -, -S (O) ₂-O-, -S (O) ₂-NH-, -S (O) ₂-N (C _1-6 alkyl) -, and R ¹⁰ is hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 carbocyclic ring, etc.

In some embodiments, R ¹ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1E, I-1G, I-1H, or I-2B) can be hydrogen, F, Cl, -CN, C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _3-6 carbocyclic ring optionally substituted with 1-3 substituents independently selected from C _1-6 alkyl and F, 4 to 7 membered heterocyclic ring optionally substituted with 1-3 substituents independently selected from C _1-6 alkyl and F, phenyl optionally substituted with 1-3 substituents independently selected from C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, F, -CN, and Cl, or 5 or 6 membered heteroaryl having 1-4 ring nitrogen atoms and optionally substituted with 1-3 substituents independently selected from C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, F, and Cl. In some embodiments, R ¹ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1E, I-1G, I-1H, or I-2B) can be hydrogen, F, Cl, -CN, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -O- (C _1-4 alkyl) , -C (=O) -O- (C _1-4 alkyl) , -C (=O) -NH- (C _1-4 alkyl) , phenyl,

In some embodiments, R ¹ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1E, I-1G, I-1H, or I-2B) can be hydrogen, F, methyl, ethyl, isopropyl, cyclopropyl, methoxy, -C (=O) -O-isopropyl, -C (=O) -NH-isopropyl,

In some embodiments, R ¹ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1E, I-1G, I-1H, or I-2B) can also be any of the G ¹ groups as defined in connection with Formula II herein.

R ² in Formula I is typically hydrogen or an optionally substituted C _1-6 alkyl. For example, in some embodiments, R ² in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G) can be hydrogen, a C _1-4 alkyl (e.g., methyl) , or a C _1-4 alkyl substituted with one or more substituents independently selected from F, –OH, C _1-4 alkoxy, cyclopropyl, and C _1-4 heteroalkyl (such as -O–CH ₂CH ₂-O-CH ₃) . In some embodiments, R ² in Formula I can also be an oxygen protecting group (e.g., described herein) . In some preferred embodiments, R ² in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G) is hydrogen or methyl.

In some embodiments, X in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G) is O.

In some embodiments, X in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G) is NR ²⁰, wherein R ²⁰ is defined herein. In some embodiments, R ²⁰ is hydrogen, a C _1-4 alkyl (e.g., methyl) , or a nitrogen protecting group (e.g., described herein) . In some preferred embodiments, R ²⁰ is methyl.

In some embodiments, X in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G) is an optionally substituted 4-7 membered monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O, such as an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH ₂, –NH (C _1-6 alkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl) group, etc. For example, in some embodiments, X is

In some embodiments, L in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G) can be absent or a C _1-6 alkylene. For example, in some embodiments, L in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G) can be absent, -CH ₂-, or – (CH ₂) ₂-.

In some embodiments, R ³ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G) can be hydrogen.

In some embodiments, R ³ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G) can be -NR ²¹R ²², wherein R ²¹ and R ²² are independently hydrogen, or an optionally substituted C _1-6 alkyl. For example, in some embodiments, R ³ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G) can be –NH (C _1-6 alkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl) , such as –NHCH ₃ or -N (CH ₃) ₂.

In some embodiments, R ³ in Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-2A, I-1C, I-1D, I-1E, I-1F, or I-1G) can be an optionally substituted monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O, such as an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH ₂, –NH (C _1-6 alkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl) group, etc.

Any of the X group can be combined with any of the L and any of the R ³ group defined herein for Formula I. In some preferred embodiments, X-L-R ³ is

In some preferred embodiments, the compound of Formula I can have a Formula I-1H or I-2B:

wherein R ¹, R ⁴, R ⁵, and R ⁶ can be any of those defined herein in any combination. For example, in some embodiments, R ⁵ is hydrogen. In some embodiments, all of R ⁶ are hydrogen. In some embodiments, R ⁴ is methyl, ethyl, isopropyl, -CF ₃, cyclopropyl, phenyl, -NH ₂, or -NH-CH ₃. In some embodiments, R ¹ is hydrogen, F, methyl, ethyl, isopropyl, cyclopropyl, methoxy, -C (=O) -O-isopropyl, -C (=O) -NH-isopropyl,

Other suitable definitions of R ¹, R ⁴, R ⁵, and R ⁶ include any of those described herein in any combination.

In some embodiments, the present disclosure provides a compound of Formula II, or a pharmaceutically acceptable salt thereof:

wherein:

G ¹ is selected from:

a)

b)

c)

d) C _1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, methyl, C _1-6 alkoxy optionally substituted with fluorine, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, and 4-7 membered heterocyclic ring optionally substituted with fluorine and/or methyl groups,

e) a halogen or -CN,

f) C _1-6 alkoxy optionally substituted with fluorine,

g) optionally substituted phenyl,

h) C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, or

i) a 4-7 membered heterocyclic ring optionally substituted with fluorine and/or methyl groups;

wherein Q ¹ and Q ⁴ are independently C or N, Q ², Q ³, and Q ⁵ are independently CH, N, O, or S, provided that the ring of Q ¹-Q ⁵ is a 5-membered heteroaryl ring; wherein R ³⁰ and R ³¹ are independently hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group; or R ³⁰ and R ³¹ are joined to form an optionally substituted 4-7 membered heterocyclic ring;

R ⁴⁰ is hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring; and

R ⁴¹ is hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group when applicable;

G ² is an optionally substituted fused bicyclic heteroaryl group, preferably, G ² is

wherein each of J ¹, J ⁴, and J ⁹ is independently C or N,

J ² is CR ^5B or N,

J ³ is CR ^5B, N, or NR ^5A, as valence permits,

each of J ⁵, J ⁶, J ⁷, and J ⁸ is independently CR ⁶ or N,

provided that the bicyclic ring of J ¹-J ⁹ is a heteroaryl ring;

R ^5A is hydrogen, -C (=O) -R ⁷, -S (O) ₂R ⁴, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl;

R ^5B and R ⁶ at each occurrence is independently hydrogen, halogen, -CN, -OH, -C (=O) -R ⁷, -S (O) ₂R ⁴, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _1-6 alkoxy, optionally substituted C _3-6 cycloalkoxy, optionally substituted C _3- ₆ carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl; or when possible, R ^5A and R ^5B, two R ⁶ groups, or R ^5A and one R ⁶ group, together with the intervening atoms, are joined to form a 5-7 membered ring structure; or when J ¹ is N, and J ³ is N or NR ^5A, J ² can be CR ^5B, wherein R ^5B is an oxo group;

R ⁴ is an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted amino group; and

R ⁷ is OH, an optionally substituted C _1-6 alkoxy, or an optionally substituted amino group, provided that when -C (=O) -R ⁷ is attached to N, R ⁷ is not OH;

wherein:

In some embodiments, G ¹ in Formula II is

wherein R ³⁰ and R ³¹ can be any of those defined herein in any combination. For example, in some embodiments, one of R ³⁰ and R ³¹ is hydrogen or C _1-6 alkyl, and the other of R ³⁰ and R ³¹ is defined above. In some embodiments, one of R ³⁰ and R ³¹ is hydrogen or C _1-6 alkyl, and the other of R ³⁰ and R ³¹ is C _1-6 alkyl or a C _3-6 cycloalkyl. In some embodiments, R ³⁰ and R ³¹ are joined to form a monocyclic 4-7 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from O, N, and S, with at least one of which being N, for example, an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH ₂, –NH (C _1-6 alkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl) group, etc. In some embodiments, -NR ³⁰R ³¹ is –NH (C _1-6 alkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl) , wherein the C _1-6 alkyl can be independently, for example, methyl, ethyl, isopropyl, etc.

In some embodiments, G ¹ in Formula II is

wherein R ⁴⁰ is defined herein. For example, in some embodiments, R ⁴⁰ is C _1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH. In some embodiments, R ⁴⁰ is C _1-6 alkyl such as methyl, ethyl, or isopropyl. In some embodiments, R ⁴⁰ is a C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups.

In some embodiments, G ¹ in Formula II is

wherein Q ¹-Q ⁵ and R ⁴¹ can be any of those defined herein in any combination. For example, G ¹ can be a 5-membered heteroaryl moiety selected from:

In some embodiments, R ⁴¹ is C _1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH. In some embodiments, R ⁴¹ is C _1-6 alkyl such as methyl, ethyl, or isopropyl. In some embodiments, R ⁴¹ is a C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups.

In some embodiments, G ¹ in Formula II is an unsubstituted C _1-6 alkyl, such as methyl, ethyl, isopropyl, etc. In some embodiments, G ¹ in Formula II is a C _1-6 alkyl substituted with 1-3 substituents independently selected from fluorine, methyl, C _1-6 alkoxy optionally substituted with fluorine, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, and 4-7 membered heterocyclic ring optionally substituted with fluorine and/or methyl groups. For example, in some embodiments, G ¹ in Formula II is a C _1-6 alkyl substituted with 1-3 fluorine, such as CF ₃.

In some embodiments, G ¹ in Formula II is F, Cl, or CN.

In some embodiments, G ¹ in Formula II is C _1-6 alkoxy optionally substituted with fluorine, such as methoxy, ethoxy, isopropoxy, trifluoromethoxy, etc.

In some embodiments, G ¹ in Formula II is phenyl, which is optionally substituted 1-3 substituents independently selected from F, Cl, -CN, C _1-6 alkyl, C _1-6 alkyl substituted with 1-3 fluorine, C _1-6 alkoxy, C _1-6 alkoxy substituted with 1-3 fluorine, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) (C _1-6 alkyl) , cyclopropyl, and cyclobutyl.

In some embodiments, G ¹ in Formula II is cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl group.

In some embodiments, G ¹ in Formula II is a 4-7 membered heterocyclic ring, such as a monocyclic 4-7 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from O, N, and S, for example, azetidine, oxetane, pyrrolidine, piperidine, piperazine, morpholine, etc., which is optionally substituted with fluorine and/or methyl groups.

In some embodiments, G ² in Formula II is

wherein J ¹-J ⁹ can be any of those defined herein in any combination. For example, in some embodiments, G ² in Formula II is selected from:

wherein R ^5A, R ^5B, and R ⁶ can be any of those defined herein in any combination.

In some embodiments, G ² in Formula II is

wherein R ^5A, R ^5B, and R ⁶ can be any of those defined herein in any combination. For example, in some embodiments, R ^5A is hydrogen, -S (O) ₂-R ⁴, -C (O) -R ⁷, optionally substituted C _1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH) , or optionally substituted C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ; and R ^5B is hydrogen, halogen, -CN, optionally substituted C _1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH) , or optionally substituted C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ; or R ^5A and R ^5B are joined to form a 5 or 6 membered ring structure.

In some embodiments, G ² in Formula II can also be any of the A groups (e.g., A-1 to A-8) as defined herein in connection with Formula I.

Any combination of G ¹ and G ² is suitable for Formula II. For example, in some embodiments, the compound of Formula II can be characterized as having Formula II-1, II-2, or II-3:

wherein the variables R ^5A, R ^5B, R ⁶, R ³⁰, R ³¹, R ⁴⁰, R ⁴¹, R ², R ³, X, and L can be any of those defined herein in any combination. For example, in some embodiments, one of R ³⁰ and R ³¹ is hydrogen or C _1-6 alkyl, and the other of R ³⁰ and R ³¹ is defined above. In some embodiments, one of R ³⁰ and R ³¹ is hydrogen or C _1-6 alkyl, and the other of R ³⁰ and R ³¹ is C _1-6 alkyl or a C _3-6 cycloalkyl. In some embodiments, R ³⁰ and R ³¹ are joined to form a monocyclic 4-7 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from O, N, and S, with at least one of which being N, for example, an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH ₂, –NH (C _1-6 alkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl) group, etc. In some embodiments, -NR ³⁰R ³¹ is –NH (C _1-6 alkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl) , wherein the C _1-6 alkyl can be independently, for example, methyl, ethyl, isopropyl, etc.

In some embodiments, R ⁴⁰ is C _1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH. In some embodiments, R ⁴⁰ is C _1-6 alkyl such as methyl, ethyl, or isopropyl. In some embodiments, R ⁴⁰ is a C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups.

For example, in some embodiments, R ^5A is hydrogen, -S (O) ₂-R ⁴, -C (O) -R ⁷, optionally substituted C _1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH) , or optionally substituted C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ; and R ^5B is hydrogen, halogen, -CN, optionally substituted C _1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH) , or optionally substituted C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ; or R ^5A and R ^5B are joined to form a 5 or 6 membered ring structure.

In some embodiments, G ¹ in Formula II is C _1-6 alkyl, CF ₃, -CH ₂-O- (C _1-6 alkyl) , cyclopropyl, cyclobutyl, phenyl, F, Cl, CN, C _1-6 alkoxy,

and G ² in Formula II is

wherein R ^5A, R ^5B, and R ⁶ can be any of those defined herein in any combination. For example, in some embodiments, R ^5A is hydrogen, -S (O) ₂-R ⁴, -C (O) -R ⁷, optionally substituted C _1-6 alkyl (e.g , optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH) , or optionally substituted C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ; and R ^5B is hydrogen, halogen, -CN, optionally substituted C _1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH) , or optionally substituted C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ; or R ^5A and R ^5B are joined to form a 5 or 6 membered ring structure.

In some embodiments, G ² in Formula II (e.g., Formula II-1, II-2, or II-3) can be selected from B-1 to B-4:

wherein R ^5B and R ⁶ can be any of those defined herein in any combination.

In some embodiments, when present, R ^5B in Formula II (e.g., Formula II-1, II-2, or II-3 or Formula II-1A, II-2A, or II-3A as described below) or B-1 to B-2 moiety can be selected from:

a) hydrogen,

b) a C _1-6 alkyl, such as methyl, ethyl, isopropyl, etc.

c) a C _1-6 alkyl substituted with 1-3 substituents independently selected from fluorine, methyl, C _1-6 heteroalkyl, and –OH, e.g., -CH ₂CH ₂-N (CH ₃) ₂, CF ₃,

d) a C _1-6 alkyl substituted with an optionally substituted phenyl or an optionally substituted 5 or 6 membered heteroaryl, e.g., benzyl or substituted benzyl,

e) a C _1-6 alkyl substituted with a C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) , wherein the C _3-6 cycloalkyl is optionally substituted with fluorine and/or methyl groups, such as –CH ₂-cyclopropyl, or

f) cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups.

As used herein, substitution with a C _1-6 heteroalkyl can be through any of the attaching point of the C _1-6 heteroalkyl. For example, as a substituent, C _1-6 heteroalkyl can be attached to the remainder of the structure via a terminal heteroatom, terminal carbon atom, internal heteroatom, or internal carbon atom, for example, –O-CH ₂CH ₂-OCH ₃, where the attaching point is via the terminal oxygen atom, HO-CH ₂CH ₂-O-CH ₂-, where the attaching point is via the terminal carbon atom, -N- (CH ₃) ₂, where the attaching point is via the internal nitrogen atom, -CH (OCH ₃) (CH ₃) , where the attaching point is via the internal carbon atom.

In some embodiments, when present, R ^5A in Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, or II-3A) can be selected from:

a) hydrogen,

b) a C _1-6 alkyl, such as methyl, ethyl, isopropyl, etc.

d) -SO ₂-R ⁴, wherein R ⁴ is defined herein, such as methyl, ethyl, isopropyl, -CF ₃, cyclopropyl, phenyl, -NH ₂, and -NH-CH ₃,

e) –CO-R ⁷, wherein R ⁷ is defined herein, such as -NH (C _1-6 alkyl) , –NH (C _3-6 cycloalkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl) ,

f) a C _1-6 alkyl substituted with an optionally substituted phenyl or an optionally substituted 5 or 6 membered heteroaryl, e.g., benzyl or substituted benzyl,

g) a C _1-6 alkyl substituted with a C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) , wherein the C _3-6 cycloalkyl is optionally substituted with fluorine and/or methyl groups, such as –CH ₂-cyclopropyl, or

h) cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups.

In some embodiments, when present, R ⁶ in Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, or II-3A) at each occurrence can be independently hydrogen, F, Cl, -CN, C _1-4 alkyl optionally substituted with 1-3 fluorine, C _1-4 alkoxy optionally substituted with 1-3 fluorine, C _3-6 cycloalkyl optionally substituted with 1-3 fluorine, C _3-6 cycloalkoxy optionally substituted with 1-3 fluorine. In some preferred embodiments, 2, 3, or 4 of the R ⁶ groups are hydrogen.

In any of the embodiments described herein, when applicable, G ² in Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, or II-3A) can be selected from:

R ² in Formula II is typically hydrogen or an optionally substituted C _1-6 alkyl. For example, in some embodiments, R ² in Formula II (e.g., Formula II-1, II-2, or II-3) can be hydrogen, a C _1-4 alkyl (e.g., methyl) , or a C _1-4 alkyl substituted with one or more substituents independently selected from F, –OH, C _1-4 alkoxy, cyclopropyl, and C _1-4 heteroalkyl (such as -O–CH ₂CH ₂-O-CH ₃) . In some embodiments, R ² in Formula II can also be an oxygen protecting group (e.g., described herein) . In some preferred embodiments, R ² in Formula II (e.g., Formula II-1, II-2, or II-3) is hydrogen or methyl.

In some embodiments, X in Formula II (e.g., Formula II-1, II-2, or II-3) is O.

In some embodiments, X in Formula II (e.g., Formula II-1, II-2, or II-3) is NR ²⁰, wherein R ²⁰ is defined herein. In some embodiments, R ²⁰ is hydrogen, a C _1-4 alkyl (e.g., methyl) , or a nitrogen protecting group (e.g., described herein) . In some preferred embodiments, R ²⁰ is methyl.

In some embodiments, X in Formula II (e.g., Formula II-1, II-2, or II-3) is an optionally substituted 4-7 membered monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O, such as an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH ₂, –NH (C _1-6 alkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl) group, etc. For example, in some embodiments, X is

In some embodiments, L in Formula II (e.g., Formula II-1, II-2, or II-3) can be absent or a C _1-6 alkylene. For example, in some embodiments, L in Formula II (e.g., Formula II-1, II-2, or II-3) can be absent, -CH ₂-, or – (CH ₂) ₂-.

In some embodiments, R ³ in Formula II (e.g., Formula II-1, II-2, or II-3) can be hydrogen.

In some embodiments, R ³ in Formula II (e.g., Formula II-1, II-2, or II-3) can be -NR ²¹R ²², wherein R ²¹ and R ²² are independently hydrogen, or an optionally substituted C _1-6 alkyl. For example, in some embodiments, R ³ in Formula II (e.g., Formula II-1, II-2, or II-3) can be –NH (C _1-6 alkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl) , such as –NHCH ₃ or -N (CH ₃) ₂.

In some embodiments, R ³ in Formula II (e.g., Formula II-1, II-2, or II-3) can be an optionally substituted monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O, such as an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH ₂, –NH (C _1-6 alkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl) group, etc.

Any of the X group can be combined with any of the L and any of the R ³ group defined herein for Formula II (e.g., Formula II-1, II-2, or II-3) . In some preferred embodiments, X-L-R ³ is

In some preferred embodiments, the compound of Formula II can have a Formula II-1A, II-2A, or II-3A:

wherein the variables R ^5A, R ^5B, R ⁶, R ³⁰, R ³¹, R ⁴⁰, and R ⁴¹ can be any of those defined herein in any combination.

For example, in some embodiments, one of R ³⁰ and R ³¹ is hydrogen or C _1-6 alkyl, and the other of R ³⁰ and R ³¹ is defined above. In some embodiments, one of R ³⁰ and R ³¹ is hydrogen or C _1-6 alkyl, and the other of R ³⁰ and R ³¹ is C _1-6 alkyl or a C _3-6 cycloalkyl. In some embodiments, R ³⁰ and R ³¹ are joined to form a monocyclic 4-7 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from O, N, and S, with at least one of which being N, for example, an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH ₂, –NH (C _1-6 alkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl) group, etc. In some embodiments, -NR ³⁰R ³¹ is –NH (C _1-6 alkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl) , wherein the C _1-6 alkyl can be independently, for example, methyl, ethyl, isopropyl, etc.

In some embodiments, R ⁴⁰ is C _1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH. In some embodiments,

R ⁴⁰ is C _1-6 alkyl such as methyl, ethyl, or isopropyl. In some embodiments, R ⁴⁰ is a C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups.

In some embodiments, R ⁴¹ is C _1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH. In some embodiments,

R ⁴¹ is C _1-6 alkyl such as methyl, ethyl, or isopropyl. In some embodiments, R ⁴¹ is a C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups.

R ^5A, R ^5B, R ⁶ can be any of those described herein in any combination.

In some embodiments, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt thereof:

wherein:

R ^5A is hydrogen, -C (=O) -R ⁷, -S (O) ₂R ⁴, optionally substituted C _1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH) , or optionally substituted C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ;

R ^5B is hydrogen, halogen, -CN, optionally substituted C _1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH) , or optionally substituted C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ;

R ⁶ at each occurrence is independently hydrogen, halogen, -CN, -OH, -C (=O) -R ⁷, -S (O) ₂R ⁴, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _1-6 alkoxy, optionally substituted C _3-6 cycloalkoxy, optionally substituted C _3- ₆ carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl; or when possible, R ^5A and R ^5B, two R ⁶ groups, or one R ^5A and one R ⁶ group, together with the intervening atoms, are joined to form a 5-7 membered ring structure;

wherein:

In some embodiments, the moiety of

in Formula III (e.g., Formula III-1 as described below) can be selected from B-1 to B-4:

wherein R ^5B and R ⁶ can be any of those defined herein in any combination.

In some embodiments, R ^5B in Formula III (e.g., Formula III-1) or B-1 to B-2 moiety can be selected from:

a) hydrogen,

b) a C _1-6 alkyl, such as methyl, ethyl, isopropyl, etc.

In some embodiments, R ^5A in Formula III (e.g., Formula III-1) can be selected from:

a) hydrogen,

b) a C _1-6 alkyl, such as methyl, ethyl, isopropyl, etc.

In some embodiments, R ⁶ in Formula III (e.g., Formula III-1) at each occurrence can be independently hydrogen, F, Cl, -CN, C _1-4 alkyl optionally substituted with 1-3 fluorine, C _1-4 alkoxy optionally substituted with 1-3 fluorine, C _3-6 cycloalkyl optionally substituted with 1-3 fluorine, C _3-6 cycloalkoxy optionally substituted with 1-3 fluorine. In some preferred embodiments, 2, 3, or 4 of the R ⁶ groups are hydrogen.

In some embodiments, the moiety of

in Formula III (e.g., Formula III-1) is selected from:

In some preferred embodiments, the moiety of

in Formula III (e.g., Formula III-1) is selected from:

R ² in Formula III is typically hydrogen or an optionally substituted C _1-6 alkyl. For example, in some embodiments, R ² in Formula III can be hydrogen, a C _1-4 alkyl (e.g., methyl) , or a C _1-4 alkyl substituted with one or more substituents independently selected from F, –OH, C _1-4 alkoxy, cyclopropyl, and C _1-4 heteroalkyl (such as -O–CH ₂CH ₂-O-CH ₃) . In some embodiments, R ² in Formula III can also be an oxygen protecting group (e.g., described herein) . In some preferred embodiments, R ² in Formula III is hydrogen or methyl.

In some embodiments, X in Formula III is O.

In some embodiments, X in Formula III is NR ²⁰, wherein R ²⁰ is defined herein. In some embodiments, R ²⁰ is hydrogen, a C _1-4 alkyl (e.g., methyl) , or a nitrogen protecting group (e.g., described herein) . In some preferred embodiments, R ²⁰ is methyl.

In some embodiments, X in Formula III is an optionally substituted 4-7 membered monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O, such as an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH ₂, –NH (C _1-6 alkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl) group, etc. For example, in some embodiments, X is

In some embodiments, L in Formula III can be absent or a C _1-6 alkylene. For example, in some embodiments, L in Formula III can be absent, -CH ₂-, or – (CH ₂) ₂-.

In some embodiments, R ³ in Formula III can be hydrogen.

In some embodiments, R ³ in Formula III can be -NR ²¹R ²², wherein R ²¹ and R ²² are independently hydrogen, or an optionally substituted C _1-6 alkyl. For example, in some embodiments, R ³ in Formula III can be –NH (C _1-6 alkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl) , such as –NHCH ₃ or -N (CH ₃) ₂.

In some embodiments, R ³ in Formula III can be an optionally substituted monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O, such as an azetidine, pyrrolidine, piperidine, piperizine, morpholine, which can be optionally substituted with methyl, fluorine, hydroxyl, -NH ₂, –NH (C _1-6 alkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl) group, etc.

Any of the X group can be combined with any of the L and any of the R ³ group defined herein for Formula III. In some preferred embodiments, X-L-R ³ is

In some preferred embodiments, the compound of Formula III can have a Formula III-1:

wherein the variables R ^5A, R ^5B, and R ⁶ can be any of those defined herein in any combination.

In some embodiments, the present disclosure also provides a compound selected from any of Compound Nos 1-77, or a pharmaceutically acceptable salt thereof:

In some embodiments, to the extent applicable, the genus of compounds in the present disclosure also excludes any of the compounds specifically prepared and disclosed prior to the filing of this disclosure.

Method of Synthesis

The compounds of the present disclosure can be readily synthesized by those skilled in the art in view of the present disclosure. Exemplified synthesis are also shown in the Examples section.

In some embodiments, the present disclosure also provides synthetic methods and synthetic intermediates for preparing the compounds of Formula I, II, or III, as represented by the schemes herein.

As shown in Scheme 1, compounds of Formula I can be prepared from reacting a compound of S-6 with an acryloyl (H ₂C=CH–C (=O) –) donor, which can be acryloyl chloride or acryloyl anhydride, etc., under suitable conditions. Compounds of S-6 can be typically prepared from a compound of S-5 by reducing the nitro group, for example, using hydrogenation, such as in the presence of Pd/C. Compounds of S-5 can be typically prepared by reacting S-3 with an agent of S-4, under conditions to replace the Lg ² with X-L-R ³. In some embodiments, Lg ² is a halo such as F, Cl, Br, etc. or an oxygen containing leaving group such as mesylate, tosylate, trifluoromethanesulfonate, and the like. In some embodiments, Lg ² is F. Typically, the agent of S-4 is an amine, such as

which can react with the compound of S-3 to replace the Lg ² and form the compound of S-5.

Compounds of S-3 can be prepared from reacting S-1 and S-2 under suitable conditions. In some embodiments, Lg ¹ is a halo such as F, Cl, Br, etc., an oxygen containing leaving group such as mesylate, tosylate, trifluoromethanesulfonate, or a sulfone such as -SO ₂Me. Suitable conditions for carrying out the transformations in Scheme 1 include any of those known in the art for similar transformations. Exemplary suitable conditions are also described herein in the Examples section. The variables X, R ¹, R ², R ³, L, and A in Scheme 1 can be any of those defined herein in any combination.

In some embodiments, the introduction of the acryloyl group can occur earlier in the synthetic process. For example, as shown in Scheme 2 below, compounds of Formula I can be prepared from reacting the analine S-11 with the pyrimidine S-1 under suitable conditions. In some embodiments, Lg ¹ is a halo such as F, Cl, Br, etc., an oxygen containing leaving group such as mesylate, tosylate, trifluoromethanesulfonate, or a sulfone such as -SO ₂Me. Analine of S-11 can be prepared from S-10 through deprotection of Pg ¹, which can be any nitrogen protecting group (e.g., described herein) , for example, an acid labile protecting group such as Boc (tert-butyloxycarbonyl) . The protected analine S-10 can be prepared by reacting S-9 with an acryloyl (H ₂C=CH–C (=O) –) donor, which can be acryloyl chloride or acryloyl anhydride, etc., under suitable conditions. S-9 can be prepared by reducing the nitro precursor S-8, for example, using hydrogenation, such as in the presence of Pd/C. Compounds of S-8 can be prepared from reacting S-4 and S-7 under suitable conditions. In some embodiments, Lg ² is a halo such as F, Cl, Br, etc. or an oxygen containing leaving group such as mesylate, tosylate, trifluoromethanesulfonate. In some embodiments, Lg ² is F. Typically, the agent of S-4 is an amine, such as

which can react with the compound of S-7 to replace the Lg ² and form the compound of S-8. Suitable conditions for carrying out the transformations in Scheme 2 include any of those known in the art for similar transformations. Exemplary suitable conditions are also described herein in the Examples section. The variables X, R ¹, R ², R ³, L, and A in Scheme 2 can be any of those defined herein in any combination.

Compounds of S-1 can be readily prepared by those skilled in the art in view of the present disclosure. Typically, S-1 can be prepared from coupling a compound of S-12 with S-13 under suitable conditions. In some embodiments, Lg ³ is a halogen such as Cl. In some embodiments, G ¹⁰ can be hydrogen, a boronic acid or ester, or a metal. The reaction between S-12 and S-13 can be facilitated by a Lewis acid such as AlCl ₃, a suitable base, such as potassium tert-butoxide, or transition metal catalyst such as palladium. Exemplary procedures are also described herein in the Examples section. The variables Lg ¹, Lg ³, R ¹, R ², G ¹⁰, and A in Scheme 3 can be any of those defined herein in any combination.

The above synthetic process of Formula I is illustrative, which can be applied similarly by those skilled in the art for the synthesis of compounds of Formula II and III. For example, for the synthesis of compounds of Formula II, those skilled in the art would use the appropriate starting material,

instead of S-1, wherein G ¹, G ², and Lg ¹ can be any of those described herein in any combination. Similarly, for compounds of Formula III, the synthesis can use a starting material,

instead of S-1, wherein R ^5A, R ^5B, R ⁶,and Lg ¹ can be any of those described herein in any combination.

As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in “Protective Groups in Organic Synthesis” , 4 ^th ed. P.G.M. Wuts; T.W. Greene, John Wiley, 2007, and references cited therein. The reagents for the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) , Sigma (St. Louis, Missouri, USA) . Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991) , Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989) , Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991) , March's Advanced Organic Chemistry, (Wiley, 7 ^th Edition) , and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999) , and any of available updates as of this filing.

Pharmaceutical Compositions

Certain embodiments are directed to a pharmaceutical composition comprising one or more of the compounds of the present disclosure.

The pharmaceutical composition can optionally contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-77, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are known in the art. Non-limiting suitable excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro (Lippincott, Williams &Wilkins, Baltimore, Md., 2005; incorporated herein by reference) , which discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof.

The pharmaceutical composition can include any one or more of the compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition comprises a compound of Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-77, or a pharmaceutically acceptable salt thereof) , e.g., in a therapeutically effective amount. In any of the embodiments described herein, the pharmaceutical composition can comprise a therapeutically effective amount of a compound selected from compound Nos. 1-77, or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition can also be formulated for delivery via any of the known routes of delivery, which include but are not limited to oral, parenteral, inhalation, etc.

In some embodiments, the pharmaceutical composition can be formulated for oral administration. The oral formulations can be presented in discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients for the preparation of compositions for oral administration are known in the art. Non-limiting suitable excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1, 3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

In some embodiments, the pharmaceutical composition is formulated for parenteral administration (such as intravenous injection or infusion, subcutaneous or intramuscular injection) . The parenteral formulations can be, for example, an aqueous solution, a suspension, or an emulsion. Excipients for the preparation of parenteral formulations are known in the art. Non-limiting suitable excipients include, for example, 1, 3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.

In some embodiments, the pharmaceutical composition is formulated for inhalation. The inhalable formulations can be, for example, formulated as a nasal spray, dry powder, or an aerosol administrable through a metered-dose inhaler. Excipients for preparing formulations for inhalation are known in the art. Non-limiting suitable excipients include, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, and mixtures of these substances. Sprays can additionally contain propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

The pharmaceutical composition can include various amounts of the compounds of the present disclosure, depending on various factors such as the intended use and potency and selectivity of the compounds. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-77, or a pharmaceutically acceptable salt thereof) . In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present disclosure and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound of the present disclosure is an amount effective to treat a disease or disorder as described herein, which can depend on the recipient of the treatment, the disease or disorder being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency (e.g., for inhibiting an EGFR and/HER2 mutant protein as described herein) , its rate of clearance and whether or not another drug is co-administered.

For veterinary use, a compound of the present disclosure can be administered as a suitably acceptable formulation in accordance with normal veterinary practice. The veterinarian can readily determine the dosing regimen and route of administration that is most appropriate for a particular animal.

In some embodiments, all the necessary components for the treatment of EGFR and/or HER2-related disorder using a compound of the present disclosure either alone or in combination with another agent or intervention traditionally used for the treatment of such disease can be packaged into a kit. Specifically, in some embodiments, the present disclosure provides a kit for use in the therapeutic intervention of the disease comprising a packaged set of medicaments that include the compound disclosed herein as well as buffers and other components for preparing deliverable forms of said medicaments, and/or devices for delivering such medicaments, and/or any agents that are used in combination therapy with the compound of the present disclosure, and/or instructions for the treatment of the disease packaged with the medicaments. The instructions may be fixed in any tangible medium, such as printed paper, or a computer readable magnetic or optical medium, or instructions to reference a remote computer data source such as a world wide web page accessible via the internet.

Method of Treatment

Compounds of the present disclosure are useful as therapeutic active substances, for example, for the treatment and/or prophylaxis of diseases or disorders that are associated with an EGFR and/or HER2 exon 20 mutation, such as an insertion mutation.

In some embodiments, the present disclosure provides a method of inhibiting an EGFR and/or HER2 mutant protein which has an exon 20 mutation, such as one or more insertion, deletion, and/or point mutations in the exon 20 domain of the EGFR and/or HER2, the method comprising contacting a cell with an effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-77, or a pharmaceutically acceptable salt thereof) .

In some embodiments, the present disclosure provides a method of treating a disease or disorder, e.g., a cancer associated with EGFR and/or HER2 mutant protein which has an exon 20 mutation, in a subject in need thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-77, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein.

In some embodiments, a method for treatment of cancer is provided, the method comprising administering to a subject in need thereof an effective amount of any of the compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-77, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising the compound of the present disclosure. Non-limiting examples of cancer include lung cancer, breast cancer, stomach cancer, colorectal cancer, pancreatic cancer, prostate cancer, myeloma, head and neck cancer, ovarian cancer, uterine cancer, esophageal cancer, and metastatic cell carcinoma. In some embodiments, the cancer comprises non-small cell lung cancer.

In some embodiments the present disclosure provides a method of treating a disease or disorder (e.g., a cancer described herein) in a subject in need thereof, wherein the method comprises determining if the subject has an EGFR and/or HER2 exon 20 mutation, such as an insertion mutation, and if the subject is determined to have EGFR and/or HER2 exon 20 mutation, e.g., an insertion mutation, then administering to the subject a therapeutically effective dose of at least one compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-77, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising the at least one compound of the present disclosure. Mutation detection methods are known the art including PCR analyses and nucleic acid sequencing as well as FISH and CGH. In particular aspects, the exon 20 mutations are detected by DNA sequencing, such as from a tumor or circulating free DNA from plasma.

As used herein, EGFR and/or HER2 exon 20 mutation (s) include any of those described herein and those described in WO2015/195228, WO2015/175632, WO2020/061470, WO2020/068867, WO2020/068873, WO2020/039060, and references cited therein; see also Vyse, S. and Huang P.H. Signal Transduction and Targeted Therapy (2019) 4: 5; https: //doi. org/10.1038/s41392-019-0038-9.

In some embodiments, the EGFR exon 20 mutation (s) may comprise one or more point mutations, insertions, and/or deletions of 3-18 nucleotides between amino acids 763-778. In some embodiments, the EGFR exon 20 mutation (s) may be located at one or more residues selected from the group consisting of A763, A767, S768, V769, D770, N771, P772, and H773. In some embodiments, in addition to an EGFR exon 20 mutation, the subject herein may also have one or more EGFR exon 19 mutation such as exon 19 deletion, L858R, and L861Q, etc.

In some embodiments, the EGFR exon 20 mutation (s) includes an exon 20 insertion such as H773_V774insH, A767_v769ASV, N771_P772insH, D770_N771insG, H779_V774insH, N771delinsHH, S768_D770dupDVD, A767_V769dup ASV, A767_V769dupASV, P772_H773dup, N771_H773dupNPH, S768_D770dupSVD, N771delinsGY, S768_D770delinsSVD, D770_D770delinsGY, A767_V769dupASV, and/or H773dup. In some specific embodiments, the EGFR exon 20 mutation (s) comprises A763insFQEA, A767insASV, S768dupSVD, V769insASV, D770insSVD, D770insNPG, H773insNPH, N771del insGY, N771del insFH and/or N771dupNPH.

In some embodiments, the cancer herein is associated with an insertion mutation in the exon 20 domain of EGFR. In some embodiments, the cancer herein is associated with a mutation in the exon 20 domain of EGFR selected from A763insFQEA, V769insASV, D770insSVD, or H773insNPH, or T790M. In some embodiments, the cancer is associated with an NPH insertion in the exon 20 domain of EGFR, H773insNPH.

In some embodiments, the cancer is associated with a T790M mutation in the exon 20 domain of EGFR concurrent with an exon 19 deletion mutation and/or an exon 21 point mutation.

In some embodiments, the HER2 exon 20 mutation may comprise one or more point mutations, insertions, and/or deletions of 3-18 nucleotides between amino acids 770-785. The one or more HER2 exon 20 mutations may be at residue A775, G776, S779, and/or P780. In some embodiments, the one or more HER2 exon 20 mutations may be A775insV G776C, A775insYVMA, G776V, G776C V777insV, G776C V777insC, G776del insVV, G776del insVC, and/or P780insGSP.

In some embodiments, the cancer herein is also associated with a mutation in the exon 20 domain of HER2. In some embodiments, the cancer is associated with an YVMA insertion mutation in the exon 20 domain of HER2.

Compounds of the present disclosure can be used as a monotherapy or in a combination therapy. In some embodiments, the combination therapy includes treating the subject with a targeted agent, chemotherapeutic agent, therapeutic antibody, radiation, cell therapy, or immunotherapy. In some embodiments, compounds of the present disclosure can also be co-administered with an additional pharmaceutically active compound, either concurrently or sequentially in any order, to a subject in need thereof (e.g., a subject having a cancer associated with an EGFR and/HER2 mutation as described herein) . In some embodiments, the additional pharmaceutically active compound can be a targeted agent, a chemotherapeutic agent, a therapeutic antibody, etc. Any of the known chemotherapeutics can be used in combination with the compounds of the present disclosure. In some embodiments, compounds of the present disclosure can also be used in combination with a radiation therapy, hormone therapy, cell therapy, surgery and immunotherapy, which therapies are well known to those skilled in the art.

Many chemotherapeutics are presently known in the art and can be used in combination with the compounds of the present disclosure. In some embodiments, the chemotherapeutic is selected from the group an antimetabolite, a mitotic inhibitor, alkylating agent, a platinum-based antineoplastic drug, an antibody-drug conjugate consisting of the EGFR monoclonal antibody and toxic payload such as T-DM1, a targeted agent such as c-MET tyrosine kinase inhibitor, immune checkpoint inhibitors such as anti-PD-1/PD-L1 or anti-CTLA4 antibody, an mTOR inhibitor, a VEGF inhibitor, an aromatase inhibitor, a CDK4/6 inhibitor, and any combination thereof.

Non-limiting examples of useful additional pharmaceutically active compounds include but not limited to

(Imatinib Mesylate) ,

(carfilzomib) ,

(bortezomib) , Casodex (bicalutamide) ,

(gefitinib) , venetoclax, and Adriamycin. Non-limiting examples of useful additional pharmaceutically active compounds also include but not limited to alkylating agents such as thiotepa and cyclosphosphamide (CYTOXANTM) ; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, CasodexTM, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU) ; folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2, 2', 2” -trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ( “Ara-C” ) ; cyclophosphamide; thiotepa; taxanes, e.g. paclitaxel and docetaxel; retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

Non-limiting examples of useful additional pharmaceutically active compounds also include but not limited to anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, (NolvadexTM) , raloxifene, aromatase inhibiting 4 (5) -imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston) ; and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16) ; ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11) ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO) .

Where desired, the compounds or pharmaceutical composition of the present disclosure can be used in combination with commonly prescribed anti-cancer drugs such as

ABVD, AVICINE, Abagovomab, Acridine carboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins, Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy) , Calyculin, cell-cycle nonspecific antineoplastic agents, Dichloroacetic acid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE chemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole, Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1, Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin, Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford V, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar, Tesetaxel, Triplatin tetranitrate, Tris (2-chloroethyl) amine, Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.

The compounds of the present disclosure may also be used in combination with an additional pharmaceutically active compound that disrupts or inhibits RAS-RAF-ERK or PI3K-AKT-TOR signaling pathways. In other such combinations, the additional pharmaceutically active compound is a PD-1 and PD-L1 antagonist. The compounds or pharmaceutical compositions of the disclosure can also be used in combination with an amount of one or more substances selected from EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, Mcl-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immune therapies, including monoclonal antibodies, immunomodulatory imides (IMiDs) , anti-PD-1, anti-PDL-1, anti-CTLA4, anti-4-1-BB, anti-LAG1, anti-GITR and anti-OX40 antibodies, CAR-T cells, and BiTEs.

Exemplary anti-PD-1 or anti-PDL-1antibodies and methods for their use are described by Goldberg et al., Blood 110 (1) : 186-192 (2007) , Thompson et al., Clin. Cancer Res. 13 (6) : 1757-1761 (2007) , and Korman et al., International Application No. PCT/JP2006/309606 (publication no. WO 2006/121168 A1) , each of which are expressly incorporated by reference herein, include: pembrolizumab

nivolumab

Yervoy ^TM (ipilimumab) or Tremelimumab (to CTLA-4) , galiximab (to B7.1) , M7824 (a bifunctional anti-PD-L1/TGF-β Trap fusion protein) , AMP224 (to B7DC) , BMS-936559 (to B7-H1) , MPDL3280A (to B7-H1) , MEDI-570 (to ICOS) , AMG 404, AMG557 (to B7H2) , MGA271 (to B7H3) , IMP321 (to LAG-3) , BMS-663513 (to CD137) , PF-05082566 (to CD137) , CDX-1127 (to CD27) , anti-OX40 (Providence Health Services) , huMAbOX40L (to OX40L) , Atacicept (to TACI) , CP-870893 (to CD40) , Lucatumumab (to CD40) , Dacetuzumab (to CD40) , Muromonab-CD3 (to CD3) , Ipilumumab (to CTLA-4) . Immune therapies also include genetically engineered T-cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTEs) . Non-limiting useful additional agents also include anti-EGFR antibody, anti-EGFR/cMET antibody and anti-EGFR antibodies such as cetuximab (Erbitux) , panitumumab (Vectibix) , zalutumumab, nimotuzumab, matuzumab, and EGFR inhibitors such as gefitinib (Iressa) , erlotinib (Tarceva) , lapatinib (TykerB) , osimertinib (Tagrisso) , etc. Non-limiting useful additional agents also include CDK inhibitors such as CDK4/6 inhibitors, such as palbociclib, abemaciclib, ribociclib, etc. Non-limiting useful additional agents also include MEK inhibitors such as trametinib

The administering herein is not limited to any particular route of administration. For example, in some embodiments, the administering can be orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In some embodiments, the administering is orally.

Dosing regimen including doses can vary and can be adjusted, which can depend on the recipient of the treatment, the disease or disorder being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered.

Definitions

It is meant to be understood that proper valences are maintained for all moieties and combinations thereof.

It is also meant to be understood that a specific embodiment of a variable moiety herein can be the same or different as another specific embodiment having the same identifier.

Suitable atoms or groups for the variables herein are independently selected. The definitions of the variables can be combined. Using Formula I as an example, any of the definitions of one of R ¹, R ², R ³, X, L, and A in Formula I can be combined with any of the definitions of the others of X, R ¹, R ², R ³, X, L, and A in Formula I. Such combination is contemplated and within the scope of the present disclosure.

Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5 ^th Edition, John Wiley &Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 ^rd Edition, Cambridge University Press, Cambridge, 1987. The disclosure is not intended to be limited in any manner by the exemplary listing of substituents described herein.

Compounds of the present disclosure can comprise one or more asymmetric centers and/or axial chirality, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, atropisomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981) ; Wilen et al., Tetrahedron 33: 2725 (1977) ; Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962) ; and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972) . The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers including racemic mixtures. When a stereochemistry is specifically drawn, it should be understood that with respect to that particular chiral center or axial chirality, the compound exists predominantly as the as-drawn stereoisomer, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC area, or both, or with a non-detectable amount of the other stereoisomer (s) . The presence and/or amounts of stereoisomers can be determined by those skilled in the art in view of the present disclosure, including through the use of chiral HPLC.

When a range of values is listed, it is intended to encompass each value and sub–range within the range. For example “C _1–6” is intended to encompass, C ₁, C ₂, C ₃, C ₄, C ₅, C ₆, C _1–6, C _1–5, C _1–4, C _1–3, C _1–2, C _2–6, C _2–5, C _2–4, C _2–3, C _3–6, C _3–5, C _3–4, C _4–6, C _4–5, and C _5–6.

As used herein, the term “compound (s) of the present disclosure” refers to any of the compounds described herein according to Formula I (e.g., Formula I-1, I-2, I-1A, I-1B, I-1C, I-1D, I-1E, I-1F, I-1G, I-1H, I-2A, I-2B) , Formula II (e.g., Formula II-1, II-2, II-3, II-1A, II-2A, II-3A) , Formula III (e.g., Formula III-1) , any of compound Nos. 1-77, isotopically labeled compound (s) thereof (such as a deuterated analog wherein one of the hydrogen atoms is substituted with a deuterium atom with an abundance above its natural abundance) , possible stereoisomers thereof (including diastereoisomers, enantiomers, and racemic mixtures) , geometric isomers thereof, atropisomers thereof, tautomers thereof, conformational isomers thereof, and/or pharmaceutically acceptable salts thereof (e.g., acid addition salt such as HCl salt or base addition salt such as Na salt) . For the avoidance of doubt, Compound Nos. 1-77 or Compounds 1-77 refers to the compounds described herein labeled as integers 1, 2, 3, …, 77, see for example the title compounds of Examples 1-21 and Table 1. Hydrates and solvates of the compounds of the present disclosure are considered compositions of the present disclosure, wherein the compound (s) is in association with water or solvent, respectively.

Compounds of the present disclosure can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I. Compounds that contain other isotopes of these and/or other atoms are within the scope of this disclosure.

As used herein, the phrase “administration” of a compound, “administering” a compound, or other variants thereof means providing the compound or a prodrug of the compound to the individual in need of treatment.

As used herein, the term "alkyl" as used by itself or as part of another group refers to a straight-or branched-chain aliphatic saturated hydrocarbon. In some embodiments, the alkyl group is a C _1-6 alkyl group. In one embodiment, the alkyl group is a C _1-4 alkyl groupselected from methyl, ethyl, propyl (n-propyl) , isopropyl, butyl (n-butyl) , sec-butyl, tert-butyl, and iso-butyl. As used herein, the term "alkylene" as used by itself or as part of another group refers to a divalent radical derived from an alkyl group. For example, non-limiting straight chain alkylene groups include -CH ₂-CH ₂-CH ₂-CH ₂-, -CH ₂-CH ₂-CH ₂-, -CH ₂-CH ₂-, and the like.

As used herein, the term “heteroalkyl” refers to an alkyl group as defined above, with one or more carbon being replaced with a heteroatom, such as O or N. Those skilled in the art would understand that an O atom will replace a CH ₂ unit and an N atom will replace a CH unit. A heteroalkyl can be designated by its number of carbons. For example, a C _1-4 heteroalkyl refers to a heteroalkyl group containing 1-4 carbons. Examples of heteroalkyl include but not limited to –O-CH ₂CH ₂-OCH ₃, HO-CH ₂CH ₂-O-CH ₂-, -CH ₂CH ₂-N (H) -CH ₃, -N- (CH ₃) ₂, -CH (CH ₃) (OCH ₃) , etc. When optionally substituted, either the heteroatom or the carbon atom of the heteroalkyl group can be substituted with a permissible substituent. As used herein, the term "heteroalkylene" as used by itself or as part of another group refers to a divalent radical derived from a heteroalkyl group.

As used herein, the term "alkenyl" as used by itself or as part of another group refers to a straight-or branched-chain aliphatic hydrocarbon containing one or more, such as one, two or three carbon-to-carbon double bonds. In one embodiment, the alkenyl group is a C _2-6 alkenyl group. In another embodiment, the alkenyl group is a C _2-4 alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

As used herein, the term "alkynyl" as used by itself or as part of another group refers to a straight-or branched-chain aliphatic hydrocarbon containing one or more, such as one to three carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-carbon triple bond. In one embodiment, the alkynyl group is a C _2-6 alkynyl group. In another embodiment, the alkynyl group is a C _2-4 alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

As used herein, the term "alkoxy" as used by itself or as part of another group refers to a radical of the formula OR ^a1, wherein R ^a1 is an alkyl.

As used herein, the term "haloalkyl" as used by itself or as part of another group refers to an alkyl substituted with one or more fluorine, chlorine, bromine and/or iodine atoms. In preferred embodiments, the haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms.

“Carbocyclyl” or “carbocyclic” as used by itself or as part of another group refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ( “C _3–10 carbocyclyl” ) and zero heteroatoms in the non–aromatic ring system. The carbocyclyl group can be either monocyclic ( “monocyclic carbocyclyl” ) or contain a fused, bridged or spiro ring system such as a bicyclic system ( “bicyclic carbocyclyl” ) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclic ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ( “C _3–10 cycloalkyl” ) . In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ( “C _3–8 cycloalkyl” ) . In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ( “C _3–6 cycloalkyl” ) . In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ( “C _5–6 cycloalkyl” ) . In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ( “C _5–10 cycloalkyl” ) .

“Heterocyclyl” or “heterocyclic” as used by itself or as part of another group refers to a radical of a 3–to 10–membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ( “3–10 membered heterocyclyl” ) . In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic ( “monocyclic heterocyclyl” ) or a fused, bridged, or spiro ring system, such as a bicyclic system ( “bicyclic heterocyclyl” ) , and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclic ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclic ring, or ring systems wherein the heterocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclic ring system.

Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiiranyl. Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2, 5–dione. Exemplary 5–membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C ₆ aryl ring (also referred to herein as a 5, 6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6, 6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

“Aryl” as used by itself or as part of another group refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ( “C _6–14 aryl” ) . In some embodiments, an aryl group has six ring carbon atoms ( “C ₆ aryl” ; e.g., phenyl) . In some embodiments, an aryl group has ten ring carbon atoms ( “C ₁₀ aryl” ; e.g., naphthyl such as 1–naphthyl and 2–naphthyl) . In some embodiments, an aryl group has fourteen ring carbon atoms ( “C ₁₄ aryl” ; e.g., anthracyl) . “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.

“Aralkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more aryl groups, preferably, substituted with one aryl group. Examples of aralkyl include benzyl, phenethyl, etc. When an aralkyl is said to be optionally substituted, either the alkyl portion or the aryl portion of the aralkyl can be optionally substituted.

“Heteroaryl” as used by itself or as part of another group refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ( “5–10 membered heteroaryl” ) . In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl) .

Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6–membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5, 6–bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6, 6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroaralkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more heteroaryl groups, preferably, substituted with one heteroaryl group. When a heteroaralkyl is said to be optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl can be optionally substituted.

As commonly understood by those skilled in the art, alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene refer to the corresponding divalent radicals of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, respectively.

An “optionally substituted” group, such as an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refers to the respective group that is unsubstituted or substituted. In general, the term “substituted” , whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent can be the same or different at each position. Typically, when substituted, the optionally substituted groups herein can be substituted with 1-5 substituents. Substituents can be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent or a sulfur atom substituent, as applicable.

Unless expressly stated to the contrary, combinations of substituents and/or variables are allowable only if such combinations are chemically allowed and result in a stable compound. A “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject) .

In some embodiments, the “optionally substituted” alkyl, alkenyl, alkynyl, carbocyclic, cycloalkyl, alkoxy, cycloalkoxy, or heterocyclic group herein can be unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, -OH, protected hydroxyl, oxo (as applicable) , NH ₂, protected amino, NH (C _1-4 alkyl) or a protected derivative thereof, N (C _1-4 alkyl ( (C _1-4 alkyl) , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, 3-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from F, -OH, oxo (as applicable) , C _1-4 alkyl, fluoro-substituted C _1-4 alkyl (e.g., CF ₃) , C _1-4 alkoxy and fluoro-substituted C _1-4 alkoxy. In some embodiments, the “optionally substituted” aryl or heteroaryl group herein can be unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, -OH, -CN, NH ₂, protected amino, NH (C _1-4 alkyl) or a protected derivative thereof, N (C _1-4 alkyl ( (C _1-4 alkyl) , –S (=O) (C _1-4 alkyl) , –SO ₂ (C _1-4 alkyl) , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1, 2 or 3 ring heteroatoms independently selected from O, S, and N, 3-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from F, -OH, oxo (as applicable) , C _1-4 alkyl, fluoro-substituted C _1-4 alkyl, C _1-4 alkoxy and fluoro-substituted C _1-4 alkoxy. Exemplary carbon atom substituents include, but are not limited to, halogen, –CN, –NO ₂, –N ₃, –SO ₂H, –SO ₃H, –OH, –OR ^aa, –ON (R ^bb) ₂, –N (R ^bb) ₂, –N (R ^bb) ₃ ⁺X ^–, –N (OR ^cc) R ^bb, –SH, –SR ^aa, –SSR ^cc, –C (=O) R ^aa, –CO ₂H, –CHO, –C (OR ^cc) ₂, –CO ₂R ^aa, –OC (=O) R ^aa, –OCO ₂R ^aa, –C (=O) N (R ^bb) ₂, –OC (=O) N (R ^bb) ₂, –NR ^bbC (=O) R ^aa, –NR ^bbCO ₂R ^aa, –NR ^bbC (=O) N (R ^bb) ₂, –C (=NR ^bb) R ^aa, –C (=NR ^bb) OR ^aa, –OC (=NR ^bb) R ^aa, –OC (=NR ^bb) OR ^aa, –C (=NR ^bb) N (R ^bb) ₂, –OC (=NR ^bb) N (R ^bb) ₂, –NR ^bbC (=NR ^bb) N (R ^bb) ₂, –C (=O) NR ^bbSO ₂R ^aa, –NR ^bbSO ₂R ^aa, –SO ₂N (R ^bb) ₂, –SO ₂R ^aa, –SO ₂OR ^aa, –OSO ₂R ^aa, –S (=O) R ^aa, –OS (=O) R ^aa, –Si (R ^aa) ₃, –OSi (R ^aa) ₃ –C (=S) N (R ^bb) ₂, – C (=O) SR ^aa, –C (=S) SR ^aa, –SC (=S) SR ^aa, –SC (=O) SR ^aa, –OC (=O) SR ^aa, –SC (=O) OR ^aa, –SC (=O) R ^aa, –P (=O) (R ^aa) ₂, -P (=O) (OR ^cc) ₂, –OP (=O) (R ^aa) ₂, –OP (=O) (OR ^cc) ₂, –P (=O) (N (R ^bb) - ₂) ₂, –OP (=O) (N (R ^bb) ₂) ₂, -NR ^bbP (=O) (R ^aa) ₂, –NR ^bbP (=O) (OR ^cc) ₂, –NR ^bbP (=O) (N (R ^bb) ₂) ₂, –P (R ^cc) ₂, -P (OR ^cc) ₂, –P (R ^cc) ₃ ⁺X ^-, -P (OR ^cc) ₃ ⁺X ^-, -P (R ^cc) ₄, -P (OR ^cc) ₄, –OP (R ^cc) ₂, –OP (R ^cc) ₃ ⁺X ^-, -OP (OR ^cc) ₂, -OP (OR ^cc) ₃ ⁺X ^-, -OP (R ^cc) ₄, -OP (OR ^cc) ₄, –B (R ^aa) ₂, –B (OR ^cc) ₂, –BR ^aa (OR ^cc) , C _1–10 alkyl, C _1–10 haloalkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _3–10 carbocyclyl, 3–14 membered heterocyclyl, C _6–14 aryl, and 5–14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups; wherein X ^-is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN (R ^bb) ₂, =NNR ^bbC (=O) R ^aa, =NNR ^bbC (=O) OR ^aa, =NNR ^bbS (=O) ₂R ^aa, =NR ^bb, or =NOR ^cc; each instance of R ^aa is, independently, selected from C _1–10 alkyl, C _1–10 haloalkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _3–10 carbocyclyl, 3–14 membered heterocyclyl, C _6–14 aryl, and 5–14 membered heteroaryl, or two R ^aa groups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;

each instance of R ^bb is, independently, selected from hydrogen, –OH, –OR ^aa, –N (R ^cc) ₂, –CN, –C (=O) R ^aa, –C (=O) N (R ^cc) ₂, –CO ₂R ^aa, –SO ₂R ^aa, –C (=NR ^cc) OR ^aa, –C (=NR ^cc) N (R ^cc) ₂, –SO ₂N (R ^cc) ₂, –SO ₂R ^cc, –SO ₂OR ^cc, –SOR ^aa, –C (=S) N (R ^cc) ₂, –C (=O) SR ^cc, –C (=S) SR ^cc, –P (=O) (R ^aa) ₂, -P (=O) (OR ^cc) ₂, –P (=O) (N (R ^cc) ₂) ₂, C _1–10 alkyl, C _1–10 haloalkyl, C _2–10 alkenyl, C _2– ₁₀ alkynyl, C _3–10 carbocyclyl, 3–14 membered heterocyclyl, C _6–14 aryl, and 5–14 membered heteroaryl, or two R ^bb groups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups; wherein X ^-is a counterion;

each instance of R ^cc is, independently, selected from hydrogen, C _1–10 alkyl, C _1–10 haloalkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _3–10 carbocyclyl, 3–14 membered heterocyclyl, C _6–14 aryl, and 5–14 membered heteroaryl, or two R ^cc groups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups; each instance of R ^dd is, independently, selected from halogen, –CN, –NO ₂, –N ₃, –SO ₂H, –SO ₃H, –OH, –OR ^ee, –ON (R ^ff) ₂, –N (R ^ff) ₂, –N (R ^ff) ₃ ⁺X ^–, –N (OR ^ee) R ^ff, –SH, –SR ^ee, –SSR ^ee, –C (=O) R ^ee, –CO ₂H, –CO ₂R ^ee, –OC (=O) R ^ee, –OCO ₂R ^ee, –C (=O) N (R ^ff) ₂, –OC (=O) N (R ^ff) ₂, –NR ^ffC (=O) R ^ee, –NR ^ffCO ₂R ^ee, –NR ^ffC (=O) N (R ^ff) ₂, –C (=NR ^ff) OR ^ee, –OC (=NR ^ff) R ^ee, –OC (=NR ^ff) OR ^ee, –C (=NR ^ff) N (R ^ff) ₂, –OC (=NR ^ff) N (R ^ff) ₂, –NR ^ffC (=NR ^ff) N (R ^ff) ₂, –NR ^ffSO ₂R ^ee, –SO ₂N (R ^ff) ₂, –SO ₂R ^ee, –SO ₂OR ^ee, –OSO ₂R ^ee, –S (=O) R ^ee, –Si (R ^ee) ₃, –OSi (R ^ee) ₃, –C (=S) N (R ^ff) ₂, –C (=O) SR ^ee, –C (=S) SR ^ee, –SC (=S) SR ^ee, –P (=O) (OR ^ee) ₂, –P (=O) (R ^ee) ₂, –OP (=O) (R ^ee) ₂, –OP (=O) (OR ^ee) ₂, C _1–6 alkyl, C _1–6 haloalkyl, C _2–6 alkenyl, C _2–6 alkynyl, C _3–10 carbocyclyl, 3–10 membered heterocyclyl, C _6–10 aryl, 5–10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups, or two geminal R ^dd substituents can be joined to form =O or =S; wherein X ^-is a counterion;

each instance of R ^ee is, independently, selected from C _1–6 alkyl, C _1–6 haloalkyl, C _2–6 alkenyl, C _2–6 alkynyl, C _3–10 carbocyclyl, C _6–10 aryl, 3–10 membered heterocyclyl, and 3–10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups;

each instance of R ^ff is, independently, selected from hydrogen, C _1–6 alkyl, C _1–6 haloalkyl, C _2–6 alkenyl, C _2–6 alkynyl, C _3–10 carbocyclyl, 3–10 membered heterocyclyl, C _6–10 aryl and 5–10 membered heteroaryl, or two R ^ff groups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups; and

each instance of R ^gg is, independently, halogen, –CN, –NO ₂, –N ₃, –SO ₂H, –SO ₃H, –OH, –OC _1–6 alkyl, –ON (C _1–6 alkyl) ₂, –N (C _1–6 alkyl) ₂, –N (C _1–6 alkyl) ₃ ⁺X ^–, –NH (C _1–6 alkyl) ₂ ⁺X ^–, –NH ₂ (C _1–6 alkyl) ⁺X ^–, –NH ₃ ⁺X ^–, –N (OC _1–6 alkyl) (C _1–6 alkyl) , –N (OH) (C _1–6 alkyl) , –NH (OH) , –SH, –SC _1–6 alkyl, –SS (C _1–6 alkyl) , –C (=O) (C _1–6 alkyl) , –CO ₂H, –CO ₂ (C _1–6 alkyl) , –OC (=O) (C _1–6 alkyl) , –OCO ₂ (C _1–6 alkyl) , –C (=O) NH ₂, –C (=O) N (C _1–6 alkyl) ₂, –OC (=O) NH (C _1–6 alkyl) , –NHC (=O) (C _1–6 alkyl) , –N (C _1–6 alkyl) C (=O) (C _1–6 alkyl) , –NHCO ₂ (C _1–6 alkyl) , –NHC (=O) N (C _1–6 alkyl) ₂, –NHC (=O) NH (C _1–6 alkyl) , –NHC (=O) NH ₂, –C (=NH) O (C _1–6 alkyl) , –OC (=NH) (C _1–6 alkyl) , –OC (=NH) OC _1–6 alkyl, –C (=NH) N (C _1–6 alkyl) ₂, –C (=NH) NH (C _1–6 alkyl) , –C (=NH) NH ₂, –OC (=NH) N (C _1–6 alkyl) ₂, –OC (NH) NH (C _1– ₆ alkyl) , –OC (NH) NH ₂, –NHC (NH) N (C _1–6 alkyl) ₂, –NHC (=NH) NH ₂, –NHSO ₂ (C _1–6 alkyl) , – SO ₂N (C _1–6 alkyl) ₂, –SO ₂NH (C _1–6 alkyl) , –SO ₂NH ₂, –SO ₂C _1–6 alkyl, –SO ₂OC _1–6 alkyl, –OSO ₂C _1–6 alkyl, –SOC _1–6 alkyl, –Si (C _1–6 alkyl) ₃, –OSi (C _1–6 alkyl) ₃ –C (=S) N (C _1–6 alkyl) ₂,C (=S) NH (C _1–6 alkyl) , C (=S) NH ₂, –C (=O) S (C _1–6 alkyl) , –C (=S) SC _1–6 alkyl, –SC (=S) SC _1–6 alkyl, –P (=O) (OC _1–6 alkyl) ₂, –P (=O) (C _1–6 alkyl) ₂, –OP (=O) (C _1–6 alkyl) ₂, –OP (=O) (OC _1–6 alkyl) ₂, C _1–6 alkyl, C _1–6 haloalkyl, C _2–6 alkenyl, C _2–6 alkynyl, C _3–10 carbocyclyl, C _6–10 aryl, 3–10 membered heterocyclyl, 5–10 membered heteroaryl; or two geminal R ^gg substituents can be joined to form =O or =S; wherein X ^– is a counterion.

A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge) . An anionic counterion may also be multivalent (i.e., including more than one formal negative charge) , such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F ^–, Cl ^–, Br ^–, I ^–) , NO ₃ ^–, ClO ₄ ^–, OH ^–, H ₂PO ₄ ^–, HSO ₄ ^–, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like) , carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like) , BF ₄ ^–, PF ₄ ^–, PF ₆ ^–, AsF ₆ ^–, SbF ₆ ^–, B [3, 5- (CF ₃) ₂C ₆H ₃] ₄] ^–, BPh ₄ ^–, Al (OC (CF ₃) ₃) ₄ ^–, and a carborane anion (e.g., CB ₁₁H ₁₂ ^–or (HCB ₁₁Me ₅Br ₆) ^–) . Exemplary counterions which may be multivalent include CO ₃ ^2-, HPO ₄ ^2-, PO ₄ ^3- _, B ₄O ₇ ^2-, SO ₄ ^2-, S ₂O ₃ ^2-, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like) , and carboranes.

“Halo” or “halogen” refers to fluorine (fluoro, –F) , chlorine (chloro, –Cl) , bromine (bromo, –Br) , or iodine (iodo, –I) .

“Acyl” refers to a moiety selected from the group consisting of –C (=O) R ^aa, –CHO, –CO ₂R ^aa, –C (=O) N (R ^bb) ₂, –C (=NR ^bb) R ^aa, –C (=NR ^bb) OR ^aa, –C (=NR ^bb) N (R ^bb) ₂, –C (=O) NR ^bbSO ₂R ^aa, –C (=S) N (R ^bb) ₂, –C (=O) SR ^aa, or –C (=S) SR ^aa, wherein R ^aa and R ^bb are as defined herein.

Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, –OH, –OR ^aa, –N (R ^cc) ₂, –CN, –C (=O) R ^aa, –C (=O) N (R ^cc) ₂, –CO ₂R ^aa, –SO ₂R ^aa, –C (=NR ^bb) R ^aa, –C (=NR ^cc) OR ^aa, – C (=NR ^cc) N (R ^cc) ₂, –SO ₂N (R ^cc) ₂, –SO ₂R ^cc, –SO ₂OR ^cc, –SOR ^aa, –C (=S) N (R ^cc) ₂, –C (=O) SR ^cc, –C (=S) SR ^cc, –P (=O) (OR ^cc) ₂, –P (=O) (R ^aa) ₂, –P (=O) (N (R ^cc) ₂) ₂, C _1–10 alkyl, C _1–10 haloalkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _3–10 carbocyclyl, 3–14 membered heterocyclyl, C _6–14 aryl, and 5–14 membered heteroaryl, or two R ^cc groups attached to a nitrogen atom are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups, and wherein R ^aa, R ^bb, R ^cc, and R ^dd are as defined above.

In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group) . Nitrogen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 ^rd edition, John Wiley &Sons, 1999, incorporated by reference herein. Exemplary nitrogen protecting groups include, but not limited to, those forming carbamates, such as Carbobenzyloxy (Cbz) group, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, tert-Butyloxycarbonyl (BOC) group, Troc, 9-Fluorenylmethyloxycarbonyl (Fmoc) group, etc., those forming an amide, such as acetyl, benzoyl, etc., those forming a benzylic amine, such as benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, etc., those forming a sulfonamide, such as tosyl, Nosyl, etc., and others such as p-methoxyphenyl.

Exemplary oxygen atom substituents include, but are not limited to, –R ^aa, –C (=O) SR ^aa, –C (=O) R ^aa, –CO ₂R ^aa, –C (=O) N (R ^bb) ₂, –C (=NR ^bb) R ^aa, –C (=NR ^bb) OR ^aa, –C (=NR ^bb) N (R ^bb) ₂, –S (=O) R ^aa, –SO ₂R ^aa, –Si (R ^aa) _3, –P (R ^cc) ₂, –P (R ^cc) ₃ ⁺X ^-, -P (OR ^cc) ₂, -P (OR ^cc) ₃ ⁺X ^-, –P (=O) (R ^aa) ₂, –P (=O) (OR ^cc) ₂, and –P (=O) (N (R ^bb) ₂) ₂, wherein X ^-, R ^aa, R ^bb, and R ^cc are as defined herein. In certain embodiments, the oxygen atom substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group) . Oxygen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 ^rd edition, John Wiley &Sons, 1999, incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, alkyl ethers or substituted alkyl ethers such as methyl, allyl, benzyl, substituted benzyls such as 4-methoxybenzyl, methoxylmethyl (MOM) , benzyloxymethyl (BOM) , 2–methoxyethoxymethyl (MEM) , etc., silyl ethers such as trymethylsilyl (TMS) , triethylsilyl (TES) , triisopropylsilyl (TIPS) , t-butyldimethylsilyl (TBDMS) , etc., acetals or ketals, such as tetrahydropyranyl (THP) , esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc., carbonates, sulfonates such as methanesulfonate (mesylate) , benzylsulfonate, and tosylate (Ts) , etc.

The term “leaving group” is given its ordinary meaning in the art of synthetic organic chemistry, for example, it can refer to an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502) . Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine) ) , alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy) , arylcarbonyloxy, aryloxy, methoxy, N, O-dimethylhydroxylamino, pixyl, and haloformates.

The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.

The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa) . The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to- (adifferent enamine) tautomerizations.

The term “subject” (alternatively referred to herein as “patient” ) as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

As used herein, the terms "treat, " "treating, " "treatment, " and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. As used herein, the terms "treat, " "treating, " "treatment, " and the like may include "prophylactic treatment, " which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

Examples

The various starting materials, intermediates, and compounds of the preferred embodiments can be isolated and purified where appropriate using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds can be performed using conventional methods such as by melting point, mass spectrum, nuclear magnetic resonance, and various other spectroscopic analyses. Exemplary embodiments of steps for performing the synthesis of products described herein are described in greater detail infra.

Example 1 Synthesis of Compound 18

Step 1: AlCl ₃ (1.42 g, 10.65 mmol) was added to a solution of isopropyl 2, 4-dichloropyrimidine-5-carboxylate (1.0 g, 4.25 mmol) in 1, 2-dichloroethane (15 mL) at 0℃. After stirring at 0℃ for 10 min, indole (470 mg, 4 mmol) was added, and the mixture was stirred at 55℃ for 2 h. The mixture was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to afford 18-1.

Step 2: To a solution of 18-1 (500 mg, 1.58 mmol) in DMF (5 mL) was added NaH (95 mg, 60%, 2.37 mmol) at 0℃. After stirring at 0℃ for 10min, methanesulfonyl chloride (272 mg, 2.37 mmol) was added dropwise and the mixture was stirred at room temperature for 2 h. The mixture was poured into water and filtered. The filter cake was washed with water and dried to afford 18-2 which was used directly in the next step without purification.

Step 3: A mixture of crude 18-2 (300 mg, 0.76 mmol) , 4-fluoro-2-methoxy-5-nitroaniline (170 mg, 0.91 mmol) , p-TsOH (144 mg, 0.84 mmol) in dioxane (8 mL) was stirred at 100℃ for 12 h. The mixture was cooled, poured into water and filtered. The filter cake was washed with water and dried to afford 18-3 which was used directly in the next step without purification.

Step 4: A mixture of crude 18-3 (400 mg, 0.73 mmol) , [2- (dimethylamino) ethyl] - (methyl) amine (97 mg, 0.95 mmol) and K ₂CO ₃ (305 mg, 2.2 mmol) in NMP (2 mL) was stirred at 50℃ for 2 h. The mixture was cooled, poured into water and extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 10/1) to afford 18-4.

Step 5: A mixture of 18-4 (600 mg, 0.96 mmol) and 10%Pd/C (179 mg) in MeOH (60 mL) was stirred at room temperature for 12 h under H ₂ atmosphere. The mixture was filtered and concentrated to afford 18-5 which was used directly in the next step without purification.

Step 6: Acryloyl chloride (9 mg, 0.1 mmol) was added dropwise to a solution of crude 18-5 (60 mg, 0.1 mmol) and DIEA (26 mg, 0.2 mmol) in dichloromethane (2 mL) at 0℃. After stirring at 0℃ for 5 min, the mixture was poured into 10 mL of ice-water and extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 5%to 35%) to afford 18 as 0.5 FA salt. LCMS (ESI, m/z) : [M+H] ⁺ = 650.3; HNMR (300 MHz, DMSO-d ₆, ppm) : δ 10.08 (s, 1H) , 9.13 (s, 1H) , 8.81 (s, 1H) , 8.60 (s, 1H) , 8.22 (s, 0.5H) , 8.03 (s, 1H) , 7.88 (d, J = 8.3 Hz, 1H) , 7.76 (d, J = 8.0 Hz, 1H) , 7.39 (t, J = 7.7 Hz, 1H) , 7.24 (t, J = 7.6 Hz, 1H) , 7.04 (s, 1H) , 6.46-6.23 (m, 2H) , 5.78-5.74 (m, 1H) , 4.97-4.89 (m, 1H) , 3.81 (s, 3H) , 3.51 (s, 3H) , 2.88 (t, J = 5.9 Hz, 2H) , 2.72 (s, 3H) , 2.33 (t, J = 5.8 Hz, 2H) , 2.21 (s, 6H) , 1.08 (d, J = 6.2 Hz, 6H) .

Example 2 Synthesis of Compound 71

Step 1: To a solution of 4-fluoro-2-methoxy-5-nitro-aniline (50 g, 268.6 mmol) , Et ₃N (54.2 g, 537.2 mmol) and DMAP (3.3 g, 26.9 mmol) in dichloromethane (500 mL) was added (Boc) ₂O (70.3 g, 322.3 mmol) at room temperature in several portions. The mixture was stirred at room temperature for 2 h and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to afford 71-1.

Step 2: A mixture of N ₁, N ₁, N ₂-trimethylethane-1, 2-diamine (24.5 g, 240.6 mmol) , 71-1 (57.4 g, 200.5 mmol) and DIEA (25.9 g, 200.5 mmol) in dimethylacetamide (800 mL) was stirred at 60℃ for 2 h. The mixture was quenched with water and extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous Na ₂SO ₄, filtered and concentrated to afford 71-2 which was used directly in the next step without purification.

Step 3: A mixture of crude 71-2 (66.3 g, 179.95 mmol) and 10%Pd/C (600 mg) in ethyl acetate (1000 mL) was stirred at room temperature for 16 h under H ₂ atmosphere. The reaction mixture was filtered and concentrated to afford 71-3 which was used directly in the next step without purification.

Step 4: Acryloyl chloride (18.4 g, 203.5 mmol) was added dropwise to a solution of crude 71-3 (53 g, 156.6 mmol) and DIEA (60.7 g, 469.8 mmol) in dichloromethane (500 mL) at 0℃. After stirring at 0℃ for 2 h, the mixture was poured into 10 mL of ice-water and extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 15/1) to afford 71-4.

Step 5: A mixture of 71-4 (38.3 g, 97.6 mmol) and 3N HCl/MeOH (400 mL) was stirred at room temperature for 16 h. The mixture was concentrated. The residue was neutralized with saturated aqueous NaHCO ₃, and the mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 10/1) to afford 71-5.

Step 6: A mixture of 2, 4-dichloro-5-iodopyrimidine (2.0 g, 7.3 mmol) and AlCl ₃ (1.07 g, 8.45 mmol) in dichloroethane (20 mL) was stirred at 80℃ for 0.5 h under N ₂. After cooling to room temperature, indole (811 mg, 6.93 mmol) was added. The resulting mixture was stirred at 80℃ for 18 h under N ₂. The mixture was cooled, quenched with ice-water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by flash chromatography (12 g, 0 to 100%of ethyl acetate in petroleum ether) to afford 71-6.

Step 7: To a solution of 71-6 (1.0 g, 2.8 mmol) in dry THF (20 mL) was added NaH (60%in oil, 225 mg, 5.6 mmol) at 0℃. The mixture was stirred at 0℃ for 1 h. Ethanesulfonyl chloride (542 mg, 4.2 mmol) was added at 0℃ and the solution was stirred at room temperature for 2 h. The mixture was quenched with ice water, and extracted with ethyl acetate. The combined organic layers were dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by flash chromatography (12 g, 0%to 30%of ethyl acetate in petroleum ether) to afford 71-7.

Step 8: A mixture of 71-7 (550 mg, 1.23 mmol) , copper (I) iodide (46.8 mg, 0.25 mmol) and bis (triphenylphosphine) palladium (II) chloride (86 mg, 0.12 mmol) in triethylamine (6 mL) and DMF (0.05 mL) in a sealed tube was stirred at room temperature under nitrogen. 3-methylbut-1-yne (251 mg, 3.69 mmol) was then added via syringe. The mixture was stirred at room temperature for 16 h, and then quenched with ethyl acetate and water. The separated organic layer was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by flash chromatography (0%to 20%ethyl acetate in petroleum) to afford 71-8.

Step 9: A mixture of 71-8 (424 mg, 1.45 mmol) , Pd ₂ (dba) ₃ (110 mg, 0.12 mmol) , BINAP (150 mg, 0.24 mmol) and cesium carbonate (1.18 g, 3.63 mmol) in anhydrous 1, 4-dioxane (10 mL) was stirred at 100℃ for 16 h under nitrogen. The mixture was cooled, poured into water and extracted with ethyl acetate. The combined organic layers were dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 5%to 55%) to afford 71 as mono TFA salt. LCMS (ESI, m/z) : [M+H] ⁺ = 644.2; HNMR (400 MHz, D ₂O, ppm) : δ 8.93 (s, 1H) , 8.50 (s, 1H) , 8.43 (s, 1H) , 8.16 (s, 1H) , 7.88 (d, J = 8.4 Hz, 1H) , 7.45 (t, J = 7.7 Hz, 1H) , 7.26 (t, J = 7.6 Hz, 1H) , 7.02 (s, 1H) , 6.57 (dd, J = 17.0, 10.2 Hz, 1H) , 6.30 (d, J = 16.9 Hz, 1H) , 5.82 (d, J = 11.4 Hz, 1H) , 3.84 (s, 3H) , 3.72 (q, J = 7.2 Hz, 2H) , 3.35-3.28 (m, 4H) , 2.96-2.86 (m, 1H) , 2.81 (s, 6H) , 2.64 (s, 3H) , 1.29 (d, J = 6.9 Hz, 6H) , 1.12 (t, J = 7.3 Hz, 3H) .

Example 3 Synthesis of Compound 74

Step 1: To a solution of 3-bromo-1H-indazole (5.0 g, 25.4 mmol) in DMF (40 mL) was added 60%NaH (670 mg, 27.9 mmol) in portions at 0℃. The resulting mixture was stirred for 20 min at 0℃, and SEMCl (4.23 g, 25.4 mmol) was added at 0℃. The resulting mixture was stirred for an additional 2 h at room temperature. The mixture was quenched with ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 8/1) to afford 74-1.

Step 2: A mixture of 3-bromo-1- [ [2- (trimethylsilyl) ethoxy] methyl] indazole (2.0 g, 6.1 mmol) , Pd (dppf) Cl ₂ (890 mg, 1.2 mmol) , KOAc (2.4 g, 24.4 mmol) and 4, 4, 5, 5-tetramethyl-2- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (1.86 g, 7.3 mmol) in dioxane (30 mL) was stirred at 0℃ under argon atmosphere for 16 h. The mixture was then concentrated to afford crude 74-2 which was used directly in the next step without purification.

Step 3: A mixture of crude 74-2 (2.6 g, 6.9 mmol) , 2, 4-dichloro-5-methylpyrimidine (1.25 g, 7.7 mmol) , Pd (dppf) Cl ₂ (508 mg, 0.7 mmol) and Cs ₂CO ₃ (6.78 g, 20.8 mmol) in dioxane (30 mL) was stirred at 80℃ under argon atmosphere for 2 h. The resulting mixture was concentrated and purified by prep-TLC (dichloromethane/methanol = 12/1) to afford 74-3.

Step 4: To a mixture of 74-3 (500 mg, 1.3 mmol) , 71-5 (428 mg, 1.47 mmol) , Pd ₂ (dba) ₃ (122 mg, 0.13 mmol) and Davephos (105 mg, 0.27 mmol) in THF (10 mL) /H ₂O (5 mL) was added Cs ₂CO ₃ (1.30 g, 4 mmol) . The resulting reaction mixture was stirred at 80℃ under argon atmosphere for 16 h, then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by prep-TLC (dichloromethane/methanol = 15/1) to afford 74-4.

Step 5: A solution of 74-4 (400 mg, 0.63 mmol) in dichloromethane/TFA (10 mL/10 mL) was stirred at room temperature for 2 h. The mixture was concentrated. The residue was partitioned between sat. NaHCO ₃ and dichloromethane. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by prep-TLC (dichloromethane/methanol = 10/1) to afford 74-5.

Step 6: To a solution of 74-5 (100 mg, 0.2 mmol) in pyridine (3 mL) was added methanesulfonyl chloride (69 mg, 0.6 mmol) at 0℃. The resulting mixture was stirred at room temperature for 16 h. The mixture was purified by reverse phase HPLC (acetonitrile with 0.05%of TFA in water: 10%to 35%) to afford 74 as 0.3 FA salt. LCMS (ESI, m/z) : [M+H] ⁺ = 579.4; HNMR (300 MHz, DMSO-d ₆, ppm) : δ 10.07 (s, 1H) , 8.60-8.44 (m, 3H) , 8.41 (d, J = 8.4 Hz, 1H) , 8.23 (s, 0.3H) , 8.00 (d, J = 8.4 Hz, 1H) , 7.64 (t, J = 7.2 Hz, 1H) , 7.31 (t, J = 7.2 Hz, 1H) , 7.03 (s, 1H) , 6.43 (dd, J = 16.8, 10.2 Hz, 1H) , 6.17 (dd, J = 16.8, 2.1 Hz, 1H) , 5.72 (dd, J = 10.2, 2.1 Hz, 1H) , 3.78 (s, 3H) , 3.61 (s, 3H) , 2.92 (t, J = 6.0 Hz, 2H) , 2.72 (s, 3H) , 2.51 (s, 3H) , 2.40-2.36 (m, 2H) , 2.24 (s, 6H) .

Example 4 Synthesis of Compound 43

Step 1: To a solution of indole (5.0 g, 42.7 mmol) and ammonium thiocyanate (3.9 g, 51.3 mmol) in methanol (50 mL) was added ceric ammonium nitrate (53.8 g, 98.2 mmol) in methanol (300 mL) at room temperature. The mixture was stirred at room temperature for 15 min. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to ethyl acetate/petroleum ether = 1/4) to afford 43-1.

Step 2: To a solution of 43-1 (2.09 g, 12 mmol) in ethanol (36 mL) was added a solution of sodium sulfide (2.81 g, 36 mmol) in water (4.8 mL) . The mixture was stirred at 50℃ for 2 h under N ₂ atmosphere. To above mixture was added 2-iodopropane (2.45 g, 14.4 mmol) , and the resulting mixture was stirred for an additional 1 h. After being cooled to room temperature, the mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂SO ₄, filtered and concentrated to afford 43-2 which was used directly in the next step without purification.

Step 3: To a solution of crude 43-2 in dichloromethane (240 mL) was added 3-chloroperoxybenzoic acid (9.96 g, 57.6 mmol) at room temperature. The mixture was stirred for 30 min and washed with water, brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to ethyl acetate/petroleum ether = 1/2) to afford 43-3.

Step 4: A mixture of 43-3 (446 mg, 2.0 mmol) , 2, 4-dichloropyrimidine (592 mg, 4.0 mmol) and potassium carbonate (828 mg, 6.0 mmol) in acetonitrile (20 mL) was stirred at 50℃ for 16 h under N ₂ atmosphere. After being cooled to room temperature, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 15%to 95%) to afford 43-4.

Step 5: A mixture of 43-4 (55 mg, 0.17 mmol) , 71-5 (44 mg, 0.15 mmol) , (±) -2, 2'-bis (diphenylphosphino) -1, 1'-binaphthalene (19 mg, 0.03 mmol) , cesium carbonate (98 mg, 0.3 mmol) and tris (dibenzylideneacetone) dipalladium (14 mg, 0.015 mmol) in 1, 4-dioxane (1.5 mL) was stirred at 130℃ for 30 min under N ₂ atmosphere under microwave conditions. After being cooled to room temperature, the reaction mixture was filtered, and the filtrate was purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 10%to 95%) to afford 43 as a mono TFA salt. LCMS (ESI, m/z) : [M+H] ⁺ = 592.3; HNMR (400 MHz, DMSO-d ₆, ppm) : δ 9.47 (s, 1H) , 9.26 (brs, 1H) , 8.90 (s, 1H) , 8.67 (s, 1H) , 8.48-8.46 (m, 2H) , 8.13 (s, 1H) , 7.83-7.81 (m, 1H) , 7.37-7.25 (m, 3H) , 7.01 (s, 1H) , 6.59 (dd, J = 17.2, 10.0 Hz, 1H) , 6.26- 6.22 (m, 1H) , 5.76-5.73 (m, 1H) , 3.79 (s, 3H) , 3.40-3.33 (m, 1H) , 3.28-3.26 (m, 4H) , 2.78-2.77 (m, 6H) , 2.60 (s, 3H) , 1.20 (d, J = 6.8 Hz, 6H) .

Example 5 Synthesis of Compound 46

Step 1: A mixture of 3- (methylsulfonyl) -1H-indole (6.9 g, 35 mmol) , potassium carbonate (12.4 g, 90 mmol) and ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (5.8 g, 25 mmol) in acetonitrile (200 mL) was stirred at 70℃ for 16 h. The reaction mixture was filtered, and the filter was concentrated. The residue was triturated with methyl tert-butyl ether to afford 46-1.

Step 2: To a mixture of 46-1 (5.5 g, 17.2 mmol) in dichloromethane (250 mL) was added 3-chloroperbenzoic acid (7.7 g. 37.8 mmol) . The reaction was stirred at 20℃ for 16 h. The mixture was diluted with dichloromethane. The mixture was washed with saturated sodium bicarbonate solution, 2 M sodium sulfite solution, brine and concentrated to afford crude 46-2.

Step 3: A mixture of crude 46-2 (5.9 g, 14.2 mmol) , 4-fluoro-2-methoxy-5-nitroaniline (3.3 g, 18 mmol) and 4-methylbenzenesulfonic acid (3.1 g, 18 mmol) in pentan-2-ol (100 mL) was stirred at 110℃ for 4 h. Then the mixture was cooled to 50℃ and filtered to afford 46-3.

Step 4: A mixture of 46-3 (5.5 g, 10 mmol) , N, N, N'-trimethylethylenediamine (1.4 g, 14 mmol) and N, N-diisopropylethylamine (3.2 g, 25 mmol) in dimethylacetamide (70 mL) was stirred at 70℃ for 8 h. The mixture was cooled and filtered to afford 46-4.

Step 5: A mixture of 46-4 (6.5 g, 10.6 mmol) and potassium hydroxide (12.0 g, 212 mmol, in 100 mL water) in tetrahydrofuran (100 mL) /water (100 mL) was stirred at 50℃ for 24 h, then cooled to room temperature. The solids were collected by filtration to afford 46-5.

Step 6: A mixture of 46-5 (583 mg, 1.0 mmol) , O- (7-Aza-1H-benzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (456 mg, 1.2 mmol) and N, N-diisopropylethylamine (387 mg, 3.0 mmol) in N, N-dimethylformamide (20 mL) was stirred at 0℃ for 0.5 h. Then propan-2-amine (71 mg, 1.2 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water, and solids were collected by filtration to afford 46-6.

Step 7: A mixture of 46-6 (300 mg, 0.48 mmol) and 10%Pd/C (40 mg) in methanol (2 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 5 h under hydrogen atmosphere, then filtered. The filtrate was concentrated to afford crude 46-7.

Step 8: To a solution of crude 46-7 (50 mg, 0.08 mmol) and N, N-diisopropylethylamine (22 mg, 0.17 mmol) in dichloromethane (5 mL) was added a solution of acryloyl chloride (7.2 mg, 0.08 mmol) in dichloromethane (2 mL) dropwise at 0℃. After being stirred for 10 min at 0℃, the mixture was concentrated and purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 15%to 95%) to afford 46. LCMS (ESI, m/z) : [M+H] ⁺ = 649.3; HNMR (400 MHz, methanol-d ₄, ppm) : δ 11.30 (s, 1H) , 8.83 (s, 1H) , 8.78 (s, 1H) , 8.70 (d, J = 8.0 Hz, 1H) , 8.45 (d, J = 4.8 Hz, 1H) , 7.88-7.86 (m, 1H) , 7.35-7.31 (m, 2H) , 7.00 (s, 1H) , 6.50-6.45 (m, 2H) , 5.83 (dd, J = 9.6, 2.4 Hz, 1H) , 4.26-4.23 (m, 1H) , 4.00 (s, 3H) , 3.52-3.49 (m, 2H) , 3.30-3.29 (m, 2H) , 3.22 (s, 3H) , 2.88 (s, 6H) , 2.74 (s, 3H) , 1.28 (d, J = 6.8 Hz, 6H) .

Example 6 Synthesis of Compound 50

Step 1: Compound 50-1 was prepared following the procedure for the synthesis of 46-1 in example 5.

Step 2: To a solution of 50-1 (1.0 g, 4.1 mmol) in dichloromethane (30 mL) was added a solution of sulfurochloridic acid (1.2 g, 10.3 mmol) in dichloromethane (2 mL) at 0℃ under nitrogen. The reaction was stirred at 0℃ for 1 h. The mixture was filtered and the filter cake was purified by silica gel column chromatography (dichloromethane/methanol = 10/1) to afford 50-2.

Step 3: To a solution of 50-2 (330 mg, 1 mmol) in chloroform (30 mL) was added phosphorus pentachloride (624 mg, 3 mmol) . The reaction mixture was stirred at 70℃ for 16 h.The mixture was cooled and added to ammonia (10 mL) . The resulting mixture was stirred at room temperature for 16 h. The mixture was extracted with dichloromethane, and the extract was washed with water. The organic layer was concentrated and purified by silica gel column chromatography (petroleum ether to petroleum ether/ethyl acetate = 1/1) to afford 50-3.

Step 4: To a solution of 50-3 (100 mg, 0.31 mmol) in sec-pentanol (5 mL) was added 71-5 (90 mg, 0.31 mmol) and p-toluenesulfonic acid (106 mg, 0.62 mmol) at room temperature. The reaction was stirred at 120℃ for 16 h under N ₂ atmosphere. The mixture was filtered, and the filter cake was purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 5%to 40%) to afford 50. LCMS (ESI, m/z) : [M+H] ⁺ = 579.3; HNMR (400 MHz, methanol-d ₄, ppm) : δ 8.55 (s, 1H) , 8.30 (s, 1H) , 8.07 (s, 1H) , 7.99-7.97 (m, 1H) , 7.70-7.67 (m, 1H) , 7.31-7.28 (m, 2H) , 6.91 (s, 1H) , 6.43-6.31 (m, 2H) , 5.82 (dd, J = 9.6, 2.4 Hz, 1H) , 3.97 (s, 3H) , 3.45-3.42 (m, 2H) , 3.23-3.20 (m, 2H) , 2.81 (s, 6H) , 2.64 (s, 3H) , 2.24 (s, 3H) .

Example 7 Synthesis of Compound 62

Step 1: To a solution of indole (5.85 g, 50 mmol) and sodium trifluoromethanesulfinate (15.6 g, 100 mmol) in acetonitrile (50 mL) was added triphosgene (29.7 g, 100 mmol) in several portions at 0℃ under N ₂ atmosphere. The mixture was stirred at 0℃ for 2 h, followed by addition of 5 wt%NaOH at 0℃. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to ethyl acetate/petroleum ether = 1/4) to afford 62-1.

Step 2: Compound 62-2 was prepared following the procedure for the synthesis of 46-1 in example 5.

Step 3: Compound 62-3 was prepared following the procedure for the synthesis of 43-3 in example 4.

Step 4: Compound 62 was prepared following the procedure for the synthesis of 43 in example 4 as a mono TFA salt. LCMS (ESI, m/z) : [M+H] ⁺ = 618.2; HNMR (400 MHz, DMSO-d ₆, ppm) : δ 9.46 (s, 1H) , 9.37 (brs, 1H) , 9.22 (s, 1H) , 9.03 (s, 1H) , 8.56 (d, J = 5.6 Hz, 1H) , 8.47 (brs, 1H) , 8.16 (s, 1H) , 7.80 (d, J = 8.0 Hz, 1H) , 7.46-7.35 (m, 3H) , 7.00 (s, 1H) , 6.62 (dd, J = 16.8, 10.4 Hz, 1H) , 6.24 (dd, J = 16.8, 1.6 Hz, 1H) , 5.75-5.72 (m, 1H) , 3.80 (s, 3H) , 3.28-3.26 (m, 4H) , 2.77 (s, 6H) , 2.60 (s, 3H) . FNMR (376 MHz, DMSO-d _6, ppm) : δ -79.62 (3F) .

Example 8 Synthesis of Compound 72

Step 1: To a solution of indole (6.38 g, 54.5 mmol) in tetrahydrofuran (60 mL) was added potassium tert-butoxide (6.72 g, 60 mmol) at room temperature. The mixture was stirred for 30 min under N ₂ atmosphere. A solution of triethylborane (1.0 M in tetrahydrofuran, 60 mL, 60 mmol) was then added dropwise, and the reaction was stirred for an additional 30 min. To above mixture was added ethanesulfonyl chloride (7.68 g, 60 mmol) at -15℃ over 30 min. The resulting mixture was stirred at -15℃ for 4 h, and then warmed to room temperature and stirred overnight. The reaction was quenched with sat. NH ₄Cl aq. (100 mL) , and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to ethyl acetate/petroleum ether = 1/1) to afford 72-1.

Step 2: Compound 72-2 was prepared following the procedure for the synthesis of 46-1 in example 5.

Step 3: A mixture of 72-2 (600 mg, 1.5 mmol) , phenylboronic acid (220 mg, 1.8 mmol) , sodium carbonate (318 mg, 3.0 mmol) , and tetrakis (triphenylphosphine) palladium (87 mg, 0.075 mmol) in 1, 4-dioxane (10 mL) /water (1 mL) was stirred for 6 h at 90℃ under N ₂ atmosphere. The mixture was filtered and concentrated. The residue was purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 15%to 95%) to afford 72-3.

Step 4: 72 was prepared following the procedure for the synthesis of 74-4 in example 3 as a mono TFA salt. LCMS (ESI, m/z) : [M+H] ⁺ = 654.3; HNMR (400 MHz, DMSO-d ₆, ppm) : δ9.43 (s, 1H) , 9.25 (brs, 1H) , 8.99 (s, 1H) , 8.66 (s, 1H) , 8.24 (s, 1H) , 7.70 (dd, J = 15.6, 7.2 Hz, 2H) , 7.62 (s, 1H) , 7.29-7.18 (m, 5H) , 7.13-7.11 (m, 2H) , 6.97 (s, 1H) , 6.59 (dd, J = 17.2, 10.4 Hz, 1H) , 6.30-6.26 (m, 1H) , 5.79-5.75 (m, 1H) , 3.85 (s, 3H) , 3.30-3.19 (m, 4H) , 3.09 (q, J =7.2 Hz, 2H) , 2.75 (s, 6H) , 2.56 (s, 3H) , 0.92 (t, J = 7.2 Hz, 3H) .

Example 9 Synthesis of Compound 40

Step 1: A mixture of 72-1 (448 mg, 2.1 mmol) , 2, 4-dichloro-5-methylpyrimidine (695 mg, 4.3 mmol) and potassium carbonate (886 mg, 6.4 mmol) in acetonitrile (20 mL) was stirred at 50℃ for 16 h under N ₂ atmosphere. After being cooled to room temperature, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 15%to 95%) to afford 40-1.

Step 2: A mixture of 40-1 (74 mg, 0.22 mmol) , 71-5 (58 mg, 0.2 mmol) , 2, 2'-bis (diphenylphosphino) -1, 1'-binaphthalene (25 mg, 0.04 mmol) , cesium carbonate (130 mg, 0.4 mmol) and tris (dibenzylideneacetone) dipalladium (18 mg, 0.02 mmol) in 1, 4-dioxane (3 mL) was stirred under microwave conditions for 30 min at 130℃ under N ₂ atmosphere. After being cooled to room temperature, the reaction mixture was filtered and concentrated. The residue was purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 10%to 95%) to afford 40 as a mono TFA salt. LCMS (ESI, m/z) : [M+H] ⁺ = 592.3; HNMR (400 MHz, DMSO-d ₆, ppm) : δ 9.41 (s, 1H) , 9.15 (brs, 1H) , 8.59-8.51 (m, 2H) , 8.34 (s, 1H) , 8.22 (s, 1H) , 7.85-7.82 (m, 1H) , 7.64-7.61 (m, 1H) , 7.31-7.28 (m, 2H) , 6.93 (s, 1H) , 6.54 (dd, J = 16.8, 10.0 Hz, 1H) , 6.28-6.24 (m, 1H) , 5.77-5.74 (m, 1H) , 3.82 (s, 3H) , 3.29 (q, J = 7.2 Hz, 2H) , 3.23-3.19 (m, 4H) , 2.74 (s, 3H) , 2.73 (s, 3H) , 2.53 (s, 3H) , 2.09 (s, 3H) , 1.13 (t, J = 7.2 Hz, 3H) .

Example 10 Synthesis of Compound 4

Step 1: Compound 4-1 was prepared following the procedure for the synthesis of 71-6 in example 2.

Step 2: To a solution of 4-1 (2 g, 6.5 mmol) and Boc ₂O (1.52 g, 7 mmol) in dichloromethane (100 mL) was added 4-dimethylaminopyridine (36.6 mg, 0.03 mmol) . The reaction was stirred at room temperature for 2 h. The reaction was filtered and the filter cake was washed with petroleum ether (10 mL) to afford 4-2.

Step 3: A mixture of 4-2 (814 mg, 2 mmol) , cyclopropylboronic acid (172 mg, 2 mmol) , potassium phosphate (2 g, 9.4 mmol) , tricyclohexylphosphane (100 mg, 0.36 mmol) , and palladium acetate (40 mg, 0.18 mmol) in toluene (40 mL) and water (4 mL) was stirred at 100℃ under N ₂ for 1 h. The mixture was cooled, poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 1/5) to afford 4-3.

Step 4: To a solution of 4-3 (600 mg, 1.63 mmol) in methanol (15 mL) and tetrahydrofuran (15 mL) was added a solution of potassium carbonate (1.2 g, 8.6 mmol) in water (30 mL) . The reaction mixture was stirred at 65℃ overnight. The mixture was cooled, poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na ₂SO ₄ and concentrated to afford 4-4.

Step 5: Compound 4 was prepared following the procedure for the synthesis of 50 in example 6 as a mono TFA salt. LCMS (ESI, m/z) : [M+H] ⁺ = 526.6; HNMR (400 MHz, DMSO-d ₆, ppm) : δ 11.99 (s, 1H) , 9.54 (s, 1H) , 9.38 (s, 1H) , 8.72 (brs, 1H) , 8.48 (s, 1H) , 8.30 (s, 2H) , 8.10 (s, 1H) , 7.44 (d, J = 8.0 Hz, 1H) , 7.13 (t, J = 7.2 Hz, 1H) , 7.00-6.96 (m, 2H) , 6.61-6.54 (m, 1H) , 6.26-6.21 (m, 1H) , 5.74 (d, J = 11.2 Hz, 1H) , 3.82 (s, 3H) , 3.29-3.25 (m, 4H) , 2.78 (s, 3H) , 2.77 (s, 3H) , 2.60 (s, 3H) , 2.03-1.99 (m, 1H) , 1.01-0.99 (m, 2H) , 0.66-0.65 (m, 2H) .

Example 11 Synthesis of Compound 8

Step 1: To a solution of 2-chloro-1-methoxy-3-nitrobenzene (4.0 g, 21.4 mmol) in dry THF (60 mL) was added vinylmagnesium bromide (1 M in THF, 64 mL, 64.0 mmol) at -78℃ dropwise under N ₂ atmosphere. The mixture was stirred at -78℃ for 2 h. The reaction was quenched with sat. NH ₄Cl solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether/ethyl acetate = 10/1) to afford 8-1.

Step 2: Compound 8-2 was prepared following the procedure for the synthesis of 71-6 in example 2.

Step 3: Compound 8 was prepared following the procedure for the synthesis of 50 in example 6. LCMS (ESI, m/z) : [M+H] ⁺ = 575.6; HNMR (400 MHz, DMSO-d ₆, ppm) : δ 12.12 (s, 1H) , 9.57 (s, 1H) , 9.42 (s, 1H) , 9.28 (s, 1H) , 8.68 (s, 1H) , 8.40 (d, J = 2.8 Hz, 1H) , 8.01 (s, 1H) , 7.02 (s, 1H) , 6.61 (dd, J = 16.8, 10.0 Hz, 1H) , 6.25 (d, J = 17.2 Hz, 1H) , 5.75 (d, J = 10.8 Hz, 1H) , 3.85 (s, 3H) , 3.78 (s, 3H) , 3.32-3.26 (m, 4H) , 2.79 (s, 3H) , 2.77 (s, 3H) , 2.63 (s, 3H) .

Example 12 Synthesis of Compound 9

Step 1: To a solution of o-toluidine (5.35 g, 50 mmol) and triethylamine (5.56 g, 55 mmol) in dichloromethane (40 mL) was added a solution of isobutyl chloride (5.83 g, 55 mmol) in dichloromethane (10 mL) at 0℃, and the reaction was stirred for 30 min under N ₂ atmosphere. The mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with brine, dried over Na ₂SO ₄, filtered and concentrated. The residue was triturated with dichloromethane/petroleum ether (1/2) to afford 9-1.

Step 2: To a solution of 9-1 (1.0 g, 5.6 mmol) in anhydrous tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexane, 6.72 mL, 16.8 mmol) at 0℃ under N ₂ atmosphere. The mixture was allowed to warm to room temperature slowly, and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride at 0℃, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to ethyl acetate/petroleum ether = 1/20) to afford 9-2.

Step 3: To a solution of 9-2 (280 mg, 1.76 mmol) in 2-methyl-tetrahydrofuran (4 mL) was added methylmagnesium bromide (3.0 M in 2-methyltetrahydrofuran, 1.76 mL, 5.28 mmol) dropwise at 0℃ under N ₂ atmosphere. The mixture was stirred for 0.5 h at room temperature. A solution of 2, 4-dichloropyrimidine (521 mg, 3.52 mmol) in 2-methyltetrahydrofuran (2 mL) was then added dropwise at room temperature. The mixture was stirred at reflux overnight. After being cooled to room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to ethyl acetate/petroleum ether = 1/5) to afford 9-3.

Step 4: Compound 9 was prepared following the procedure for the synthesis of 50 in example 6. LCMS (ESI, m/z) : [M+H] ⁺ = 528.2; HNMR (400 MHz, DMSO-d ₆, ppm) : δ 11.35 (s, 1H) , 10.10 (s, 1H) , 8.56 (s, 1H) , 8.32 (d, J = 5.2 Hz, 1H) , 8.00 (s, 1H) , 7.81 (d, J = 8.0 Hz, 1H) , 7.33 (d, J = 8.0 Hz, 1H) , 7.05 (t, J = 7.2 Hz, 1H) , 7.00-6.94 (m, 3H) , 6.33 (dd, J = 16.8, 10.0 Hz, 1H) , 6.15 (dd, J = 16.8, 1.6 Hz, 1H) , 5.68 (dd, J = 12.0, 2.0 Hz, 1H) , 3.86-3.79 (m, 1H) , 3.76 (s, 3H) , 2.82 (t, J = 5.6 Hz, 2H) , 2.67 (s, 3H) , 2.25 (t, J = 5.6 Hz, 2H) , 2.16 (s, 6H) , 1.16 (d, J = 6.8 Hz, 6H) .

Example 13 Synthesis of Compound 14

Compound 14-3 was prepared following the procedures for the synthesis of 18-4 in example 1.

Compound 14 was prepared following the procedures for the synthesis of 46 in example 5. LCMS (ESI, m/z) : [M+H] ⁺ = 585.3; HNMR (300 MHz, DMSO-d ₆, ppm) : δ 10.13 (s, 1H) , 8.76 (s, 1H) , 8.34 (s, 1H) , 8.29-8.24 (m, 2H) , 8.13-8.10 (m, 1H) , 8.01 (s, 1H) , 7.48-7.43 (m, 1H) , 7.21-7.16 (m, 1H) , 7.04-7.00 (m, 2H) , 6.48-6.38 (m, 1H) , 6.26-6.20 (m, 1H) , 5.77-5.73 (m, 1H) , 4.05-3.98 (m, 1H) , 3.85 (s, 3H) , 3.81 (s, 3H) , 2.92-2.89 (m, 2H) , 2.74 (s, 3H) , 2.36-2.32 (m, 2H) , 2.22 (s, 6H) , 1.09-1.07 (d, J = 6.6 Hz, 6H) .

Example 14 Synthesis of Compound 16

Step 1: A solution of 1M lithium hydroxide (48 mL, 48 mmol) was added to ethyl 2- (1H-indol-2-yl) acetate (3.2 g, 16 mmol) in tetrahydrofuran (48 mL) /methanol (48 mL) at room temperature. The mixture was stirred at room temperature for 1 h and concentrated. The residue was quenched with water, and the aqueous layer was washed with diethyl ether, then acidified to about pH 2 with 1M HCl and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford crude 16-1.

Step 2: To a suspension of crude 16-1 (2.6 g, 15 mmol) in dichloromethane (100 mL) was added 1, 1'-carbonyldiimidazole (2.65 g, 16.3 mmol) followed by addition of 2 M dimethylamine solution in tetrahydrofuran (9 mL) admixed with N, N-diisopropylethylamine (3.9 g, 30 mmol) . The mixture was stirred at room temperature for 2 h and poured into ice water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was triturated with ethyl acetate/tert-butyl methyl ether (1/10) and filtered. The filter cake was dried to afford 16-2.

Step 3: Compound 16-3 was prepared following the procedure for the synthesis of 71-6 in example 2.

Step 4: To a solution of 16-3 (375 mg, 1.2 mmol) in tetrahydrofuran (25 mL) was added lithium aluminum tetrahydride (135 mg, 3.6 mmol) in portions at 0℃ under N ₂ atmosphere. The reaction mixture was stirred at 0℃ for 2 h before quenched with water (0.13 mL) , 15% NaOH (0.39 mL) and water (0.13 mL) . The mixture was filtered and the cake was washed with ethyl acetate. The filtrate was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane/methanol = 10/1) to afford 16-4.

Step 5: Compound 16 was prepared following the procedure for the synthesis of 50 in example 6. LCMS (ESI, m/z) : [M+H] ⁺ = 557.3; HNMR (400 MHz, DMSO-d ₆, ppm) : δ 8.34-8.33 (m, 2H) , 7.93 (d, J = 8.0 Hz, 1H) , 7.42 (d, J = 8.0 Hz, 1H) , 7.19-7.09 (m, 3H) , 6.95 (s, 1H) , 6.54-6.52 (m, 1H) , 6.27-6.23 (m, 1H) , 5.76 (d, J = 11.6 Hz , 1H) , 3.82 (s, 3H) , 3.54-3.50 (m, 2H) , 3.38-3.34 (m, 2H) , 3.25-3.20 (m, 4H) , 2.80 (s, 6H) , 2.74 (d, J = 10.0 Hz , 6H) , 2.56 (s, 3H) .

Example 15 Synthesis of Compound 19

Step 1: To a solution of 2, 4-dichloropyrimidin-5-ol (1.0 g, 6.1 mmol) , DIAD (1.84 g, 9.1 mmol) , PPh ₃ (2.4 g, 9.1 mmol) in THF (20 mL) was added isobutanol (674 mg, 9.1 mmol) dropwise at 0℃. The mixture was stirred at room temperature for 3 h, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to afford 19-1.

Compound 19 was prepared following the procedures for the synthesis of 18 in example 1 as a mono FA salt. LCMS (ESI, m/z) : [M+H] ⁺ = 572.6; HNMR (300 MHz, DMSO-d ₆, ppm) : δ 10.09 (s, 1H) , 8.78 (s, 1H) , 8.55 (d, J = 8.1 Hz, 1H) , 8.32 (s, 1H) , 8.19 (s, 2H) , 7.79 (s, 1H) , 7.50 (d, J = 8.1 Hz, 1H) , 7.23 (t, J = 7.8 Hz, 1H) , 7.09 (d, J = 7.6 Hz, 1H) , 7.01 (s, 1H) , 6.42 (dd, J = 16.9, 10.0 Hz, 1H) , 6.18 (dd, J = 16.9, 2.2 Hz, 1H) , 5.76-5.65 (m, 1H) , 3.95 (d, J = 6.4 Hz, 2H) , 3.89 (s, 3H) , 3.83 (s, 3H) , 2.92 (t, J = 6.1 Hz, 2H) , 2.72 (s, 3H) , 2.39 (t, J =5.9 Hz, 2H) , 2.26 (s, 6H) , 2.24-2.15 (m, 1H) , 1.07 (s, 3H) , 1.05 (s, 3H) .

Example 16 Synthesis of Compound 22

Compound 22-3 was prepared following the procedures for the synthesis of 18-4 in example 1.

Step 1: A mixture of 22-3 (500 mg, 0.9 mmol) , 3, 3-difluoroazetidine hydrochloride (175 mg, 1.35 mmol) , Pd (OAc) ₂ (60 mg, 0.27 mmol) , XantPhos (156 mg, 0.27 mmol) and Cs ₂CO ₃ (881 mg, 2.7 mmol) in DMSO (8 mL) was stirred at 110℃ for 9 h under argon atmosphere. The mixture was cooled and purified by reverse phase flash chromatography to afford 22-4.

Compound 22 was prepared following the procedures for the synthesis of 18 in example 1 as 0.7 FA salt. LCMS (ESI, m/z) : [M+H] ⁺ = 591.4; HNMR (400 MHz, DMSO-d ₆, ppm) : δ10.09 (s, 1H) , 8.82 (s, 1H) , 8.36 (d, J = 5.2 Hz, 1H) , 8.24 (s, 0.7H) , 7.98 (s, 1H) , 7.71 (d, J =8.4 Hz, 1H) , 7.38 (d, J = 7.2 Hz, 1H) , 7.12-7.04 (m, 2H) , 6.98 (s, 1H) , 6.94 (d, J = 5.2 Hz, 1H) , 6.43-6.37 (dd, J = 10.0, 2.1 Hz, 1H) , 6.24-6.19 (dd, J = 14.8, 2.0 Hz, 1H) , 5.75-5.72 (dd, J = 10.0, 2.0 Hz, 1H) , 4.53 (t, J = 12.8 Hz, 4H) , 3.83 (s, 3H) , 3.67 (s, 3H) , 2.88 (t, J = 6.0 Hz, 2H) , 2.69 (s, 3H) , 2.33 (t, J = 6.0 Hz, 2H) , 2.22 (s, 6H) .

Example 17 Synthesis of Compound 26

Step 1: To a solution of 2, 4-dichloro-5- (chloromethyl) pyrimidine (6.0 g, 30.4 mmol) in acetone (80 mL) was added NaI (5.47 g, 36.5 mmol) in portions at room temperature. The mixture was stirred at room temperature for 2 h under nitrogen atmosphere, then filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 9/1) to afford 26-1.

Step 2: To a solution of isopropyl alcohol (884 mg, 14.7 mmol) in THF (10 mL) was added NaH (423 mg, 17.65 mmol) at 0℃. The mixture was stirred at 0℃ for 30 min. The above mixture was added to 2, 4-dichloro-5- (iodomethyl) pyrimidine (4.25 g, 14.7 mmol) in THF (40 mL) dropwise at 0℃. The mixture was stirred at 0℃ for an additional 2 h. The reaction was quenched with sat. NH ₄Cl (aq. ) at 0℃ and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by reverse phase flash chromatography (acetonitrile with 0.05%of TFA in water: 10%to 70%) to afford 26-2.

Compound 26 was prepared following the procedures for the synthesis of 18 in example 1 as mono TFA salt. LCMS (ESI, m/z) : [M+H] ⁺ = 572.4; HNMR (400 MHz, DMSO-d ₆, ppm) : δ 9.61 (s, 1H) , 9.29 (brs, 1H) , 8.40-8.37 (m, 3H) , 8.30 (d, J = 7.2 Hz, 1H) , 8.13 (s, 1H) , 7.53 (d, J = 8.4 Hz, 1H) , 7.23 (t, J = 7.6 Hz, 1H) , 7.08 (t, J = 7.2 Hz, 1H) , 7.01 (s, 1H) , 6.63-6.56 (m, 1H) , 6.30 (d, J = 18.2 Hz, 1H) , 5.79 (d, J = 11.5 Hz, 1H) , 4.50 (s, 2H) , 3.90 (s, 3H) , 3.88 (s, 3H) , 3.83-3.77 (m, 1H) , 3.36-3.30 (m, 2H) , 3.30-3.22 (m, 2H) , 2.81 (s, 3H) , 2.80 (s, 3H) , 2.62 (s, 3H) , 1.24 (d, J = 6.0 Hz, 6H) .

Example 18 Synthesis of Compound 30

Step 1: To a solution of 1H-indole (6.0 g, 51.2 mmol) in DMF (60 mL) was added NaH (60%wt, 2.46 g, 61.5 mmol) at 0℃. The mixture was stirred at room temperature for 30 min. The above mixture was then added to 1, 4-dibromobutane (33.18 g, 153.7 mmol) in DMF (60 mL) at 0℃. The reaction mixture was stirred at room temperature for 1 h, and quenched with sat. NH ₄Cl (aq. ) at 0℃. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 19/1) to afford 30-1.

Step 2: A mixture of 30-1 (33.0 g, 130.9 mmol) and NaI (88.3 g, 588.9 mmol) in acetonitrile (500 mL) was stirred at 80℃ overnight, then cooled to room temperature and concentrated. The residue was dissolved in water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford 30-2, which was used directly in the next step without purification.

Step 3: A mixture of crude 30-2 (30.0 g, 100.3 mmol) , K ₃PO ₄ (42.6 g, 200.6 mmol) and Pd (PPh ₃) ₄ (11.59 g, 10.0 mmol) in dioxane (300 mL) was stirred at 100℃ overnight. The mixture was cooled, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column (petroleum ether/ethyl acetate = 20/1 to 5/1) to afford 30-3.

Compound 30-6 was prepared following the procedures for the synthesis of 18-4 in example 1.

Step 4: A mixture of 30-6 (1.0 g, 1.68 mmol) , 1-isopropyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (0.6 g, 2.5 mmol) , Pd (dppf) Cl ₂ (246 mg, 0.34 mmol) and Cs ₂CO ₃ (1.1 g, 3.36 mmol) in dioxane/H ₂O (5/1, 20 mL) was stirred at 100℃ for 2 h under N ₂ atmosphere. The mixture was cooled, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column (petroleum ether/ethyl acetate = 5/1) to afford 30-7.

Compound 30 was prepared following the procedures for the synthesis of 18 in example 1. LCMS (ESI, m/z) : [M+H] ⁺ = 648.3; HNMR (300 MHz, DMSO-d ₆, ppm) : δ 10.04 (s, 1H) , 8.74 (s, 1H) , 8.55 (s, 1H) , 8.01 (s, 1H) , 7.42-7.35 (m, 2H) , 7.21 (s, 1H) , 7.05-6.98 (m, 3H) , 6.86 (t, J = 7.2 Hz, 1H) , 6.40-6.36 (m, 1H) , 6.26-6.20 (m, 1H) , 5.76 (d, J = 10.2 Hz, 1H) , 4.31-4.27 (m, 1H) , 4.10-4.06 (m, 2H) , 3.85 (s, 3H) , 2.95-2.85 (m, 2H) , 2.74-2.72 (m, 2H) , 2.68 (s, 3H) , 2.36-2.26 (m, 2H) , 2.28 (s, 6H) , 2.05-1.91 (m, 2H) , 1.79-1.69 (m, 2H) , 1.22 (d, J = 6.6 Hz, 6H) .

Example 19 Synthesis of Compound 47

Compound 47-3 was prepared following the procedures for the synthesis of 46-4 in example 5.

Compound 47-5 was prepared following the procedures for the synthesis of 46 in example 5.

Step 1: A mixture of 47-5 (102 mg, 0.18 mmol) and sodium hydroxide (73 mg, 1.83 mmol) in tetrahydrofuran (4 mL) /water (2 mL) was stirred at 50℃ for 120 h, and then concentrated to remove the organic solvent. The resulting mixture was acidified with acetic acid and purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 15%to 95%) to afford 47 as a mono TFA salt. LCMS (ESI, m/z) : [M+H] ⁺ = 544.3; HNMR (400 MHz, DMSO-d ₆, ppm) : δ 12.42 (brs, 1H) , 9.44 (s, 1H) , 9.16 (brs, 1H) , 8.53 (s, 1H) , 8.47 (s, 1H) , 8.29 (s, 1H) , 8.22 (s, 1H) , 8.07-8.05 (m, 1H) , 7.61-7.59 (m, 1H) , 7.25-7.18 (m, 2H) , 6.93 (s, 1H) , 6.60-6.49 (m, 1H) , 6.26 (d, J = 16.8 Hz, 1H) , 5.76 (d, J = 10.0 Hz, 1H) , 3.82 (s, 3H) , 3.30-3.12 (m, 4H) , 2.74 (s, 3H) , 2.73 (s, 3H) , 2.54 (s, 3H) , 2.11 (s, 3H) .

Example 20 Synthesis of Compound 53

A mixture of 47-3 (1.2 g, 2.25 mmol) and sodium hydroxide (540 mg, 13.5 mmol) in tetrahydrofuran (8 mL) /water (4 mL) was stirred at 50℃ for 240 h, then acidified with acetic acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 55-1 which was used directly in the next step without purification.

A mixture of crude 53-1 (500 mg, crude, ～0.59 mmol) , 2- (7-aza-1H-benzotriazole-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (269 mg, 0.71 mmol) , N, N-diisopropylethylamine (381 mg, 2.95 mmol) and ammonium chloride (78 mg, 1.48 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 6 h, then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 15%to 95%) to afford 53-2.

Compound 53 was prepared following the procedures for the synthesis of 46 in example 5 as a mono TFA salt. LCMS (ESI, m/z) : [M+H] ⁺ = 543.3; HNMR (400 MHz, DMSO-d ₆, ppm) : δ 9.44 (s, 1H) , 9.19 (brs, 1H) , 8.52 (s, 1H) , 8.42 (s, 1H) , 8.33 (s, 1H) , 8.26 (s, 1H) , 8.22-8.19 (m, 1H) , 7.73-7.50 (m, 2H) , 7.19-7.14 (m, 2H) , 7.12-6.97 (m, 1H) , 6.93 (s, 1H) , 6.58-6.50 (m, 1H) , 6.28-6.22 (m, 1H) , 5.78-5.74 (m, 1H) , 3.82 (s, 3H) , 3.27-3.16 (m, 4H) , 2.75-2.73 (m, 6H) , 2.54 (s, 3H) , 2.15 (s, 3H) .

Example 21 Synthesis of Compound 64

Compound 64-3 was prepared following the procedures for the synthesis of 30-3 in example 18.

Compound 64-4 was prepared following the procedure for the synthesis of 18-1 in example 1.

Compound 64-5 was prepared following the procedure for the synthesis of 50 in example 6.

Step 1: To a solution of 64-5 (100 mg, 0.17 mmol) in dioxane (2 mL) and H ₂O (2 mL) was added LiOH. H ₂O (57 mg, 1.37 mmol) in portions. The mixture was stirred at room temperature for 3 h. The mixture was concentrated and the residue was purified by prep-HPLC (acetonitrile with 0.05%of formic acid in water: 15%to 95%) to afford 64-6.

Step 2: A mixture of 64-6 (35 mg, 0.06 mmol) , HATU (47 mg, 0.12 mmol) and isopropylamine (19 mg, 0.31 mmol) in DMF (7 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated and the residue was purified by prep-HPLC (acetonitrile with 0.05%of TFA in water: 8%to 25%) to afford 64 as mono TFA salt. LCMS (ESI, m/z) : [M+H] ⁺ = 611.5; HNMR (400 MHz, DMSO-d ₆, ppm) : δ 9.64 (s, 1H) , 9.50 (brs, 1H) , 8.42 (s, 1H) , 8.35 (s, 1H) , 7.99 (d, J = 8.0 Hz, 1H) , 7.71 (d, J = 8.0 Hz, 1H) , 7.34 (d, J = 8.0 Hz, 1H) , 7.30-7.20 (m, 1H) , 7.08 (t, J = 7.8 Hz, 1H) , 7.02-6.96 (m, 2H) , 6.70 (d, J = 11.8 Hz, 1H) , 6.29 (d, J = 16.8 Hz, 1H) , 5.79 (d, J = 10.2 Hz, 1H) , 4.11 (t, J = 7.2 Hz, 2H) , 3.88 (s, 3H) , 3.60-3.20 (m, 4H) , 3.03 (t, J = 7.2 Hz, 2H) , 2.78 (d, J = 3.6 Hz, 6H) , 2.60 (s, 3H) , 2.01(q, J = 7.2 Hz, 1H) , 1.30-1.02 (m, 2H) , 0.98 (d, J = 6.6 Hz, 6H) .

Compounds of Formulae I, II, and III can be prepared by following the synthetic methods described herein. Table 1 lists representative analytical data for some of compounds prepared similarly to the processes described in Examples 1-21.

Table 1. Characterization of Representative Compounds of the Present Disclosure

Biological Example 1. Assay for LU0387 Cell Proliferation

Patient-derived xenograft cell line of LU0387 (ADC) with EGFR exon 20 insert mutation at 2319 (H773-V774insNPH) (CrownBio) were grown in DMEM medium supplemented with 10%fetal bovine serum at 37 ℃ with 5%CO ₂ in air. Cells grown in log phase were trypsinized and seeded into a 96-well cell culture plate at the density of 1.5 x 10 ⁴ per well with 90 uL and incubated overnight. The next day, 10 uL of serial diluted compounds for each well were added at a final DMSO concentration of 0.5%. On day 6, 50 uL media solution containing 1x compound was transferred to the assay plate to prevent water evaporation. On day 9, cell-titer Glo reagent was added to each well of cells and luminescence signal was measured using a Envision 2104 Multilabel Reader. Wells with culture media only was used as Blank. Inhibition rate is calculated with the formula of %inhibition=100 * (DMSO Control –Treated Well) / (DMSO Control –Blank) . Cell growth inhibition of IC ₅₀ is calculated with the equation of Y=Bottom + (Top-Bottom) / (1+10^ ( (LogIC ₅₀-X) *HillSlope) )

In Table 2 below, the IC50 levels are described as I, II, or III, wherein I represents that IC50 value is in the range of less than or equal to 100 nM; II represents that IC50 value is in the range of less than or equal to 1000 nM and more than 100 nM; and III represents that IC50 value is more than 1000 nM.

Table 2. Inhibition of LU0387 Cell Proliferation by Representative Compounds

Compound	IC ₅₀ (nM)	Compound	IC ₅₀ (nM)	Compound	IC ₅₀ (nM)	Compound	IC ₅₀ (nM)
Control A*	I	21	I	43	I	65	I
Control B*	II	22	II	44	I	66	I
1	I	23	II	45	I	67	I
2	I	24	I	46	III	68	III
3	I	25	I	47	III	69	I
4	II	26	I	48	II	70	I
5	I	27	I	49	I	71	I
6	I	28	II	50	I	72	I
7	I	29	I	51	II	73	II
8	III	30	II	52	III	74	I
9	I	31	I	53	I	75	II
10	I	32	I	54	III	76	II
11	I	33	I	55	I	77	I
12	I	34	I	56	I
13	I	35	II	57	I
14	I	36	I	58	I
15	II	37	I	59	III
16	II	38	I	60	III
17	I	39	I	61	II
18	I	40	I	62	III
19	II	41	II	63	II
20	II	42	I	64	II

*: Control A: isopropyl 2- ( (5-acrylamido-4- ( (2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate

Control B: N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ( (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide

The Summary and Abstract sections may set forth one or more but not all exemplary embodiments of the present disclosure as contemplated by the inventor (s) , and thus, are not intended to limit the present disclosure and the appended claims in any way.

The present disclosure has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed.

With respect to aspects of the disclosure described as a genus, all individual species are individually considered separate aspects of the disclosure. If aspects of the disclosure are described as "comprising" a feature, embodiments also are contemplated "consisting of” or "consisting essentially of” the feature.

The foregoing description of the specific embodiments will so fully reveal the general nature of the disclosure that others can, by applying knowledge within the skill of the art, readily modify and/or adapt for various applications such specific embodiments, without undue experimentation, without departing from the general concept of the present disclosure. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.

The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments.

All of the various aspects, embodiments, and options described herein can be combined in any and all variations.

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. To the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.

Claims

A compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein:

A is a fused bicyclic heteroaryl group substituted with a substituent having a –SO ₂-or – C (=O) -group and optionally further substituted, preferably, A is A-I or A-II:

wherein each of J ¹, J ³, J ⁴, and J ⁹ is independently C or N,

J ² is CR ⁵ or N,

each of J ⁵, J ⁶, J ⁷, and J ⁸ is independently CR ⁶ or N,

provided that the bicyclic ring of J ¹-J ⁹ is a heteroaryl ring;

R ⁴ is an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted amino group;

R ⁵ is hydrogen, halogen, -CN, -OH, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl; or when both J ¹ and J ³ are N, R ⁵ can also be an oxo group;

R ⁶ at each occurrence is independently hydrogen, halogen, -CN, -OH, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, an optionally substituted C _1-6 alkoxy, an optionally substituted C _3-6 cycloalkoxy, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl; and

R ⁷ is OH, an optionally substituted C _1-6 alkoxy, or an optionally substituted amino group, provided that when J ³ is N, R ⁷ is not OH;

wherein:

R ¹ is –L ¹-R ¹⁰, wherein L ¹ is absent, an optionally substituted C _1-6 alkylene, optionally substituted C _2-6 alkenylene, optionally substituted C _2-6 alkynylene, optionally substituted C _1-6 heteroalkylene, -C (=O) -O-, -C (=O) -NH-, -C (=O) -N (C _1-6 alkyl) -, -S (O) ₂-O-, -S (O) ₂-NH-, -S (O) ₂-N (C _1-6 alkyl) -, -P (=O) (C _1-6 alkyl) -, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenylene, or optionally substituted 5 or 6 membered heteroarylene, and R ¹⁰ is hydrogen, halogen, -CN, -C (=O) -O- (C _1-6 alkyl) , -C (=O) -NH- (C _1-6 alkyl) , -C (=O) -N (C _1-6 alkyl) (C _1-6 alkyl) , -S (O) ₂-O- (C _1-6 alkyl) , -S (O) ₂-NH- (C _1-6 alkyl) , -S (O) ₂-N (C _1-6 alkyl) (C _1-6 alkyl) , optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl;

R ² is hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or an oxygen protecting group;

X is O, NR ²⁰, or an optionally substituted 4 to 7 membered heterocyclic ring, wherein R ²⁰ is hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group;

L is absent or an optionally substituted C _1-6 alkylene, optionally substituted C _1-6 heteroalkylene, optionally substituted C _3-6 carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring;

R ³ is hydrogen, -NR ²¹R ²², or an optionally substituted 4 to 7 membered heterocyclyl, wherein R ²¹ and R ²² are independently hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A in Formula I is selected from A-1 to A-18:
The compound of claim 2, or a pharmaceutically acceptable salt thereof, characterized as having Formula I-1:
The compound of claim 2, or a pharmaceutically acceptable salt thereof, characterized as having Formula I-2:
The compound of claim 2, or a pharmaceutically acceptable salt thereof, characterized as having Formula I-1A, I-1B, or I-2A:
The compound of claim 2, or a pharmaceutically acceptable salt thereof, characterized as having Formula I-1C:
The compound of claim 2, or a pharmaceutically acceptable salt thereof, characterized as having Formula I-1D or I-1E:
The compound of claim 2, or a pharmaceutically acceptable salt thereof, characterized as having Formula I-1F or I-1G:
The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein A in Formula I is A-3 or A-4.
The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein A in Formula I is A-9, A-10, A-11, A-12, or A-13.
The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein A in Formula I is A-5, A-6, A-7, or A-8.
The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein A in Formula I is A-14, A-15, A-16, A-17, or A-18.
The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein when present, R ⁴ is an optionally substituted C _1-6 alkyl, such as unsubstituted C _1- ₆ alkyl (e.g., methyl, ethyl, or isopropyl) or a C _1-6 alkyl substituted with 1-3 substituents independently selected from F, Cl, -CN, C _1-6 alkyl, C _1-6 alkyl substituted with 1-3 fluorine, C _1-6 alkoxy, C _1-6 alkoxy substituted with 1-3 fluorine, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) (C _1-6 alkyl) , cyclopropyl, cyclobutyl, optionally substituted 4-7 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from O, N, and S, optionally substituted phenyl, and optionally substituted 5 or 6 membered heteroaryl having 1-4 ring heteroatoms independently selected from O, N, and S.
The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein when present, R ⁴ is an optionally substituted C _3-6 carbocyclic ring, such as unsubstituted C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) or C _3-6 cycloalkyl substituted with 1-3 substituents independently selected from F, Cl, -CN, C _1-6 alkyl, C _1-6 alkyl substituted with 1-3 fluorine, C _1-6 alkoxy, C _1-6 alkoxy substituted with 1-3 fluorine, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) (C _1-6 alkyl) , cyclopropyl, and cyclobutyl.
The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein when present, R ⁴ is an optionally substituted phenyl, such as substituted with 1-3 substituents independently selected from F, Cl, -CN, C _1-6 alkyl, C _1-6 alkyl substituted with 1-3 fluorine, C _1-6 alkoxy, C _1-6 alkoxy substituted with 1-3 fluorine, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) (C _1-6 alkyl) , cyclopropyl, and cyclobutyl.
The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein when present, R ⁴ is an optionally substituted amino group, such as –NH ₂, or a substituted amino group selected from monosubstituted amino group (e.g., monoalkylamine, such as -NH (C _1-6 alkyl) , monocycloalkylamine, such as –NH (C _3-6 cycloalkyl) ) or disubstituted amino group (e.g., dialkylamine, such as -N (C _1-6 alkyl) (C _1-6 alkyl) ) .
The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein when present, R ⁴ is selected from methyl, ethyl, isopropyl, -CF ₃, cyclopropyl, phenyl, -NH ₂, and -NH-CH ₃.
The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein when present, R ⁵ is hydrogen, halogen, -CN, an optionally substituted C _1-6 alkyl or an optionally substituted C _3-6 cycloalkyl.
The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein when present, R ⁵ is

a) hydrogen;

b) a C _1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH; or

c) a C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups.
The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein 2, 3, or all of R ⁶ are hydrogen.
The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein when present, R ⁶ at each occurrence is independently hydrogen, F, Cl, -CN, C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _3-6 cycloalkyl optionally substituted with 1-3 fluorine, C _3-6 cycloalkoxy optionally substituted with 1-3 fluorine, .
The compound of any one of claims 1, 2, 11, and 12, or a pharmaceutically acceptable salt thereof, wherein when present, R ⁷ is an optionally substituted amino group, such as –NH ₂, or a substituted amino group selected from monosubstituted amino group (e.g., monoalkylamine, such as -NH (C _1-6 alkyl) , monocycloalkylamine, such as –NH (C _3-6 cycloalkyl) ) or disubstituted amino group (e.g., dialkylamine, such as -N (C _1-6 alkyl) (C _1-6 alkyl) ) .
The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein L ¹ is absent.
The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein L ¹ is – (CH ₂) _p-, -O-, -O- (CH ₂) _p-, -C (=O) -O-, -C (=O) -NH-, -C (=O) -N (C _1-6 alkyl) -, -S (O) ₂-O-, -S (O) ₂-NH-, -S (O) ₂-N (C _1-6 alkyl) -,
or 5 or 6 membered heteroarylene having 1-4 ring nitrogen atoms, wherein p is an integer of 1-4.
The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein L ¹ is -O-, -C (=O) -O-, -C (=O) -NH-,
The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is hydrogen, C _1-6 alkyl optionally substituted with 1-3 fluorine, cyclopropyl, or cyclobutyl.
The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen, F, Cl, -CN, C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1- ₆ alkoxy optionally substituted with 1-3 fluorine, C _3-6 carbocyclic ring optionally substituted with 1-3 substituents independently selected from C _1-6 alkyl and F, 4 to 7 membered heterocyclic ring optionally substituted with 1-3 substituents independently selected from C _1-6 alkyl and F, phenyl optionally substituted with 1-3 substituents independently selected from C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, F, -CN, and Cl, or 5 or 6 membered heteroaryl having 1-4 ring nitrogen atoms and optionally substituted with 1-3 substituents independently selected from C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, F, and Cl.
The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen, F, Cl, -CN, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -O- (C _1-4 alkyl) , -C (=O) -O- (C _1-4 alkyl) , -C (=O) -NH- (C _1-4 alkyl) , phenyl,
The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen, F, methyl, ethyl, isopropyl, cyclopropyl, methoxy, -C (=O) -O-isopropyl, -C (=O) -NH-isopropyl,
The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen or methyl.
The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein X is O.
The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein X is –NCH ₃.
The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein X is an optionally substituted 4-7 membered monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O.
The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein X is
The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein L is absent or a C _1-6 alkylene.
The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein L is absent, -CH ₂-, or – (CH ₂) ₂-.
The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R ³ is –NH (C _1-6 alkyl) , -N (C _1-6 alkyl) (C _1-6 alkyl) , or a 4 to 7 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, which is optionally substituted with 1-3 substituents independently selected from C _1-6 alkyl and F.
The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R ³ is –NHCH ₃ or -N (CH ₃) ₂.
The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein X-L-R ³ is
A compound of Formula II, or a pharmaceutically acceptable salt thereof:

wherein:

G ¹ is selected from:

j)

k)

l)

m) C _1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, methyl, C _1-6 alkoxy optionally substituted with fluorine, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, and 4-7 membered heterocyclic ring optionally substituted with fluorine and/or methyl groups,

n) a halogen or -CN,

o) C _1-6 alkoxy optionally substituted with fluorine,

p) optionally substituted phenyl,

q) C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, or

r) a 4-7 membered heterocyclic ring optionally substituted with fluorine and/or methyl groups;

wherein Q ¹ and Q ⁴ are independently C or N, Q ², Q ³, and Q ⁵ are independently CH, N, O, or S, provided that the ring of Q ¹-Q ⁵ is a 5-membered heteroaryl ring;

wherein R ³⁰ and R ³¹ are independently hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group; or R ³⁰ and R ³¹ are joined to form an optionally substituted 4-7 membered heterocyclic ring;

R ⁴⁰ is hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring; and

R ⁴¹ is hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group when applicable;

G ² is an optionally substituted fused bicyclic heteroaryl group, preferably, G ² is

wherein each of J ¹, J ⁴, and J ⁹ is independently C or N,

J ² is CR ^5B or N,

J ³ is CR ^5B, N, or NR ^5A, as valence permits,

each of J ⁵, J ⁶, J ⁷, and J ⁸ is independently CR ⁶ or N,

provided that the bicyclic ring of J ¹-J ⁹ is a heteroaryl ring;

R ^5A is hydrogen, -C (=O) -R ⁷, -S (O) ₂R ⁴, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl;

R ^5B and R ⁶ at each occurrence is independently hydrogen, halogen, -CN, -OH, -C (=O) -R ⁷, -S (O) ₂R ⁴, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _1-6 alkoxy, optionally substituted C _3-6 cycloalkoxy, optionally substituted C _3- ₆ carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl; or when possible, R ^5A and R ^5B, two R ⁶ groups, or R ^5A and one R ⁶ group, together with the intervening atoms, are joined to form a 5-7 membered ring structure; or when J ¹ is N, and J ³ is N or NR ^5A, J ² can be CR ^5B, wherein R ^5B is an oxo group;

R ⁴ is an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted amino group; and

R ⁷ is OH, an optionally substituted C _1-6 alkoxy, or an optionally substituted amino group, provided that when -C (=O) -R ⁷ is attached to N, R ⁷ is not OH;

wherein:

R ² is hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or an oxygen protecting group;

X is O, NR ²⁰, or an optionally substituted 4 to 7 membered heterocyclic ring, wherein R ²⁰ is hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group;

L is absent or an optionally substituted C _1-6 alkylene, optionally substituted C _1-6 heteroalkylene, optionally substituted C _3-6 carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring;

R ³ is hydrogen, -NR ²¹R ²², or an optionally substituted 4 to 7 membered heterocyclyl, wherein R ²¹ and R ²² are independently hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group.
The compound of claim 40, or a pharmaceutically acceptable salt thereof, characterized as having Formula II-1, II-2, or II-3:

wherein:

R ^5A is hydrogen, -S (O) ₂-R ⁴, -C (O) -R ⁷, optionally substituted C _1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH) , or optionally substituted C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ; and

R ^5B is hydrogen, halogen, -CN, optionally substituted C _1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH) , or optionally substituted C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ;

or R ^5A and R ^5B are joined to form a 5 or 6 membered ring structure.
The compound of claim 40 or 41, or a pharmaceutically acceptable salt thereof, wherein when present, one of R ³⁰ and R ³¹ is hydrogen or C _1-6 alkyl, and the other of R ³⁰ and R ³¹ is defined above.
The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein the other of R ³⁰ and R ³¹ is a C _1-6 alkyl or a C _3-6 cycloalkyl.
The compound of claim 40 or 41, or a pharmaceutically acceptable salt thereof, wherein when present, R ³⁰ and R ³¹ are joined to form a monocyclic 4-7 membered saturated heterocyclic ring, which is optionally substituted.
The compound of claim 40 or 41, or a pharmaceutically acceptable salt thereof, wherein when present, R ⁴⁰ is i) C _1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH; or ii) a C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups.
The compound of claim 40 or 41, or a pharmaceutically acceptable salt thereof, wherein when present, R ⁴¹ is i) C _1-6 alkyl optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH; or ii) a C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with fluorine and/or methyl groups.
The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein:

G ¹ is C _1-6 alkyl, CF ₃, -CH ₂-O- (C _1-6 alkyl) , cyclopropyl, cyclobutyl, phenyl, F, Cl, CN, C _1-6 alkoxy,
and

G ² is

wherein:

R ^5A is hydrogen, -S (O) ₂-R ⁴, -C (O) -R ⁷, optionally substituted C _1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH) , or optionally substituted C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ; and

R ^5B is hydrogen, halogen, -CN, optionally substituted C _1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH) , or optionally substituted C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ;

or R ^5A and R ^5B are joined to form a 5 or 6 membered ring structure.
The compound of any one of claims 40-47, or a pharmaceutically acceptable salt thereof, wherein:

G ² is selected from B-1 to B-4:

wherein:

R ^5B is:

a) hydrogen,

b) a C _1-6 alkyl,

c) a C _1-6 alkyl substituted with 1-3 substituents independently selected from fluorine, methyl, C _1-6 heteroalkyl, and –OH,

d) a C _1-6 alkyl substituted with an optionally substituted phenyl or an optionally substituted 5 or 6 membered heteroaryl,

e) a C _1-6 alkyl substituted with a C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) , wherein the C _3-6 cycloalkyl is optionally substituted with fluorine and/or methyl groups, or

f) cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups.
The compound of any one of claims 40-48, or a pharmaceutically acceptable salt thereof, wherein R ⁶ at each occurrence is independently hydrogen, F, Cl, -CN, C _1-4 alkyl optionally substituted with 1-3 fluorine, C _1-4 alkoxy optionally substituted with 1-3 fluorine, C _3-6 cycloalkyl optionally substituted with 1-3 fluorine, C _3-6 cycloalkoxy optionally substituted with 1-3 fluorine.
The compound of any one of claims 41-49, or a pharmaceutically acceptable salt thereof, wherein 2, 3, or all of R ⁶ are hydrogen.
The compound of any one of claims 40-50, or a pharmaceutically acceptable salt thereof, wherein G ² is selected from:
The compound of any one of claims 40-51, or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen or methyl.
The compound of any one of claims 40-52, or a pharmaceutically acceptable salt thereof, wherein X is O.
The compound of any one of claims 40-52, or a pharmaceutically acceptable salt thereof, wherein X is –NCH ₃.
The compound of any one of claims 40-52, or a pharmaceutically acceptable salt thereof, wherein X is an optionally substituted 4-7 membered monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O.
The compound of any one of claims 40-52, or a pharmaceutically acceptable salt thereof, wherein X is
The compound of any one of claims 40-56, or a pharmaceutically acceptable salt thereof, wherein L is absent or a C _1-4 alkylene.
The compound of any one of claims 40-56, or a pharmaceutically acceptable salt thereof, wherein L is absent, -CH ₂-, or – (CH ₂) ₂-.
The compound of any one of claims 40-58, or a pharmaceutically acceptable salt thereof, wherein R ³ is –NH (C _1-4 alkyl) , -N (C _1-4 alkyl) (C _1-4 alkyl) , or a 4 to 7 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, which is optionally substituted with 1-3 substituents independently selected from C _1-4 alkyl and F.
The compound of any one of claims 40-58, or a pharmaceutically acceptable salt thereof, wherein R ³ is –NHCH ₃ or -N (CH ₃) ₂.
The compound of any one of claims 40-60, or a pharmaceutically acceptable salt thereof, wherein X-L-R ³ is
A compound of Formula III, or a pharmaceutically acceptable salt thereof:

wherein:

R ^5A is hydrogen, -C (=O) -R ⁷, -S (O) ₂R ⁴, optionally substituted C _1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH) , or optionally substituted C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ;

R ^5B is hydrogen, halogen, -CN, optionally substituted C _1-6 alkyl (e.g., optionally substituted with 1-3 substituents independently selected from fluorine, C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with fluorine and/or methyl groups, C _1-6 heteroalkyl, and –OH) , or optionally substituted C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups) ;

R ⁶ at each occurrence is independently hydrogen, halogen, -CN, -OH, -C (=O) -R ⁷, -S (O) ₂R ⁴, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _1-6 alkoxy, optionally substituted C _3-6 cycloalkoxy, optionally substituted C _3- ₆ carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl; or when possible, R ^5A and R ^5B, two R ⁶ groups, or one R ^5A and one R ⁶ group, together with the intervening atoms, are joined to form a 5-7 membered ring structure;

R ⁴ is an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted amino group; and

R ⁷ is OH, an optionally substituted C _1-6 alkoxy, or an optionally substituted amino group, provided that when -C (=O) -R ⁷ is attached to N, R ⁷ is not OH;

wherein:

R ² is hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or an oxygen protecting group;

X is O, NR ²⁰, or an optionally substituted 4 to 7 membered heterocyclic ring, wherein R ²⁰ is hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group;

L is absent or an optionally substituted C _1-6 alkylene, optionally substituted C _1-6 heteroalkylene, optionally substituted C _3-6 carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring;

R ³ is hydrogen, -NR ²¹R ²², or an optionally substituted 4 to 7 membered heterocyclyl, wherein R ²¹ and R ²² are independently hydrogen, an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group.
The compound of claim 62, or a pharmaceutically acceptable salt thereof, wherein the moiety of
in Formula III is selected from B-1 to B-4:

wherein:

R ^5B is:

a) hydrogen,

b) a C _1-6 alkyl,

c) a C _1-6 alkyl substituted with 1-3 substituents independently selected from fluorine, methyl, C _1-6 heteroalkyl, and –OH,

d) a C _1-6 alkyl substituted with an optionally substituted phenyl or an optionally substituted 5 or 6 membered heteroaryl,

e) a C _1-6 alkyl substituted with a C _3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl) , wherein the C _3-6 cycloalkyl is optionally substituted with fluorine and/or methyl groups, or

f) cyclopropyl or cyclobutyl, optionally substituted with fluorine and/or methyl groups,

provided that B-1 or B-2 does not represent indole or 1-methyl indole moiety.
The compound of claim 63 or 64, or a pharmaceutically acceptable salt thereof, wherein R ⁶ at each occurrence is independently hydrogen, F, Cl, -CN, C _1-4 alkyl optionally substituted with 1-3 fluorine, C _1-4 alkoxy optionally substituted with 1-3 fluorine, C _3-6 cycloalkyl optionally substituted with 1-3 fluorine, C _3-6 cycloalkoxy optionally substituted with 1-3 fluorine.
The compound of any one of claims 62-64, or a pharmaceutically acceptable salt thereof, wherein 2, 3, or all of R ⁶ is hydrogen.
The compound of any one of claims 62-65, or a pharmaceutically acceptable salt thereof, wherein the moiety of
in Formula III is selected from:
The compound of any one of claims 62-65, or a pharmaceutically acceptable salt thereof, wherein the moiety of
in Formula III is selected from:
The compound of any one of claims 62-67, or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen or methyl.
The compound of any one of claims 62-68, or a pharmaceutically acceptable salt thereof, wherein X is O.
The compound of any one of claims 62-68, or a pharmaceutically acceptable salt thereof, wherein X is –NCH ₃.
The compound of any one of claims 62-68, or a pharmaceutically acceptable salt thereof, wherein X is an optionally substituted 4-7 membered monocyclic saturated heterocyclic ring having 1-2 heteroatoms selected from N and O.
The compound of any one of claims 62-68, or a pharmaceutically acceptable salt thereof, wherein X is
The compound of any one of claims 62-72, or a pharmaceutically acceptable salt thereof, wherein L is absent or a C _1-4 alkylene.
The compound of any one of claims 62-72, or a pharmaceutically acceptable salt thereof, wherein L is absent, -CH ₂-, or – (CH ₂) ₂-.
The compound of any one of claims 62-74, or a pharmaceutically acceptable salt thereof, wherein R ³ is –NH (C _1-4 alkyl) , -N (C _1-4 alkyl) (C _1-4 alkyl) , or a 4 to 7 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, which is optionally substituted with 1-3 substituents independently selected from C _1-4 alkyl and F.
The compound of any one of claims 62-74, or a pharmaceutically acceptable salt thereof, wherein R ³ is –NHCH ₃ or -N (CH ₃) ₂.
The compound of any one of claims 62-76, or a pharmaceutically acceptable salt thereof, wherein X-L-R ³ is
A compound selected from any of Compound Nos. 1-77, or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising the compound of any one of claims 1-78 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
A method of inhibiting a mutant EGFR and/or HER2 with one or more mutations, such as one or more insertion, deletion, and/or point mutations, in the exon 20 domain of EGFR and/or HER2, comprising contacting the mutant EGFR and/or HER2 with the compound of any one of claims 1-78 or a pharmaceutically acceptable salt thereof.
A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-78 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 79.
The method of claim 81, wherein the cancer is associated with one or more EGFR and/or HER2 mutations, e.g., one or more deletion, insertion, and/or point mutations, in the exon 20 domain of EGFR and/or HER2.
The method of claim 81 or 82, wherein the cancer is selected from lung cancer, breast cancer, stomach cancer, colorectal cancer, pancreatic cancer, prostate cancer, myeloma, head and neck cancer, ovarian cancer, uterine cancer, esophageal cancer, and metastatic cell carcinoma.
The method of claim 81 or 82, wherein the cancer comprises non-small cell lung cancer.
The method of any of claims 81-84, wherein the cancer is associated with an insertion mutation in the exon 20 domain of EGFR and/or HER2.
The method of any of claims 81-84, wherein the cancer is associated with a mutation in the exon 20 domain of EGFR selected from A763insFQEA, V769insASV, D770insSVD, or H773insNPH, or T790M.
The method of any of claims 81-84, wherein the cancer is associated with a T790M mutation in the exon 20 domain of EGFR concurrent with an exon 19 deletion mutation and/or an exon 21 point mutation.
The method of any of claims 81-84, wherein the cancer is associated with an YVMA insertion mutation in the exon 20 domain of HER2.
The method of any of claims 81-88, further comprising treating the subject with an additional therapy.
The method of claim 89, wherein the additional therapy is a targeted agent, chemotherapeutic agent, therapeutic antibody, radiation, cell therapy, or immunotherapy.
The method of claim 89, comprising administering to the subject one or more additional cytotoxic agents selected from an antimetabolite, a mitotic inhibitor, alkylating agent, a platinum-based antineoplastic drug, an antibody-drug conjugate consisting of the EGFR monoclonal antibody and toxic payload such as T-DM1, a c-MET tyrosine kinase inhibitor, immune checkpoint inhibitors such as PD-1/PD-L1 or CTLA4, an mTOR inhibitor, a VEGF inhibitor, an aromatase inhibitor, a CDK4/6 inhibitor, and any combination thereof.