KR20220145368A - Tetracyclic compounds for the treatment of HIV infection - Google Patents

Abstract

The present disclosure relates generally to certain tetracyclic compounds, pharmaceutical compositions comprising such compounds, and methods of preparing such compounds and pharmaceutical compositions. The compounds of the present disclosure are useful for treating or preventing human immunodeficiency virus (HIV) infection. (Formula (I))
[Formula (I)]

Description

Tetracyclic compounds for the treatment of HIV infection

Cross-reference to related applications

This application is based on U.S. Provisional Application Serial No. 62/980,857, filed February 24, 2020, U.S. Provisional Application Serial No. 63/036,268, filed June 8, 2020, and U.S. Provisional Application Serial No. 21, 2020, filed Claims the benefit of application 63/128,670. The entire contents of these applications are incorporated herein by reference in their entirety.

technical field

The present disclosure relates generally to certain tetracyclic compounds, pharmaceutical compositions comprising such compounds, and methods of making and using such compounds and pharmaceutical compositions.

Human immunodeficiency virus infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptases and proteases have been widely used and shown efficacy, the development of toxic and resistant strains, particularly when used in combination, may limit their usefulness (Palella, et al. N. Engl. J Med). (1998) 338 : 853-860; Richman, DD Nature (2001) 410:995-1001). Therefore, there is a need for new agents that inhibit the replication of HIV.

The goal of antiretroviral therapy is to achieve viral suppression in HIV-infected patients. Current treatment guidelines issued by the US Department of Health and Human Services provide that achieving viral suppression requires the use of combination therapy, i.e., the use of several drugs from at least two or more drug classes (Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Available at https://files.aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf 20 Feb 2020 approached to work). Moreover, decisions regarding the treatment of HIV-infected patients are complex when the patient requires treatment for other medical conditions. As standard care requires the use of many different drugs not only to suppress HIV, but also to treat other conditions the patient may experience, the potential for drug interactions is a criterion for the selection of drug therapy. Therefore, there is a need for antiretroviral treatments with reduced potential for drug interactions.

Furthermore, the HIV virus is known to mutate infected subjects (Tang, et al. Drugs (2012) 72 (9) e1-e25). Because of the propensity of the HIV virus to mutate, there is a need for effective anti-HIV drugs against a set of known HIV variants (Hurt, et al. HIV/AIDS CID (2014) 58, 423-431).

For certain patients, such as those with difficult or limited access to health care, adherence to a daily oral treatment or prophylactic regimen can be a challenge. Drugs that provide good pharmaceutical properties (e.g., improved potency, long-acting pharmacokinetics, low solubility, low clearance, and/or other properties) are modifiable with less frequent dosing and provide better patient compliance . These improvements may in turn optimize drug exposure and limit the emergence of drug resistance.

In one aspect, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof:

[Formula I]

In the above formula,

R ¹ is H, C _6-10 aryl or C _6-10 heteroaryl, C _6-10 aryl or C _6-10 heteroaryl is optionally substituted with 1 to 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _{1 -4} alkyl;

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로 이루어진 군으로부터 선택되고;Y is -C(O)NH-,

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is selected from the group consisting of;

L is -CR ^3a R ^3b- , -C(O)-, -SO _2- , -CR ^3a R ^3b -CR ^3c R ^3d- or -N(R ^a )-;

W ¹ is a bond or -CR ^4a R ^4b- ;

W ² is -CR ^5a R ^5b- , -CR ^5a R ^5b CR ^5c R ^5d- , -CR ^6a =CR ^6b- , -N(R ⁷ )-, -O-, -S(O) _n- , - C(O)NR ^e -, -CR ^5a R ^5b- N(R ⁷ )-, -CR ^5a R ^5b- O-, -CR ^5a R ^5b- S(O) _n- , -CR ^5a R ^5b- C (O)NR ^e- , -CR ^5a R ^5b- NR ^e- C(O)-, -S(O) _n N(R ^e ) -CR ^5a R ^5b- or -N(R ^e ) -S(O ) _n- CR ^5a R ^5b- ;

X is a bond or -CR ^8a R ^8b- ;

Z is -CR ^9a R ^9b- , -CR ^9a R ^9b CR ^9c R ^9d- or -CR ^10a =CR ^10b- ;

이고;T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d , U is -NR ^11- , ^- CR ^12a R ^12b- , -S(O) _n- , -C(O) - or -O-; T and U together

ego;

R ^2a , R ^2b , R ^2c , R ^2d , R ^12a and R ^12b are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, Halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a _, -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , - C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ;

(i) R ^2a and R ^2b , (ii) R ^2c and R ^2d or (iii) R ^12a and R ^12b together with the carbon atom to which they are attached are (i) 3-7 membered carbocyclic ring or (ii) a 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, a 3-7 membered carbocyclic ring or a 4-7 membered heteroatom the cyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or —OC _1-4 alkyl;

(i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, represent (i) a 3- to 7-membered carbocyclic ring or (ii) N, O and form a 3-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, the 3-7 membered carbocyclic ring or the 3-7 membered heterocyclic ring having 1 to 3 members optionally substituted with R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

R ^4a , R ^4b , R ^5a , R ^5b , R ^5c , R ^5d , R ^8a , R ^8b , R ^9a , R ^9b , R ^9c and R ^9d are independently H, C _1-6 alkyl, C _1-4 haloalkyl, halo, hydroxyl, cyano, -OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl;

(i) R ^4a and R ^4b , (ii) R ^5a and R ^5b , (iii) R ^5c and R ^5d , (iv) R ^5a and R ^5c , (v) R ^5b and R ^5d , (vi) R ^8a and any one of R ^8b , (vii) R ^9a and R ^9b , (viii) R ^9c and R ^9d , (ix) R ^9a and R ^9c , (x) R ^9b and R ^9d , (xi) R ^8b and R one of ^5a , R ^5b , R ^5c , R ^5d and R ⁷ , or (xii) one of R ^9a , R ^9b , R ^9c and R ^9d and one of R ^4a , R ^4b , R ^5a , R ^5b and R ⁷ . are, together with the carbon atoms to which they are attached, (i) a 3-7 membered carbocyclic ring or (ii) a 4-7 membered heterocyclic containing 1 or 2 heteroatoms selected from N, O and S forming a ring, the 3- to 7-membered carbocyclic ring or 4- to 7-membered heterocyclic ring is optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo, halo, cya no, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

each R ^6a , R ^6b , R ^10a and R ^10b is independently H, halo, C _1-4 haloalkyl or C _1-6 alkyl;

(i) R ^6a and R ^6b or (ii) R ^10a and R ^10b , together with the carbon atom to which each is attached, is (i) a 5- to 10-membered carbocyclic ring, (ii) N, O and a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, (iii) a 6-10 membered aromatic ring, or (iv) 1 to 3 members selected from N, O and S form a 5-10 membered heteroaromatic ring containing heteroatoms, a 5-10 membered carbocyclic ring, a 5-10 membered heterocyclic ring, a 6-10 membered aromatic ring, or a 5-10 membered ring the heteroaromatic ring is optionally substituted with 1 to 4 R ^A4 , each R ^A4 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

R ⁷ is H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, C(O)R ^c or SO ₂ R ^c ;

R ¹¹ is H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, -C(O)-R ^a , -S(O) _n- R ^a , -CH ₂ - R ^a ;

each R ^a is independently (i) H, (ii) C _1-6 alkyl, (iii) C _3-6 cycloalkyl, (iv) 5-10 membered carbocyclic ring, (v) N, O and 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, (vi) 6-10 membered aromatic ring, or (iv) 1 to 3 membered selected from N, O and S a 5- to 10-membered heteroaromatic ring containing heteroatoms;

C _1-6 alkyl, C _3-6 cycloalkyl, 5-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring is (i) oxo (ii) halo, (iii) cyano, (iv) -OC _1-4 alkyl, (v) C _1-6 alkyl, (vi) -OR ^e , (vii) 3- to 10-membered carbo cyclic ring, (viii) a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, (ix) 6-10 membered aromatic ring, or (x) N; optionally substituted with 0 to 4 substituents independently selected from the group consisting of 5 to 10 membered heteroaromatic rings containing 1 to 3 heteroatoms selected from O and S; the 3-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A5 ; , each R ^A5 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

R ^b is H, C _1-4 alkyl, C _1-4 haloalkyl or C _3-6 cycloalkyl;

R ^f is H, halo, C _1-4 alkyl or C _1-4 haloalkyl;

each R ^c is independently H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl; C(O)R ^d or —SO ₂ R ^d ;

each R ^d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, —NR ^e ₂ or —OR ^e ;

each R ^e is independently H, C _1-4 alkyl or C _3-6 cycloalkyl, each C _1-4 alkyl or C _3-6 cycloalkyl optionally substituted with halo or cyano;

each n is 0, 1 or 2.

In another embodiment, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another embodiment, the present disclosure provides a kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and instructions for use.

In another embodiment, the present disclosure provides a method of treating HIV infection in a human having or at risk of having an infection, said method comprising a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof , or administering a pharmaceutical composition of the present disclosure to a human.

In another embodiment, the present disclosure relates to the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for the treatment of HIV infection in a human having or at risk of having an infection. provides

In another aspect, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in medical treatment.

In another embodiment, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in treating HIV infection.

In another aspect, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a medicament of the present disclosure, in the manufacture of a medicament for treating an HIV infection in a human having or at risk of having an infection. Use of the pharmaceutical composition is provided.

In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments disclosed herein. However, it will be understood by one of ordinary skill in the art that the embodiments disclosed herein may be practiced without these details. The following description of several embodiments is made with the understanding that the present disclosure is to be regarded as an exemplification of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are provided for convenience only and are not to be construed as limiting the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

I. Justice

Unless the context requires otherwise, throughout this disclosure and the claims, the word "comprises" and its variations, such as "comprises" and "comprising," are used in an open and inclusive sense, i.e., "comprising". but not limited to these".

Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment disclosed herein. Thus, the appearances of the phrases "in one embodiment" or "in one embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Moreover, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

“Amino” refers to the —NH ₂ radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

"Oxo" refers to the =O substituent.

A prefix such as "C _uv " or (C _u -C _v ) indicates that the group that follows has u to v carbon atoms. For example, “C _1-6 alkyl” indicates that the alkyl group has 1 to 6 carbon atoms.

"Alkyl" is saturated and has 1 to 12 carbon atoms (C _1-12 alkyl), in certain embodiments 1 to 8 carbon atoms (C _1-8 alkyl), or 1 to 6 carbon atoms (C _1-6 alkyl), or a straight or branched chain hydrocarbon radical having 1 to 4 carbon atoms (C _1-4 alkyl) and consisting of carbon and hydrogen atoms attached to the remainder of the molecule by a single bond, for example methyl , ethyl, n -propyl, 1-methylethyl ( iso -propyl), n -butyl, 1-methylpropyl ( sec -butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (t- butyl), n -pentyl, hexyl, 3-methylhexyl, 2-methylhexyl, and the like.

"Alkylene" refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane do. For example, an alkylene group can have from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. Typical alkylene radicals are methylene (-CH ₂ -), 1,1 ethyl (-CH(CH ₃ )-), 1,2-ethyl (-CH ₂ CH ₂ -), 1,1-propyl (-CH (CH ₂ CH ₃ )-), 1,2-propyl (-CH ₂ CH(CH ₃ )-), 1,3-propyl (-CH ₂ CH ₂ CH ₂ -), 1,4-butyl (-CH ₂ CH ₂ CH ₂ CH ₂ -) and the like.

“Aryl” or “aromatic ring” refers to an aromatic carbocyclic group having a single ring (eg, monocyclic) or multiple rings (eg, bicyclic or tricyclic), including fused systems. As used herein, aryl is from 6 to 20 ring carbon atoms (ie, C _6-20 aryl), from 6 to 12 carbon ring atoms (ie, C _6-12 aryl), or from 6 to 10 has carbon ring atoms (ie, C _6-10 aryl). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not in any way include or overlap with heteroaryl as defined below.

"Cyano" or "carbonitrile" refers to the group -CN.

“Cycloalkyl” or “carbocyclic ring” refers to a saturated or partially saturated cyclic alkyl group having a single ring or having multiple rings, including fused, bridged and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (ie, cyclic groups having at least one double bond). As used herein, cycloalkyl is 3 to 20 ring carbon atoms (ie, C _3-20 cycloalkyl), 3 to 12 ring carbon atoms (ie, C _3-12 cycloalkyl), 3 to 10 ring carbon atoms (ie, C _3-10 cycloalkyl), 3 to 8 ring carbon atoms (ie, C _3-8 cycloalkyl), or 3 to 6 ring carbon atoms (ie, C ₃ ) _-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. "Halocycloalkyl" refers to a cycloalkyl substituted by one or more halogens.

"Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.

"Haloalkyl" refers to an alkyl group as defined above substituted by one or more halo radicals as defined above, for example trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-tri fluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

"Heteroaryl" or "heteroaromatic ring" refers to an aromatic group having a single ring, multiple rings or multiple fused rings having one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. As used herein, heteroaryl is 5 to 20 ring atoms (5- to 20-membered heteroaromatic ring) independently selected from nitrogen, oxygen and sulfur, 5 to 12 ring atoms (5- to 12-membered) heteroaromatic ring), 5 to 10 ring atoms (5 to 10 membered heteroaromatic ring) or 5 to 6 ring atoms (5 to 6 membered heteroaromatic ring); and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl and pyrazolyl. Heteroaryl does not include or overlap with aryl as defined above.

“Heterocyclyl” or “heterocyclic ring” refers to a non-aromatic radical or ring having 3 to 15 atoms, wherein 1 to 6 atoms are selected from the group consisting of nitrogen, oxygen and sulfur and are single A heteroatom attached to the rest of the molecule by a bond. In certain embodiments, "heterocyclyl" has 3 to 10 atoms, wherein 1 to 4 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or 3 to 7 atoms , wherein 1 to 2 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen, carbon or sulfur atom in the heterocyclyl may be optionally oxidized; The nitrogen atom may optionally be quaternized. As used herein, "heterocyclyl" or "heterocyclic ring", unless otherwise indicated, refers to a saturated ring, e.g., in some embodiments "heterocyclyl" or "heterocyclic" A "click ring", where described, refers to a saturated or partially saturated ring. Examples of such heterocyclyls are dioxolanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl , oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, tritianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl.

Embodiments disclosed herein are also intended to include all pharmaceutically acceptable compounds of formula (I) that are isotopically labeled by having one or more atoms replaced by atoms having a different atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds are ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ , respectively. isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I. In certain embodiments, this radiolabeled compound is useful to aid in determining or measuring the effectiveness of a compound, for example, by elucidating the site or mode of action, or binding affinity for a pharmacologically important site of action. Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII labeled with specific isotopes , compounds of VIIIa or VIIIb, for example incorporating radioactive isotopes, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, ie ³ H, and carbon-14, ie ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and prepared detection means.

In certain embodiments, substitution with a heavier isotope such as deuterium, ie ² H, may provide certain therapeutic benefits resulting from greater metabolic stability. For example, the in vivo half-life may be increased, or the dosage required may be decreased. As such, heavier isotopes may be desirable in some situations.

Substitution with positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N may be useful in positron emission tomography (PET) studies to investigate substrate receptor occupancy. Isotopes of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb Elementally labeled compounds can be prepared by routine techniques known to those skilled in the art or by processes analogous to those described in the examples given below using appropriate isotopically labeled reagents instead of previously used unlabeled reagents. have.

The methods, compositions, kits and articles of manufacture provided herein can be prepared by using a compound (e.g., Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI , VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb) or a pharmaceutically acceptable salt thereof, wherein 1 to n hydrogen atoms attached to a carbon atom are deuterium atoms or may be replaced by D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Since such compounds may increase metabolic resistance, they are useful for increasing the half-life of a compound or a pharmaceutically acceptable salt thereof when administered to a mammal. See, eg, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci ., 5(12):524-527 (1984)]. Such compounds may be synthesized by means known in the art, for example using starting materials in which one or more hydrogen atoms are replaced with deuterium.

Embodiments disclosed herein are also intended to include in vivo metabolic products of the disclosed compounds. Such products may arise primarily from enzymatic processes, for example from oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound. Accordingly, embodiments disclosed herein include compounds prepared by a process comprising administering to a mammal a compound according to embodiments disclosed herein for a period of time sufficient to produce a metabolite thereof. Such products are typically administered to an animal, such as a rat, mouse, guinea pig, monkey or human, in a detectable dose of a radiolabeled compound according to embodiments disclosed herein to allow sufficient time for metabolism to occur, urine, blood or by isolating a product of its conversion in another biological sample.

"Mammal" includes both human and domestic animals, such as laboratory animals and pet animals (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits), and non-domestic animals, such as wild animals, and the like. do.

“Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the specification includes instances where the event or circumstance does and does not. For example, "optionally substituted heterocyclyl" means that the heterocyclyl radical may or may not be substituted and that the description includes both substituted heterocyclyl radicals and heterocyclyl radicals having no substitution. it means.

"Pharmaceutically acceptable excipient" means, without limitation, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent Agents, solvents, emulsifiers, or other agents formulated in combination with the pharmacologically active ingredient of a pharmaceutical composition, compatible with the other ingredients of the formulation, and suitable for use in humans or livestock animals without undue toxicity, irritation, allergic reaction, etc. Contains pharmacologically inactive substances.

Examples of “pharmaceutically acceptable salts” of the compounds disclosed herein include suitable bases such as alkali metals (eg, sodium), alkaline earth metals (eg, magnesium), ammonium and NX ₄ ⁺ , where X is C _1-4 alkyl). Pharmaceutically acceptable salts of nitrogen atoms or amino groups include, for example, organic carboxylic acids such as acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, butyric acid, camphor acid, cinnamic acid, citric acid, digluco. Lonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, formic acid, hexanoic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, hydroxymaleic acid, malonic acid, malic acid, mandelic acid, isethionic acid, lactobionic acid, nicotinic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, sulfanilic acid, tartaric acid, undecanoic acid and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, mesitylenesulfonic acid, benzenesulfone, p-toluenesulfonic acid, naphthalenesulfonic acid and 2-naphthalenesulfonic acid; and salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, sulfuric acid and sulfamic acid. Pharmaceutically acceptable salts of a compound of a hydroxy group include an anion of the compound in combination with a suitable cation such as Na ⁺ and NX ₄ ⁺ , wherein X is independently selected from H or a C _1-4 alkyl group. do.

For therapeutic use, salts of the active ingredients of the compounds disclosed herein will typically be pharmaceutically acceptable, ie they will be salts derived from physiologically acceptable acids or bases. However, salts of acids or bases that are not pharmaceutically acceptable may also be used, for example, in the preparation or purification of compounds of Formula I or other compounds of the embodiments disclosed herein. All salts, whether derived from physiologically acceptable acids or bases, are within the scope of the embodiments disclosed herein.

Metal salts are typically prepared by reacting a metal hydroxide with a compound according to embodiments disclosed herein. Examples of metal salts prepared in this way are salts containing Li ⁺ , Na ⁺ and K ⁺ . A less soluble metal salt may be precipitated from a solution of the more soluble salt by addition of a suitable metal compound.

Furthermore, salts can be formed from acid addition of certain organic and inorganic acids, for example HCl, HBr, H 2 SO ₄ , H ₃ PO ₄ or organic sulfonic acids, to a basic center, usually an amine. Finally, it is to be understood that the compositions herein include the compounds disclosed herein in their zwitterionic as well as non-ionized forms.

"Pharmaceutical composition" refers to the formulation of a compound of the embodiments disclosed herein and a medium generally accepted in the art for delivery of the biologically active compound to a mammal, eg, a human. This medium includes all pharmaceutically acceptable excipients.

An “effective amount” or “therapeutically effective amount” refers to an amount of a compound according to embodiments disclosed herein sufficient to effect treatment of a disease-state, condition or disorder disclosed herein when administered to a patient in need thereof. Such an amount will be sufficient to cause a biological or medical response of the patient, or tissue system, sought by the investigator or clinician. The amount of a compound according to the embodiments disclosed herein that constitutes a therapeutically effective amount depends on the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the disease-state or disorder being treated. The type and severity thereof will depend on factors such as the drug used in combination or concomitantly with the compounds of the embodiments disclosed herein, and the patient's age, weight, general health, sex and diet. Such a therapeutically effective amount can be determined by one of ordinary skill in the art in light of his own knowledge, state of the art and this disclosure.

As used herein, terms such as “treating” and “treatment” refer to a compound or composition according to the present embodiment disclosed herein to alleviate or eliminate one or more symptoms of HIV infection and/or to reduce the viral load in a patient. is intended to mean the administration of In certain embodiments, the terms "treating" and "treatment" are also used to prevent the appearance of symptoms of a disease after exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or before detection of the virus in the blood. and/or by administration of a compound or composition according to the present embodiments disclosed herein to prevent the virus from reaching detectable levels in the blood, and administration to the mother before the date of birth and to the child within the first day of life, from mother to baby. and administration of a compound or composition according to the present embodiment disclosed herein for preventing perinatal transmission of HIV. The terms "treating" and "treatment" are also used to prevent HIV infection from becoming established upon exposure of an individual to the virus and/or to keep the virus from establishing a permanent infection and/or to prevent the appearance of symptoms of a disease. Administration of a compound or composition according to this embodiment disclosed herein prior to exposure of an individual to a virus (also called pre-exposure prophylaxis or PrEP) to prevent and/or prevent the virus from reaching detectable levels in the blood. include The terms “treating” and “treatment” also include administration of a compound or composition according to the present embodiments disclosed herein both before and after exposure of an individual to a virus.

As used herein, the terms "preventing" and "prevention" refer to a compound according to the present disclosure before or after exposure of a human to a virus, but before the appearance of symptoms of a disease, and/or prior to detection of the virus in the blood; composition, or pharmaceutically refers to administration of a salt. The term also refers to preventing the appearance of symptoms of a disease and/or preventing the virus from reaching detectable levels in the blood. The term includes both pre-exposure prophylaxis (PrEP) as well as post-exposure prophylaxis (PEP) and prophylactic events that are driven or “on demand”. The term also refers to the prevention of perinatal transmission of HIV from mother to child by administration to the mother before the date of birth and to the child within the first day of life. The term also refers to the prevention of transmission of HIV through blood transfusion.

The term "antiviral agent" as used herein refers to, by way of non-limiting example, the formation and/or replication of a virus in humans, including substances that interfere with host or viral mechanisms necessary for the formation and/or replication of the virus in humans. It is intended to mean an agent (compound or biological agent) effective to inhibit.

The term "inhibitor of HIV replication" as used herein is intended to mean an agent capable of reducing or abrogating the ability of HIV to replicate in a host cell, either in vitro, ex vivo or in vivo.

A compound of the embodiments disclosed herein, or a pharmaceutically acceptable salt thereof, contains one or more asymmetric centers, and as such, (R)- or (S)- in terms of absolute stereochemistry, or (D) in the case of amino acids. -or (L)- can form enantiomers, diastereomers and other stereoisomers. This disclosure is meant to include all such possible stereoisomers, as well as their racemic, scalemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L) isomers are prepared using chiral synthons or chiral reagents, or by methods such as chromatography and fractional crystallization. can be partitioned using Techniques for the preparation/separation of individual enantiomers include chiral synthesis from appropriate optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). includes When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E geometric isomers and Z geometric isomers. Likewise, all tautomers are intended to be included.

“Stereoisomers” refer to compounds that are made of the same atoms held together by the same bonds but have different three-dimensional structures that are not interchangeable. This disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers", which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another. In any of the embodiments disclosed herein, the compounds disclosed herein may be in the form of stereoisomers thereof.

“Partially unsaturated” refers to a cyclic group that is not aromatic but contains at least one double bond.

II. compound

Disclosed herein are compounds of formula (I), or pharmaceutically acceptable salts thereof:

[Formula I]

In the above formula,

R ¹ is H, C _6-10 aryl or C _6-10 heteroaryl, C _6-10 aryl or C _6-10 heteroaryl is optionally substituted with 1 to 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, —OC _1-4 alkyl or C _1-4 alkyl-OC _1-4 alkyl;

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

및

로 이루어진 군으로부터 선택되고;Y is -C(O)NH-,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

is selected from the group consisting of;

L is -CR ^3a R ^3b- , -C(O)-, -SO _2- , -CR ^3a R ^3b -CR ^3c R ^3d- or -N(R ^a )-;

W ¹ is a bond or -CR ^4a R ^4b- ;

W ² is -CR ^5a R ^5b- , -CR ^5a R ^5b CR ^5c R ^5d- , -CR ^6a =CR ^6b- , -N(R ⁷ )-, -O-, -S(O) _n- , - C(O)NR ^e -, -CR ^5a R ^5b- N(R ⁷ )-, -CR ^5a R ^5b- O-, -CR ^5a R ^5b- S(O) _n- , -CR ^5a R ^5b- C (O)NR ^e- or -CR ^5a R ^5b- NR ^e- C(O)-; -S(O) _n N(R ^e ) -CR ^5a R ^5b- , -N(R ^e ) -S(O) _n- CR ^5a R ^5b- , -N(R ^e )-C(O)-CR ^5a R ^5b- or -CR ^5a R ^5b- NR ^e- C(O)-;

X is a bond or -CR ^8a R ^8b- ;

Z is -CR ^9a R ^9b- , -CR ^9a R ^9b CR ^9c R ^9d- or -CR ^10a =CR ^10b- ;

이고;T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d , U is -NR ^11- , ^- CR ^12a R ^12b- , -S(O) _n- , -C(O) - or -O-; T and U together

ego;

R ^2a , R ^2b , R ^2c , R ^2d , R ^12a and R ^12b are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, Halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a _, -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , - C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ;

(i) R ^2a and R ^2b , (ii) R ^2c and R ^2d or (iii) R ^12a and R ^12b together with the carbon atom to which they are attached are (i) 3-7 membered carbocyclic ring or (ii) a 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, a 3-7 membered carbocyclic ring or a 4-7 membered heteroatom the cyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

R ^3a and R ^3b are independently H, C _1-6 alkyl, C _1-4 haloalkyl or —OC _1-4 alkyl;

(i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, represent (i) a 3- to 7-membered carbocyclic ring or (ii) N, O and form a 3-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, the 3-7 membered carbocyclic ring or the 3-7 membered heterocyclic ring having 1 to 3 members optionally substituted with R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

R ^4a , R ^4b , R ^5a , R ^5b , R ^5c , R ^5d , R ^8a , R ^8b , R ^9a , R ^9b , R ^9c and R ^9d are independently H, C _1-6 alkyl, C _1-4 haloalkyl, halo, hydroxyl, cyano, -OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl;

(i) R ^4a and R ^4b , (ii) R ^5a and R ^5b , (iii) R ^5c and R ^5d , (iv) R ^5a and R ^5c , (v) R ^5b and R ^5d , (vi) R ^8a and any one of R ^8b , (vii) R ^9a and R ^9b , (viii) R ^9c and R ^9d , (ix) R ^9a and R ^9c , (x) R ^9b and R ^9d , (xi) R ^8b and R one of ^5a , R ^5b , R ^5c , R ^5d and R ⁷ , or (xii) one of R ^9a , R ^9b , R ^9c and R ^9d and one of R ^4a , R ^4b , R ^5a , R ^5b and R ⁷ . is, together with the carbon atoms to which they are attached, (i) a 3-7 membered carbocyclic ring or (ii) a 4-7 membered heterocyclic ring containing 0-2 heteroatoms selected from N, O and S wherein the 3- to 7-membered carbocyclic ring or 4- to 7-membered heterocyclic ring is optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo, halo, cyano , C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

each R ^6a , R ^6b , R ^10a and R ^10b is independently H, halo, C _1-4 haloalkyl or C _1-6 alkyl;

(i) R ^6a and R ^6b or (ii) R ^10a and R ^10b , together with the carbon atom to which each is attached, is (i) a 5- to 10-membered carbocyclic ring, (ii) N, O and a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, (iii) a 6-10 membered aromatic ring, or (iv) 1 to 3 members selected from N, O and S form a 5-10 membered heteroaromatic ring containing heteroatoms, a 5-10 membered carbocyclic ring, a 5-10 membered heterocyclic ring, a 6-10 membered aromatic ring, or a 5-10 membered ring the heteroaromatic ring is optionally substituted with 1 to 4 R ^A4 , each R ^A4 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

R ⁷ is H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, C(O)R ^c or SO ₂ R ^c ;

R ¹¹ is H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, -C(O)-R ^a , -S(O) _n- R ^a , -CH ₂ - R ^a ;

each R ^a is independently (i) H, (ii) C _1-6 alkyl, (iii) C _3-6 cycloalkyl, (iv) 5-10 membered carbocyclic ring, (v) N, O and 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, (vi) 6-10 membered aromatic ring, or (iv) 1 to 3 membered selected from N, O and S a 5- to 10-membered heteroaromatic ring containing heteroatoms; C _1-6 alkyl, C _3-6 cycloalkyl, 5-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring is (i) oxo (ii) halo, (iii) cyano, (iv) -OC _1-4 alkyl, (v) C _1-6 alkyl, (vi) -OR ^e (vii) 3- to 10-membered carbocy a click ring, (viii) a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, (ix) a 6-10 membered aromatic ring, or (x) N, O and 0-4 substituents independently selected from the group consisting of a 5- to 10-membered heteroaromatic ring containing 1-3 heteroatoms selected from S; the 3-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A5 ; , each R ^A5 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

R ^b is H, C _1-4 alkyl, C _1-4 haloalkyl or C _3-6 cycloalkyl;

R ^f is H, halo, C _1-4 alkyl or C _1-4 haloalkyl;

each R ^c is independently H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, C(O)R ^d or —SO ₂ R ^d ego;

each R ^d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, —NR ^e ₂ or —OR ^e ;

each R ^e is independently H, C _1-4 alkyl or C _3-6 cycloalkyl, each C _1-4 alkyl or C _3-6 cycloalkyl optionally substituted with halo or cyano;

each n is 0, 1 or 2.

In some embodiments, in the compound of Formula I, R ¹ is H, C _6-10 aryl or C _6-10 heteroaryl, and C _6-10 aryl or C _6-10 heteroaryl is 1-4 R ^A1 optionally substituted by , and each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _{3- 6} cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl;

,

,

,

,

,

,

,

,

,

,

,

,

,

,

및

로 이루어진 군으로부터 선택되고;Y is -C(O)NH-,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

is selected from the group consisting of;

L is -CR ^3a R ^3b- , -C(O)-, -SO _2- , -CR ^3a R ^3b -CR ^3c R ^3d- or -N(R ^a )-;

W ¹ is a bond or -CR ^4a R ^4b- ;

W ² is -CR ^5a R ^5b- , -CR ^5a R ^5b CR ^5c R ^5d- , -CR ^6a =CR ^6b- , -N(R ⁷ )-, -O-, -S(O) _n- , - C(O)NR ^e -, -CR ^5a R ^5b- N(R ⁷ )-, -CR ^5a R ^5b- O-, -CR ^5a R ^5b- S(O) _n- , -CR ^5a R ^5b- C (O)NR ^e- , -CR ^5a R ^5b- NR ^e- C(O)-, -S(O) _n N(R ^e ) -CR ^5a R ^5b- or -N(R ^e ) -S(O ) _n- CR ^5a R ^5b- ;

X is a bond or -CR ^8a R ^8b- ;

Z is -CR ^9a R ^9b- , -CR ^9a R ^9b CR ^9c R ^9d- or -CR ^10a =CR ^10b- ;

이고;T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d ; U is -NR ^{11- ,} -CR ^12a R ^12b- , -S(O) _n- , -C(O) - or -O-; T and U together

ego;

R ^2a , R ^2b , R ^2c , R ^2d , R ^12a and R ^12b are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, Halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a _, -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , - C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ;

(i) R ^2a and R ^2b , (ii) R ^2c and R ^2d or (iii) R ^12a and R ^12b together with the carbon atom to which they are attached are (i) 3-7 membered carbocyclic ring or (ii) a 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, a 3-7 membered carbocyclic ring or a 4-7 membered heteroatom the cyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or —OC _1-4 alkyl;

R ^4a , R ^4b , R ^5a , R ^5b , R ^5c , R ^5d , R ^8a , R ^8b , R ^9a , R ^9b , R ^9c and R ^9d are independently H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, hydroxyl, cyano, —OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl;

each R ^6a , R ^6b , R ^10a and R ^10b is independently H, halo, C _1-4 haloalkyl or C _1-6 alkyl;

R ⁷ is H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, C(O)R ^c or SO ₂ R ^c ;

R ¹¹ is H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, -C(O)-R ^a , -S(O) _n- R ^a , -CH ₂ - R ^a ;

each R ^a is independently (i) H, (ii) C _1-6 alkyl, (iii) C _3-6 cycloalkyl, (iv) 5-10 membered carbocyclic ring, (v) N, O and 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, (vi) 6-10 membered aromatic ring, or (iv) 1 to 3 membered selected from N, O and S a 5- to 10-membered heteroaromatic ring containing heteroatoms;

C _1-6 alkyl, C _3-6 cycloalkyl, 5-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring is (i) oxo (ii) halo, (iii) cyano, (iv) -OC _1-4 alkyl, (v) C _1-6 alkyl, (vi) -OR ^e (vii) 3- to 10-membered carbocy a click ring, (viii) a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, (ix) a 6-10 membered aromatic ring, or (x) N, O and 0-4 substituents independently selected from the group consisting of a 5- to 10-membered heteroaromatic ring containing 1-3 heteroatoms selected from S; the 3-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A5 ; , each R ^A5 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

R ^b is H, C _1-4 alkyl, C _1-4 haloalkyl or C _3-6 cycloalkyl;

R ^f is H, halo, C _1-4 alkyl or C _1-4 haloalkyl;

each R ^c is independently H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl; C(O)R ^d or —SO ₂ R ^d ;

each R ^d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, —NR ^e ₂ or —OR ^e ;

each R ^e is independently H, C _1-4 alkyl or C _3-6 cycloalkyl, each C _1-4 alkyl or C _3-6 cycloalkyl optionally substituted with halo or cyano;

each n is 0, 1 or 2.

In some embodiments, in the compound of Formula I,

R ¹ is H, C _6-10 aryl or C _6-10 heteroaryl, C _6-10 aryl or C _6-10 heteroaryl optionally substituted by 1 to 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl;

,

,

,

,

,

,

,

,

,

,

,

,

,

,

및

로 이루어진 군으로부터 선택되고;Y is -C(O)NH-,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

is selected from the group consisting of;

L is -CR ^3a R ^3b- , -C(O)-, -SO _2- , -CR ^3a R ^3b -CR ^3c R ^3d- or -N(R ^a )-;

W ¹ is a bond or -CR ^4a R ^4b- ;

W ² is -CR ^5a R ^5b- , -CR ^5a R ^5b CR ^5c R ^5d- , -CR ^6a =CR ^6b- , -N(R ⁷ )-, -O-, -S(O) _n- , - C(O)NR ^e -, -CR ^5a R ^5b- N(R ⁷ )-, -CR ^5a R ^5b- O-, -CR ^5a R ^5b- S(O) _n- , -CR ^5a R ^5b- C (O)NR ^e- , -CR ^5a R ^5b- NR ^e- C(O)-, -S(O) _n N(R ^e ) -CR ^5a R ^5b- or -N(R ^e ) -S(O ) _n- CR ^5a R ^5b- ;

X is a bond or -CR ^8a R ^8b- ;

Z is -CR ^9a R ^9b- , -CR ^9a R ^9b CR ^9c R ^9d- or -CR ^10a =CR ^10b- ;

이고;T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d ; U is -NR ^{11- ,} -CR ^12a R ^12b- , -S(O) _n- , -C(O) - or -O-; T and U together

ego;

R ^2a , R ^2b , R ^2c , R ^2d , R ^12a and R ^12b are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, Halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a _, -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , - C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ;

R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or —OC _1-4 alkyl;

(i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, represent (i) a 3- to 7-membered carbocyclic ring or (ii) N, O and form a 3-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, the 3-7 membered carbocyclic ring or the 3-7 membered heterocyclic ring having 1 to 3 members optionally substituted with R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

R ^4a , R ^4b , R ^5a , R ^5b , R ^5c , R ^5d , R ^8a , R ^8b , R ^9a , R ^9b , R ^9c and R ^9d are independently H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, hydroxyl, cyano, —OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl;

each R ^6a , R ^6b , R ^10a and R ^10b is independently H, halo, C _1-4 haloalkyl or C _1-6 alkyl;

R ⁷ is H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, C(O)R ^c or SO ₂ R ^c ;

R ¹¹ is H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, -C(O)-R ^a , -S(O) _n- R ^a , -CH ₂ - R ^a ;

each R ^a is independently (i) H, (ii) C _1-6 alkyl, (iii) C _3-6 cycloalkyl, (iv) 5-10 membered carbocyclic ring, (v) N, O and 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, (vi) 6-10 membered aromatic ring, or (iv) 1 to 3 membered selected from N, O and S a 5- to 10-membered heteroaromatic ring containing heteroatoms;

C _1-6 alkyl, C _3-6 cycloalkyl, 5-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring is (i) oxo (ii) halo, (iii) cyano, (iv) -OC _1-4 alkyl, (v) C _1-6 alkyl, (vi) -OR ^e (vii) 3- to 10-membered carbocy a click ring, (viii) a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, (ix) a 6-10 membered aromatic ring, or (x) N, O and 0-4 substituents independently selected from the group consisting of a 5- to 10-membered heteroaromatic ring containing 1-3 heteroatoms selected from S; the 3-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A5 ; , each R ^A5 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

R ^b is H, C _1-4 alkyl, C _1-4 haloalkyl or C _3-6 cycloalkyl;

R ^f is H, halo, C _1-4 alkyl or C _1-4 haloalkyl;

each R ^c is independently H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl; C(O)R ^d or —SO ₂ R ^d ;

each R ^d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, —NR ^e ₂ or —OR ^e ;

each R ^e is independently H, C _1-4 alkyl or C _3-6 cycloalkyl, each C _1-4 alkyl or C _3-6 cycloalkyl optionally substituted with halo or cyano;

each n is 0, 1 or 2.

In some embodiments, in the compound of Formula I,

R ¹ is H, C _6-10 aryl or C _6-10 heteroaryl, C _6-10 aryl or C _6-10 heteroaryl optionally substituted by 1 to 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl;

,

,

,

,

,

,

,

,

,

,

,

,

,

,

및

로 이루어진 군으로부터 선택되고;Y is -C(O)NH-,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

is selected from the group consisting of;

L is -CR ^3a R ^3b- , -C(O)-, -SO _2- , -CR ^3a R ^3b -CR ^3c R ^3d- or -N(R ^a )-;

W ¹ is a bond or -CR ^4a R ^4b- ;

W ² is -CR ^5a R ^5b- , -CR ^5a R ^5b CR ^5c R ^5d- , -CR ^6a =CR ^6b- , -N(R ⁷ )-, -O-, -S(O) _n- , - C(O)NR ^e -, -CR ^5a R ^5b- N(R ⁷ )-, -CR ^5a R ^5b- O-, -CR ^5a R ^5b- S(O) _n- , -CR ^5a R ^5b- C (O)NR ^e- , -CR ^5a R ^5b- NR ^e- C(O)-, -S(O) _n N(R ^e ) -CR ^5a R ^5b- or -N(R ^e ) -S(O ) _n- CR ^5a R ^5b- ;

X is a bond or -CR ^8a R ^8b- ;

Z is -CR ^9a R ^9b- , -CR ^9a R ^9b CR ^9c R ^9d- or -CR ^10a =CR ^10b- ;

이고;T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d ; U is -NR ^{11- ,} -CR ^12a R ^12b- , -S(O) _n- , -C(O) - or -O-; T and U together

ego;

R ^2a , R ^2b , R ^2c , R ^2d , R ^12a and R ^12b are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, Halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a _, -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , - C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ;

R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or —OC _1-4 alkyl;

R ^4a , R ^4b , R ^5a , R ^5b , R ^5c , R ^5d , R ^8a , R ^8b , R ^9a , R ^9b , R ^9c and R ^9d are independently H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, hydroxyl, cyano, —OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl;

(i) R ^4a and R ^4b , (ii) R ^5a and R ^5b , (iii) R ^5c and R ^5d , (iv) R ^5a and R ^5c , (v) R ^5b and R ^5d , (vi) R ^8a and any one of R ^8b , (vii) R ^9a and R ^9b , (viii) R ^9c and R ^9d , (ix) R ^9a and R ^9c , (x) R ^9b and R ^9d , (xi) R ^8b and R one of ^5a , R ^5b , R ^5c , R ^5d and R ⁷ , or (x) one of R ^9a , R ^9b , R ^9c and R ^9d and one of R ^4a , R ^4b , R ^5a , R ^5b and R ⁷ . are, together with the carbon atoms to which they are attached, (i) a 3-7 membered carbocyclic ring or (ii) a 4-7 membered heterocyclic containing 1 or 2 heteroatoms selected from N, O and S forming a ring, the 3- to 7-membered carbocyclic ring or 4- to 7-membered heterocyclic ring is optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo, halo, cya no, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

each R ^6a , R ^6b , R ^10a and R ^10b is independently H, halo, C _1-4 haloalkyl or C _1-6 alkyl;

R ⁷ is H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, C(O)R ^c or SO ₂ R ^c ;

R ¹¹ is H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, -C(O)-R ^a , -S(O) _n- R ^a , -CH ₂ - R ^a ;

each R ^a is independently (i) H, (ii) C _1-6 alkyl, (iii) C _3-6 cycloalkyl, (iv) 5-10 membered carbocyclic ring, (v) N, O and 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, (vi) 6-10 membered aromatic ring, or (iv) 1 to 3 membered selected from N, O and S a 5- to 10-membered heteroaromatic ring containing heteroatoms;

C _1-6 alkyl, C _3-6 cycloalkyl, 5-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring is (i) oxo (ii) halo, (iii) cyano, (iv) -OC _1-4 alkyl, (v) C _1-6 alkyl, (vi) -OR ^e (vii) 3- to 10-membered carbocy a click ring, (viii) a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, (ix) a 6-10 membered aromatic ring, or (x) N, O and 0-4 substituents independently selected from the group consisting of a 5- to 10-membered heteroaromatic ring containing 1-3 heteroatoms selected from S; the 3-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A5 ; , each R ^A5 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

R ^b is H, C _1-4 alkyl, C _1-4 haloalkyl or C _3-6 cycloalkyl;

R ^f is H, halo, C _1-4 alkyl or C _1-4 haloalkyl;

each R ^c is independently H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl; C(O)R ^d or —SO ₂ R ^d ;

each R ^d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, —NR ^e ₂ or —OR ^e ;

each R ^e is independently H, C _1-4 alkyl or C _3-6 cycloalkyl, each C _1-4 alkyl or C _3-6 cycloalkyl optionally substituted with halo or cyano;

each n is 0, 1 or 2.

In some embodiments, in the compound of Formula I,

R ¹ is H, C _6-10 aryl or C _6-10 heteroaryl, C _6-10 aryl or C _6-10 heteroaryl optionally substituted by 1 to 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl;

,

,

,

,

,

,

,

,

,

,

,

,

,

,

및

로 이루어진 군으로부터 선택되고;Y is -C(O)NH-,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

is selected from the group consisting of;

L is -CR ^3a R ^3b- , -C(O)-, -SO _2- , -CR ^3a R ^3b -CR ^3c R ^3d- or -N(R ^a )-;

W ¹ is a bond or -CR ^4a R ^4b- ;

W ² is -CR ^5a R ^5b- , -CR ^5a R ^5b CR ^5c R ^5d- , -CR ^6a =CR ^6b- , -N(R ⁷ )-, -O-, -S(O) _n- , - C(O)NR ^e -, -CR ^5a R ^5b- N(R ⁷ )-, -CR ^5a R ^5b- O-, -CR ^5a R ^5b- S(O) _n- , -CR ^5a R ^5b- C (O)NR ^e- , -CR ^5a R ^5b- NR ^e- C(O)-, -S(O) _n N(R ^e ) -CR ^5a R ^5b- or -N(R ^e ) -S(O) ) _n- CR ^5a R ^5b- ;

X is a bond or -CR ^8a R ^8b- ;

Z is -CR ^9a R ^9b- , -CR ^9a R ^9b CR ^9c R ^9d- or -CR ^10a =CR ^10b- ;

이고;T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d ; U is -NR ^{11- ,} -CR ^12a R ^12b- , -S(O) _n- , -C(O) - or -O-; T and U together

ego;

R ^2a , R ^2b , R ^2c , R ^2d , R ^12a and R ^12b are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, Halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a _, -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , - C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ;

R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or —OC _1-4 alkyl;

R ^4a , R ^4b , R ^5a , R ^5b , R ^5c , R ^5d , R ^8a , R ^8b , R ^9a , R ^9b , R ^9c and R ^9d are independently H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, hydroxyl, cyano, —OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl;

each of R ^6a , R ^6b , R ^10a and R ^10b is independently H, halo, C _1-4 haloalkyl or C _1-6 alkyl;

(i) R ^6a and R ^6b or (ii) R ^10a and R ^10b , together with the carbon atom to which each is attached, is (i) a 5- to 10-membered carbocyclic ring, (ii) N, O and 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, (iii) 6-10 membered aromatic ring, or (iv) 1 to 3 members selected from N, O and S Forms a 5-10 membered heteroaromatic ring containing heteroatoms, a 5-10 membered carbocyclic ring, a 5-10 membered heterocyclic ring, a 6-10 membered aromatic ring, or a 5-10 membered ring the heteroaromatic ring is optionally substituted with 1 to 4 R ^A4 , each R ^A4 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

R ⁷ is H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, C(O)R ^c or SO ₂ R ^c ;

R ¹¹ is H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, -C(O)-R ^a , -S(O) _n- R ^a , —CH ₂ -R ^a ;

each R ^a is independently (i) H, (ii) C _1-6 alkyl, (iii) C _3-6 cycloalkyl, (iv) 5-10 membered carbocyclic ring, (v) N, O and 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, (vi) 6-10 membered aromatic ring, or (iv) 1 to 3 members selected from N, O and S a 5- to 10-membered heteroaromatic ring containing heteroatoms;

C _1-6 alkyl, C _3-6 cycloalkyl, 5-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring is (i) oxo (ii) halo, (iii) cyano, (iv) -OC _1-4 alkyl, (v) C _1-6 alkyl, (vi) -OR ^e (vii) 3- to 10-membered carbocy a click ring, (viii) a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, (ix) a 6-10 membered aromatic ring, or (x) N, O and 0-4 substituents independently selected from the group consisting of a 5- to 10-membered heteroaromatic ring containing 1-3 heteroatoms selected from S; the 3-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A5 ; , each R ^A5 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;

R ^b is H, C _1-4 alkyl, C _1-4 haloalkyl or C _3-6 cycloalkyl;

R ^f is H, halo, C _1-4 alkyl or C _1-4 haloalkyl;

each R ^c is independently H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl; C(O)R ^d or —SO ₂ R ^d ;

each R ^d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, —NR ^e ₂ or —OR ^e ;

each R ^e is independently H, C _1-4 alkyl or C _3-6 cycloalkyl, each C _1-4 alkyl or C _3-6 cycloalkyl optionally substituted with halo or cyano;

each n is 0, 1 or 2.

In some embodiments, the compound of Formula I is a compound of Formula Ia:

[Formula Ia]

.

In some embodiments, the compound of Formula I is a compound of Formula Ib:

[Formula Ib]

.

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

및

로 이루어진 군으로부터 선택된다.In some embodiments for compounds of Formula I, Ia, or Ib, Y is -C(O)NH-,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

is selected from the group consisting of

이다. 일부 실시형태에서, Y는

이다. 일부 실시형태에서, Y는

이다. 일부 실시형태에서, Y는

이다. 일부 실시형태에서, Y는

이다. 일부 실시형태에서, Y는

이다. 일부 실시형태에서, Y는

이다. 일부 실시형태에서, Y는

이다. 일부 실시형태에서, Y는

이다. 일부 실시형태에서, Y는

이다. 일부 실시형태에서, Y는

이다. 일부 실시형태에서, Y는

이다. 일부 실시형태에서, Y는

이다. 일부 실시형태에서, Y는

이다. 일부 실시형태에서, Y는

이다. 일부 실시형태에서, Y는

이다. 일부 실시형태에서, Y는

이다. 일부 실시형태에서, 화학식 I, Ia 또는 Ib의 화합물에 대해, Y는 -CONH-이다.In some embodiments for compounds of Formula I, Ia, or Ib, Y is

to be. In some embodiments, Y is

to be. In some embodiments, Y is

to be. In some embodiments, Y is

to be. In some embodiments, Y is

to be. In some embodiments, Y is

to be. In some embodiments, Y is

to be. In some embodiments, Y is

to be. In some embodiments, Y is

to be. In some embodiments, Y is

to be. In some embodiments, Y is

to be. In some embodiments, Y is

to be. In some embodiments, Y is

to be. In some embodiments, Y is

to be. In some embodiments, Y is

to be. In some embodiments, Y is

to be. In some embodiments, Y is

to be. In some embodiments, for compounds of Formula I, Ia, or Ib, Y is -CONH-.

In some embodiments, the compound of Formula I is a compound of Formula II:

[Formula II]

.

In some embodiments, the compound of Formula I, Ia, or II is a compound of Formula IIa:

[Formula IIa]

.

In some embodiments, the compound of Formula I, Ib, or II is a compound of Formula IIb:

[Formula IIb]

.

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d , and each R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, cyano, —CH ₂ R ^a— , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )- , -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- is; (i) R ^2a and R ^2b or (ii) R ^2c and R ^2d , together with the carbon atom to which they are attached, are either (i) a 3-7 membered carbocyclic ring or (ii) N, O and form a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring having 1 to 3 members optionally substituted with R ^A2 , and each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d , and each R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, cyano, —CH ₂ R ^a— , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )- , -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- is; either (i) R ^2a and R ^2b or (ii) R ^2c and R ^2d , taken together with the carbon atom to which they are attached, form a 3- to 7-membered carbocyclic ring and form a 3- to 7-membered carbocyclic ring The click ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d , and each R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, cyano, —CH ₂ R ^a— , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )- , -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- is; either (i) R ^2a and R ^2b or (ii) R ^2c and R ^2d , taken together with the carbon atom to which they are attached, form a 3- to 5-membered carbocyclic ring, and a 3- to 5-membered carbocyclic ring The click ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d , and each R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, cyano, —CH ₂ R ^a— , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )- , -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- is; either (i) R ^2a and R ^2b or (ii) R ^2c and R ^2d , taken together with the carbon atom to which they are attached, form a 3-membered carbocyclic ring, wherein the 3-membered carbocyclic ring is selected from 1 to optionally substituted with three R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d , and each R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, cyano, —CH ₂ R ^a— , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )- , -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- is; Either (i) R ^2a and R ^2b or (ii) R ^2c and R ^2d , together with the carbon atom to which they are attached, forms a 3-membered carbocyclic ring.

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d , and each R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, cyano, —CH ₂ R ^a— , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )- , -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- is; (i) R ^2a and R ^2b or (ii) R ^2c and R ^2d , together with the carbon atom to which they are attached, are 4 to 7 members containing 1 or 2 heteroatoms selected from N, O and S form a membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d , and each R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, cyano, —CH ₂ R ^a— , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )- , -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- to be. In some embodiments, T is —CR ^2a R ^2b- or —CR ^2a R ^2b -CR ^2c R ^2d , and each R ^2a , R ^2b , R ^2c and R ^2d is independently H, C _1-6 alkyl , C _1-6 Haloalkyl, C _3-6 Cycloalkyl, C _3-6 Halocycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -OR ^a , -OC(O) -NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )- or -NR ^e- C(O)R ^a- . In some embodiments, T is —CR ^2a R ^2b- or —CR ^2a R ^2b -CR ^2c R ^2d , and each R ^2a , R ^2b , R ^2c and R ^2d is independently H, C _1-6 alkyl , C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, cyano, —CH ₂ R ^a- , —CH ₂ OR ^a , or —OR ^a . In some embodiments, T is —CR ^2a R ^2b- or —CR ^2a R ^2b -CR ^2c R ^2d , and each R ^2a , R ^2b , R ^2c and R ^2d is independently H, C _1-6 alkyl , C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, cyano, —CH ₂ OR ^a or —OR ^a . In some embodiments, T is —CR ^2a R ^2b- or —CR ^2a R ^2b -CR ^2c R ^2d , and each R ^2a , R ^2b , R ^2c and R ^2d is independently H, C _1-6 alkyl , C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo or cyano. In some embodiments, T is —CR ^2a R ^2b- or —CR ^2a R ^2b -CR ^2c R ^2d , and each R ^2a , R ^2b , R ^2c and R ^2d is independently H, C _1-6 alkyl , C _1-6 haloalkyl, C _3-6 cycloalkyl or C _3-6 halocycloalkyl. In some embodiments, T is —CR ^2a R ^2b- or —CR ^2a R ^2b -CR ^2c R ^2d , and each R ^2a , R ^2b , R ^2c and R ^2d is independently H, C _1-6 alkyl or C _3-6 cycloalkyl.

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- or --CR ^2a R ^2b -CR ^2c R ^2d ; R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, cyano, — CH ₂ R ^a- , -CH ₂ OR ^a _, -OR ^a , or -NHR ^a . In some embodiments, T is —CR ^2a R ^2b- or —CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a or -OR ^a . In some embodiments, T is —CR ^2a R ^2b- or —CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl or halo. In some embodiments, T is —CR ^2a R ^2b- or —CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H or halo. In some embodiments, T is —CR ^2a R ^2b— or —CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, —C(O)—NH (R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )-, -S(O) _n- R ^a- or -OC(O)-NHR ^a . In some embodiments, T is -CR ^2a R ^2b- or --CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, -OR ^a , -NHR ^a , -C(O)-NH(R ^a ), -NR ^e- C(O)R ^a or -NR ^e- S(O) _n R ^a . In some embodiments, T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, -OR ^a or -OC( O)-NHR ^a . In some embodiments, T is -CR ^2a R ^2b- or --CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, -S(O) _n- NH(R ^a ) or -S(O) _n- R ^a- . In some embodiments, T is -CR ^2a R ^2b- or --CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, halo, cyano, -NHR ^a- or -OR ^a . In some embodiments, T is -CR ^2a R ^2b- or --CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H or -NHR ^a . In some embodiments, T is —CR ^2a R ^2b- or —CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, halo, cyano, or —OR is ^a . In some embodiments, T is -CR ^2a R ^2b- or --CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H or cyano.

In some embodiments, in a compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- and R ^2a and R ^2b , together with the carbon to which they are attached, are (i) ternary to 7 membered carbocyclic ring or (ii) a 4 to 7 membered heteroatom containing 1 or 2 heteroatoms selected from N, O and S, a 3 to 7 membered carbocyclic ring or 4-7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C ₁ -C ₆ alkyl, C ₃ -C ₆ cyclo alkyl or -OR ^e .

In some embodiments, in a compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- and R ^2a and R ^2b , together with the carbon to which they are attached, are 3-7 membered. form a carbocyclic ring, wherein the 3 to 7 membered carbocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or —OR ^e .

In some embodiments, in a compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- and R ^2a and R ^2b , together with the carbon to which they are attached, are 3 to 5 membered. form a carbocyclic ring, wherein the 3 to 5 membered carbocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or —OR ^e .

In some embodiments, in compounds of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- and R ^2a and R ^2b , together with the carbon to which they are attached, are 3 to 5 membered. A 3- to 5-membered carbocyclic ring, which forms a carbocyclic ring.

In some embodiments, in a compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- and R ^2a and R ^2b , together with the carbon to which they are attached, are N, O and S form a 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from, wherein the 4-7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or —OR ^e .

In some embodiments, in a compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- and R ^2a and R ^2b , together with the carbon to which they are attached, are N, O and S form a 4 to 5 membered heterocyclic ring containing 1 or 2 heteroatoms selected from, wherein the 4 to 5 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or —OR ^e .

In some embodiments, in a compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- and R ^2a and R ^2b , together with the carbon to which they are attached, are N, O and S to form a 4-5 membered heterocyclic ring containing 1 or 2 heteroatoms selected from

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- and R ^2a and R ^2b are independently H, C _1-6 alkyl, C _{1 - 6} haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -OR ^a or -NHR ^a . In some embodiments, T is —CR ^2a R ^2b— and R ^2a and R ^2b are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halo cycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a or -OR ^a . In some embodiments, T is —CR ^2a R ^2b— and R ^2a and R ^2b are independently H, _{C1-6 alkyl, C 1-6 haloalkyl} , C _3-6 cycloalkyl, C _3-6 halocyclo alkyl or halo. In some embodiments, T is —CR ^2a R ^2b— and R ^2a and R ^2b are independently H, C _1-6 alkyl, C _3-6 cycloalkyl, or halo. In some embodiments, T is —CR ^2a R ^2b— and R ^2a and R ^2b are independently H or halo. In some embodiments, T is -CR ^2a R ^2b- and R ^2a and R ^2b are independently H, -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )-, -S(O) _n- R ^a- or -OC(O)-NHR ^a . In some embodiments, T is -CR ^2a R ^2b- and R ^2a and R ^2b are independently H, -OR ^a , -NHR ^a , -C(O)-NH(R ^a ), -NR ^e- C (O)R ^a or -NR ^e- S(O) _n R ^a . In some embodiments, T is -CR ^2a R ^2b- and R ^2a and R ^2b are independently H, -OR ^a , or -OC(O)-NHR ^a . In some embodiments, T is -CR ^2a R ^2b- and R ^2a and R ^2b are independently H, -S(O) _n- NH(R ^a ) or -S(O) _n- R ^a- . In some embodiments, T is -CR ^2a R ^2b- and R ^2a and R ^2b are independently H, halo, cyano, -NHR ^a- or -OR ^a . In some embodiments, T is -CR ^2a R ^2b- and R ^2a and R ^2b are independently H or -NHR ^a . In some embodiments, T is —CR ^2a R ^2b— and R ^2a and R ^2b are independently H, halo, cyano, or —OR ^a . In some embodiments, T is —CR ^2a R ^2b— and R ^2a and R ^2b are independently H or cyano. In some embodiments, T is —CR ^2a R ^2b— and R ^2a and R ^2b are each H.

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- , and each R ^2a and R ^2b is independently H, C _1-6 alkyl, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, C _3-6 Halocycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^{a -} , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S (O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ; R ^2a and R ^2b , together with the carbon atom to which they are attached, represent (i) a 3 to 7 membered carbocyclic ring or (ii) 4 to 7 membered to contain 1 or 2 heteroatoms selected from N, O and S form a 7 membered heterocyclic ring, wherein the 3 to 7 membered carbocyclic ring or 4 to 7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- and each R ^2a and R ^2b is independently H, C _1-6 alkyl, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, C _3-6 Halocycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^{a -} , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S (O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ; R ^2a and R ^2b together with the carbon atom to which they are attached form a 3-7 membered carbocyclic ring, the 3-7 membered carbocyclic ring being optionally substituted with 1 to 3 R ^A2 and , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- , and each R ^2a and R ^2b is independently H, C _1-6 alkyl, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, C _3-6 Halocycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^{a -} , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S (O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ; R ^2a and R ^2b , together with the carbon atom to which they are attached, form a 3 to 5 membered carbocyclic ring, the 3 to 5 membered carbocyclic ring optionally substituted with 1 to 3 R ^A2 and , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- , and each R ^2a and R ^2b is independently H, C _1-6 alkyl, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, C _3-6 Halocycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^{a -} , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S (O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ; R ^2a and R ^2b together with the carbon atom to which they are attached form a 3-membered carbocyclic ring, the 3-membered carbocyclic ring optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- , and each R ^2a and R ^2b is independently H, C _1-6 alkyl, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, C _3-6 Halocycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^{a -} , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S (O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ; R ^2a and R ^2b together with the carbon atom to which they are attached form a 3-membered carbocyclic ring.

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- and R ^2a and R ^2b are independently H, halo, or -OR ^a . In some embodiments, T is —CR ^2a R ^2b— , R ^2a and R ^2b are independently H, halo, or —OR ^a , and each R ^a is independently H or C _1-6 alkyl. In some embodiments, T is —CR ^2a R ^2b— , R ^2a and R ^2b are independently H, halo, or —OR ^a , and each R ^a is independently H or C _1-3 alkyl. In some embodiments, T is —CR ^2a R ^2b— , R ^2a and R ^2b are independently H, halo, or —OR ^a , and each R ^a is independently H or methyl.

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is --CR ^2a R ^2b -CR ^2c R ^2d ; R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, cyano, — CH ₂ R ^a- , -CH ₂ OR ^a _, -OR ^a , or -NHR ^a . In some embodiments, T is —CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a or -OR ^a . In some embodiments, T is —CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl or halo. In some embodiments, T is —CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _3-6 cycloalkyl or halo to be. In some embodiments, T is —CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H or halo. In some embodiments, T is —CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, —C(O)—NH(R ^a )—, — NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )-, -S(O) _n- R ^a- or - OC(O)-NHR ^a . In some embodiments, T is --CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, -OR ^a , -NHR ^a , -C(O)- NH(R ^a ), -NR ^e- C(O)R ^a or -NR ^e- S(O) _n R ^a . In some embodiments, T is —CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, —OR ^a , or —OC(O)-NHR ^a . In some embodiments, T is —CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, —S(O) _n- NH(R ^a ) or — S(O) _n- R ^a- . In some embodiments, T is --CR ^2a R ^2b- CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, halo, cyano, -NHR ^a- , or -OR ^a . In some embodiments, T is —CR ^2a R ^2b -CR ^2c R ^2d and R ^2a , R ^2b , R ^2c and R ^2d are independently H or —NHR ^a . In some embodiments, T is —CR ^2a R ^2b —CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, halo, cyano, or —OR ^a . In some embodiments, T is —CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are independently H or cyano. In some embodiments, T is —CR ^2a R ^2b -CR ^2c R ^2d , and R ^2a , R ^2b , R ^2c and R ^2d are each H.

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is -CR ^2a R ^2b- CR ^2c R ^2d- , and R ^2a , R ^2b , R ^2c and R ^2d are independently H, halo or -OR ^a . In some embodiments, T is -CR ^2a R ^2b- CR ^2c R ^2d- , R ^2a , R ^2b , R ^2c and R ^2d are independently H, halo or -OR ^a , and each R ^a is independently H or C _1-6 alkyl. In some embodiments, T is -CR ^2a R ^2b- CR ^2c R ^2d- , R ^2a , R ^2b , R ^2c and R ^2d are independently H, halo or -OR ^a , and each R ^a is independently H or C _1-3 alkyl. In some embodiments, T is -CR ^2a R ^2b- CR ^2c R ^2d- , R ^2a , R ^2b , R ^2c and R ^2d are independently H, halo or -OR ^a , and each R ^a is independently H or methyl.

In some embodiments, the compound of Formula I or II is a compound of Formula III:

[Formula III]

.

In some embodiments, the compound of Formula I, Ia, II, or IIa is a compound of Formula IIIa:

[Formula IIIa]

.

In some embodiments, the compound of Formula I, Ib, II, or IIb is a compound of Formula IIIb:

[Formula IIIb]

.

In some embodiments of a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or IIIb, U is -NR ^11- , -CR ^12a R ^12b- , -S-, -S(O) ^- , -S(O) ₂ - , -C(O) - or -O-. In some embodiments, a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa or IIIb, U is -NR ¹¹ , -CR ^12a R ^12b , -C(O) ^- or -O-. In some embodiments, U is -NR ¹¹ , -CR ^12a R ^12b or -O-. In some embodiments, U is -NR ¹¹ or -CR ^12a R ^12b . In some embodiments, U is -NR ¹¹ .

In some embodiments of a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or IIIb, U is -O-, -C(O)-, -S-, -S(O)- or -S(O) _2- . In some embodiments, U is -O- or -C(O)-. In some embodiments, U is -S-, -S(O)-, or -S(O) _2- . In some embodiments, U is -S-. In some embodiments, U is -S(O)-. In some embodiments, U is -S(O) ₂ -. In some embodiments, U is -C(O)-. In some embodiments, U is -O-.

In some embodiments of compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or IIIb, R ¹¹ is H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl , C _3-6 halocycloalkyl, -C(O)-R ^a , -SR ^a , -S(O)- R ^a , -S(O) _2- R ^a , -CH ₂ - R ^a . In some embodiments, R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₃ -C ₆ cycloalkyl, or C ₃ -C ₆ halocycloalkyl. In some embodiments, R ¹¹ is H, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ halocycloalkyl. In some embodiments, R ¹¹ is H, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl. In some embodiments, R ¹¹ is H or C ₁ -C ₄ alkyl. In some embodiments, R ¹¹ is C ₃ -C ₆ halocycloalkyl. In some embodiments, R ¹¹ is C ₃ -C ₆ cycloalkyl. In some embodiments, R ¹¹ is C ₁ -C ₄ haloalkyl. In some embodiments, R ¹¹ is C ₁ -C ₄ alkyl. In some embodiments, R ¹¹ is H. In some embodiments, R ¹¹ is -C(O)-R ^a , -SR ^a , -S(O)-R ^a , -S(O) _2- R ^a , -CH ₂ -R ^a .

In some embodiments, the compound of Formula I, II, or III has Formula IV:

[Formula IV]

.

In some embodiments, the compound of Formula I, Ia, II, IIa, III, IIIa, or IV has Formula IVa:

[Formula IVa]

.

In some embodiments, the compound of Formula I, Ib, II, IIb, III, IIIb, or IV has Formula IVb:

[Formula IVb]

.

In some embodiments, in the compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R ^2a and R ^2b , together with the carbon to which they are attached, are (i) 3-7 membered carbocyclic ring forming a 3-7 membered carbocyclic ring or (ii) a 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S; the ring or 4-7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or —OR ^e .

In some embodiments, in compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa and IVb, R ^2a and R ^2b , together with the carbon to which they are attached, are from 3 to form a 7 membered carbocyclic ring, wherein the 3 to 7 membered carbocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C ₁ - C ₆ alkyl, C ₃ -C ₆ cycloalkyl or —OR ^e .

In some embodiments, in compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa and IVb, R ^2a and R ^2b , together with the carbon to which they are attached, are from 3 to form a 5 membered carbocyclic ring, wherein the 3 to 5 membered carbocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C ₁ - C ₆ alkyl, C ₃ -C ₆ cycloalkyl or —OR ^e .

In some embodiments, in compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa and IVb, R ^2a and R ^2b , together with the carbon to which they are attached, are from 3 to Forming a 5-membered carbocyclic ring, a 3- to 5-membered carbocyclic ring.

In some embodiments, in compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R ^2a and R ^2b , together with the carbon to which they are attached, are N, O and form a 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, the 4-7 membered heterocyclic ring optionally substituted with 1 to 3 R ^A2 , each of R ^A2 is independently oxo, halo, cyano, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or —OR ^e .

In some embodiments, in compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R ^2a and R ^2b , together with the carbon to which they are attached, are N, O and form a 3 to 5 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, wherein the 3 to 5 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A2 , each of R ^A2 is independently oxo, halo, cyano, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or —OR ^e .

In some embodiments, in compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R ^2a and R ^2b , together with the carbon to which they are attached, are N, form a 3 to 5 membered heterocyclic ring containing 1 or 2 heteroatoms selected from O and S.

In some embodiments, in compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa and IVb, R ^2a and R ^2b are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -OR ^a or -NHR ^a . In some embodiments, T is -CR ^2a R ^2b- and R ^2a and R ^2b are independently H, C _1-6 alkyl, C _3-6 cycloalkyl, halo, cyano, —CH ₂ R ^a- , -CH ₂ OR ^a or -OR ^a . In some embodiments, T is —CR ^2a R ^2b— and R ^2a and R ^2b are independently H, C _1-6 alkyl, C _3-6 cycloalkyl, or halo. In some embodiments, T is —CR ^2a R ^2b— and R ^2a and R ^2b are independently H or halo. In some embodiments, T is -CR ^2a R ^2b- and R ^2a and R ^2b are independently H, -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )-, -S(O) _n- R ^a- or -OC(O)-NHR ^a . In some embodiments, T is -CR ^2a R ^2b- and R ^2a and R ^2b are independently H, -OR ^a , -NHR ^a , -C(O)-NH(R ^a ), -NR ^e- C (O)R ^a or -NR ^e- S(O) _n R ^a . In some embodiments, T is -CR ^2a R ^2b- and R ^2a and R ^2b are independently H, -OR ^a , or -OC(O)-NHR ^a . In some embodiments, T is -CR ^2a R ^2b- and R ^2a and R ^2b are independently H, -S(O) _n- NH(R ^a ) or -S(O) _n- R ^a- . In some embodiments, T is -CR ^2a R ^2b- and R ^2a and R ^2b are independently H, halo, cyano, -NHR ^a- or -OR ^a . In some embodiments, T is -CR ^2a R ^2b- and R ^2a and R ^2b are independently H or -NHR ^a . In some embodiments, T is —CR ^2a R ^2b— and R ^2a and R ^2b are independently H, halo, cyano, or —OR ^a . In some embodiments, T is —CR ^2a R ^2b— and R ^2a and R ^2b are independently H or cyano. In some embodiments, T is —CR ^2a R ^2b— and R ^2a and R ^2b are each H.

In some embodiments, in the compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, each R ^2a and R ^2b is independently H, C _1-6 alkyl , C _3-6 cycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ; R ^2a and R ^2b , together with the carbon atom to which they are attached, are (i) a 3 to 7 membered carbocyclic ring or (ii) 4 to 7 membered to contain 1 or 2 heteroatoms selected from N, O and S forming a 7 membered heterocyclic ring, wherein the 3 to 7 membered carbocyclic ring or 4 to 7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, in the compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, each R ^2a and R ^2b is independently H, C _1-6 alkyl , C _3-6 cycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ; R ^2a and R ^2b , together with the carbon atom to which they are attached, form a 3-7 membered carbocyclic ring, the 3-7 membered carbocyclic ring being optionally substituted with 1 to 3 R ^A2 and , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, in the compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, each R ^2a and R ^2b is independently H, C _1-6 alkyl , C _3-6 cycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ; R ^2a and R ^2b , together with the carbon atom to which they are attached, form a 3 to 5 membered carbocyclic ring, the 3 to 5 membered carbocyclic ring being optionally substituted with 1 to 3 R ^A2 and , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, in the compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, each R ^2a and R ^2b is independently H, C _1-6 alkyl , C _3-6 cycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ; R ^2a and R ^2b together with the carbon atom to which they are attached form a 3-membered carbocyclic ring, the 3-membered carbocyclic ring optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, in the compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, each R ^2a and R ^2b is independently H, C _1-6 alkyl , C _3-6 cycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ; R ^2a and R ^2b together with the carbon atom to which they are attached form a 3-membered carbocyclic ring.

For compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, in some embodiments, R ^12a and R ^12b are independently H, -OR ^a or -OC ( O)-NHR ^a . In some embodiments, R ^12a and R ^12b are independently H, -NHR ^a , -C(O)-NH(R ^a ), -NR ^e- C(O)R ^a , -NR ^e- S(O) _n R ^a . In some embodiments, R ^12a and R ^12b are independently H, -S(O) _n- NH(R ^a ) or -S(O) _n- R ^a- . In some embodiments, R ^12a and R ^12b are independently H, halo, cyano, -NHR ^a- , or -OR ^a . In some embodiments, R ^12a and R ^12b are independently H or -NHR ^a . In some embodiments, R ^12a and R ^12b are independently H, halo, cyano or —OR ^a . In some embodiments, R ^12a and R ^12b are independently H or cyano. In some embodiments, R ^12a and R ^12b are independently H or —OR ^a . In some embodiments, R ^12a and R ^12b are independently H or —OR ^a , and R ^a is C _3-6 cycloalkyl. In some embodiments, R ^12a and R ^12b are independently H or —OR ^a , and R ^a is C _1-4 haloalkyl. In some embodiments, R ^12a and R ^12b are independently H or —OR ^a , and R ^a is C _1-4 alkyl optionally substituted with —OC _1-4 alkyl.

In some embodiments, in a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R ^12a and R ^12b together with the carbon atom to which they are attached are (i ) form a 3-7 membered carbocyclic ring or (ii) a 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, and a 3-7 membered carbocyclic ring The click ring or 4-7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _1-6 cycloalkyl or -OR ^e .

In some embodiments, in compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R ^12a and R ^12b , together with the carbon atom to which they are attached, are ternary form a to 7 membered carbocyclic ring, wherein the 3 to 7 membered carbocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _{1 -6} alkyl, C _1-6 cycloalkyl or —OR ^e .

In some embodiments, in compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa or IVb, R ^12a and R ^12b together with the carbon atom to which they are attached are N, form a 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from O and S, the 4-7 membered heterocyclic ring optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _1-6 cycloalkyl or —OR ^e .

In some embodiments, in a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R ^12a and R ^12b together with the carbon atom to which they are attached are (i ) form a 3-7 membered carbocyclic ring or (ii) a 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, and a 3-7 membered carbocyclic ring The click ring or 4-7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl or C _1-6 cycloalkyl.

In some embodiments, in a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R ^12a and R ^12b together with the carbon atom to which they are attached, (i ) 3 to 7 membered carbocyclic ring or (ii) 3 to 5 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, and 3 to 5 membered carbocyclic ring The click ring or 3 to 5 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl or C _1-6 cycloalkyl.

In some embodiments, in a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R ^12a and R ^12b together with the carbon atom to which they are attached are (i ) a 3 to 7 membered carbocyclic ring or (ii) a 3 to 5 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S.

In some embodiments, in compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R ^12a and R ^12b , together with the carbon atom to which they are attached, are ternary form a to 5 membered carbocyclic ring, wherein the 3 to 5 membered carbocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _{1 -6} alkyl or C _1-6 cycloalkyl.

In some embodiments, in compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa or IVb, R ^12a and R ^12b together with the carbon atom to which they are attached are N, form a 3 to 5 membered heterocyclic ring containing 1 or 2 heteroatoms selected from O and S, the 3 to 5 membered heterocyclic ring optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl or C _1-6 cycloalkyl.

In some embodiments, in compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R ^12a and R ^12b , together with the carbon atom to which they are attached, are ternary to 5 membered carbocyclic ring.

In some embodiments, in compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa or IVb, R ^12a and R ^12b together with the carbon atom to which they are attached are N, form a 3 to 5 membered heterocyclic ring containing 1 or 2 heteroatoms selected from O and S.

In some embodiments, in compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R ^12a and R ^12b , together with the carbon atom to which they are attached, are ternary form a carbocyclic ring.

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, each R ^2a , R ^2b , R ^12a and R ^12b is independently H , halo, or -OR ^a . In some embodiments, each R ^2a , R ^2b , R ^12a and R ^12b is independently H, halo, or —OR ^a , and each R ^a is independently H or C _1-6 alkyl. In some embodiments, each R ^2a , R ^2b , R ^12a and R ^12b is independently H, halo, or —OR ^a , and each R ^a is independently H or C _1-3 alkyl. In some embodiments, each R ^2a , R ^2b , R ^12a and R ^12b is independently H, halo, or —OR ^a , and each R ^a is independently H or methyl.

In some embodiments, the compound of Formula I or II has Formula V:

[Formula V]

.

In some embodiments, the compound of Formula I, Ia, II, or IIa has Formula Va:

[Formula Va]

.

In some embodiments, the compound of Formula (I), (Ib), (II), or (IIb) has Formula (Vb):

[Formula Vb]

.

In some embodiments, in compounds of Formulas V, Va, and Vb, R ^2a and R ^12a are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -OR ^a or -NHR ^a . In some embodiments, R ^2a and R ^12a are independently H, C _1-6 alkyl, C _3-6 cycloalkyl, halo, cyano, —CH ₂ R ^a- , —CH ₂ OR ^a , or —OR ^a . In some embodiments, R ^2a and R ^12a are independently H, C _1-6 alkyl, C _3-6 cycloalkyl, or halo. In some embodiments, R ^2a and R ^12a are independently H or halo. In some embodiments, R ^2a and R ^12a are independently H, -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )-, -S(O) _n- R ^a- or -OC(O)-NHR ^a . In some embodiments, R ^2a and R ^12a are independently H, -OR ^a , -NHR ^a , -C(O)-NH(R ^a ), -NR ^e- C(O)R ^a , or -NR ^e- S(O) _n R ^a . In some embodiments, R ^2a and R ^12a are independently H, -OR ^a , or -OC(O)-NHR ^a . In some embodiments, R ^2a and R ^12a are independently H, -S(O) _n- NH(R ^a ) or -S(O) _n- R ^a- . In some embodiments, R ^2a and R ^12a are independently H, halo, cyano, -NHR ^a- , or -OR ^a . In some embodiments, R ^2a and R ^12a are independently H or —NHR ^a . In some embodiments, R ^2a and R ^12a are independently H, halo, cyano or —OR ^a . In some embodiments, R ^2a and R ^12a are independently H or cyano. In some embodiments, R ^2a and R ^12a are each H.

In some embodiments, in compounds of Formulas V, Va, and Vb, R ^2a and R ^12a are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halo cycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^{a -} , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- .

In some embodiments, in compounds of Formulas V, Va, and Vb, R ^2a and R ^12a are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halo cycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^{a -} , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- .

In some embodiments, in compounds of Formulas V, Va, and Vb, R ^2a and R ^12a are independently H, C _1-6 alkyl, C _3-6 cycloalkyl, halo, cyano, —CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- .

In some embodiments, in compounds of Formulas V, Va, and Vb, R ^2a and R ^12a are independently H, C _1-6 alkyl, C _3-6 cycloalkyl, halo, cyano, —CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- .

In some embodiments, in compounds of Formulas V, Va, and Vb, R ^2a and R ^12a are independently H, C _1-6 alkyl, C _3-6 cycloalkyl, halo, cyano, —CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- .

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb, W ¹ is a bond or -CR ^4a R ^4b- R ^4a ; R ^4b and R ^4b are independently H, C _1-6 alkyl, C _1-4 haloalkyl, halo, hydroxyl, cyano, —OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl is; R ^4a and R ^4b , together with the carbon atom to which they are attached, represent (i) a 3- to 7-membered carbocyclic ring or (ii) a 4- to 7-membered heteroatom containing 1 or 2 heteroatoms selected from N, O and S; form a 7 membered heterocyclic ring, wherein the 3 to 7 membered carbocyclic ring or 4 to 7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e . In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb, W ¹ is a bond or -CR ^4a R ^4b- R ^4a and R ^4a and R ^4b are independently H, C _1-6 alkyl, C _1-4 haloalkyl, halo, hydroxyl, cyano, —OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl. In some embodiments, W ¹ is a bond or ^{—CR 4a} R 4b—R ^4a , and R ^4a and R ^4b are independently H, C _1-6 alkyl, halo, C _{1-4 haloalkyl} , or cyano. In some embodiments, W ¹ is a bond or ^{—CR 4a} R 4b—R ^4a , and R ^4a and R ^4b are independently H, C ₁ -C ₆ alkyl, halo, or cyano. In some embodiments, W ¹ is a bond or ^{—CR 4a} R 4b—R ^4a , and R ^4a and R ^4b are independently H, halo, or C ₁ -C ₄ alkyl. In some embodiments, W ¹ is a bond or ^{—CR 4a} R 4b-R ^4a , and R ^4a and R ^4b are independently H, fluoro, chloro, or C ₁ -C ₄ alkyl. In some embodiments, W ¹ is a bond or ^{—CR 4a} R 4b—R ^4a , and R ^4a and R ^4b are independently H or cyano. In some embodiments, W ¹ is a bond or ^{—CR 4a} R 4b—R ^4a , and R ^4a and R ^4b are independently H or C _1-4 haloalkyl.

In some embodiments, W ¹ is a bond or -CR ^4a R ^4b- , and R ^4a and R ^4b , together with the carbon atom to which they are attached, are (i) a 3-7 membered carbocyclic ring or (ii) N , O and S form a 4 to 7 membered heterocyclic ring containing 0 to 2 heteroatoms, and 1 to 3 to 7 membered carbocyclic ring or 4 to 7 membered heterocyclic ring optionally substituted with to 3 R ^A3 , each R ^A3 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e . In some embodiments, W ¹ is a bond or -CR ^4a R ^4b- , and R ^4a and R ^4b , together with the carbon atom to which they are attached, are (i) a 3-7 membered carbocyclic ring or (ii) N , O and S form a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms, and 1 to 3 to 7 membered carbocyclic ring or 1 to 4 to 7 membered heteroatom optionally substituted with to 3 R ^A3 , each R ^A3 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, W ¹ is a bond or ^{—CR 4a} R 4b—R ^4a , and R ^4a and R ^4b , together with the carbon atom to which they are attached, form a 3- to 7-membered carbocyclic ring, and The to 7 membered carbocyclic ring is optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, W ¹ is a bond or -CR ^4a R ^4b- , and R ^4a and R ^4b , together with the carbon atom to which they are attached, contain 1 or 2 heteroatoms selected from N, O and S. forming a 7-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, W ¹ is a bond or -CR ^4a R ^4b- , and R ^4a and R ^4b , together with the carbon atom to which they are attached, are (i) a 3-7 membered carbocyclic ring or (ii) N , O and S form a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from In some embodiments, W ¹ is a bond or —CR ^4a R ^4b— and R ^4a and R ^4b , together with the carbon atom to which they are attached, form a 3-7 membered carbocyclic ring.

In some embodiments, W ¹ is a bond or -CR ^4a R ^4b- , and R ^4a and R ^4b , together with the carbon atom to which they are attached, are 3-membered carbocyclic, optionally substituted with 1 to 3 R ^A3 . form a ring, and each R ^A3 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl.

In some embodiments of compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W ¹ is -CR ^4a R ^4b- , and R ^4b and R ^4b are independently H, C _1-6 alkyl, C _1-4 haloalkyl, halo, hydroxyl, cyano, —OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl; ; R ^4a and R ^4b , together with the carbon atom to which they are attached, represent (i) a 3- to 7-membered carbocyclic ring or (ii) a 4- to 7-membered heteroatom containing 1 or 2 heteroatoms selected from N, O and S; form a 7 membered heterocyclic ring, wherein the 3 to 7 membered carbocyclic ring or 4 to 7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e . In some embodiments of compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W ¹ is -CR ^4a R ^4b- , and R ^4a and R ^4b are independently H, C _1-6 alkyl, C _1-4 haloalkyl, halo, hydroxyl, cyano, —OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl . In some embodiments W ¹ is —CR ^4a R ^4b— and R ^4a and R ^4b are independently H, C ₁ -C ₆ alkyl, halo, C _1-4 haloalkyl or cyano. In some embodiments, W ¹ is —CR ^4a R ^4b— and R ^4a and R ^4b are independently H, C ₁ -C ₆ alkyl, halo, or cyano. In some embodiments, W ¹ is a bond or —CR ^4a R ^4b— , and R ^4a and R ^4b are independently H, halo, or C ₁ -C ₄ alkyl. In some embodiments, W ¹ is a bond or —CR ^4a R ^4b— , and R ^4a and R ^4b are independently H, fluoro, chloro, or C ₁ -C ₄ alkyl. In some embodiments, W ¹ is a bond or —CR ^4a R ^4b— , and R ^4a and R ^4b are independently H or cyano. In some embodiments, W ¹ is a bond or —CR ^4a R ^4b— , and R ^4a and R ^4b are independently H or C _1-4 haloalkyl.

In some embodiments, W ¹ is —CR ^4a R ^4b— and R ^4a and R ^4b , together with the carbon atom to which they are attached, are (i) a 3-7 membered carbocyclic ring or (ii) N, O and form a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, wherein the 3 to 7 membered carbocyclic ring or 4 to 7 membered heterocyclic ring is from 1 to 3 optionally substituted with R ^A3 , each R ^A3 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e . In some embodiments, W ¹ is —CR ^4a R ^4b— and R ^4a and R ^4b , together with the carbon atom to which they are attached, are (i) a 3-7 membered carbocyclic ring or (ii) N, O and form a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, wherein the 3 to 7 membered carbocyclic ring or 4 to 7 membered heterocyclic ring is from 1 to 3 optionally substituted with R ^A3 , each R ^A3 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, W ¹ is —CR ^4a R ^4b— and R ^4a and R ^4b , together with the carbon atom to which they are attached, form a 3-7 membered carbocyclic ring, and a 3-7 membered carbo The cyclic ring is optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, W ¹ is -CR ^4a R ^4b- and R ^4a and R ^4b , together with the carbon atom to which they are attached, are from 4 to containing 1 or 2 heteroatoms selected from N, O and S. form a 7 membered heterocyclic ring, wherein the 4 to 7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo, halo, cyano, C _{1 - 6} alkyl or C _3-6 cycloalkyl. In some embodiments, W ¹ is —CR ^4a R ^4b— and R ^4a and R ^4b , together with the carbon atom to which they are attached, are (i) a 3-7 membered carbocyclic ring or (ii) N, O and a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S. In some embodiments, W ¹ is a bond or —CR ^4a R ^4b— and R ^4a and R ^4b , together with the carbon atom to which they are attached, form a 3-7 membered carbocyclic ring. In some embodiments, W ¹ is -CR ^4a R ^4b- and R ^4a and R ^4b , together with the carbon atom to which they are attached, form a 3-membered carbocyclic ring optionally substituted with 1 to 3 R ^A3 . and each R ^A3 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl.

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb, W ¹ is a bond.

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb, W ² is -CR ^5a R ^5b- .

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb, W ² is -CR ^6a =CR ^6b - , R ^6a and R ^6b are independently H, halo, C _1-4 haloalkyl or C _1-6 alkyl. In some embodiments, W ² is -CR ^6a =CR ^6b - and each of R ^6a and R ^6b , together with the carbon atom to which each is attached, is (i) a 5- to 10-membered carbocyclic ring, (ii) ) 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, (iii) 6-10 membered aromatic ring, or (iv) 1 selected from N, O and S form a 5-10 membered heteroaromatic ring containing 5 to 3 heteroatoms, a 5-10 membered carbocyclic ring, a 5-10 membered heterocyclic ring, a 6-10 membered aromatic ring, or 5 The 1 to 10 membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A4 , each R ^A4 is independently halo or C _1-4 alkyl.

In some embodiments, W ² is —CR ^6a =CR ^6b —, and each R ^6a and R ^6b , together with the carbon atom to which each is attached, is (i) a 6-10 membered aromatic ring, or (ii) forming a 5-10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S, the 6 to 10 membered aromatic ring or 5 to 10 membered heteroaromatic ring having 1 to 4 heteroatoms optionally substituted with R ^A4 , and each R ^A4 is independently halo or C _1-4 alkyl.

In some embodiments, W ² is -CR ^6a =CR ^6b - and each of R ^6a and R ^6b , together with the carbon atom to which each is attached, is (i) a 5- to 10-membered carbocyclic ring or (ii) ) form a 5- to 10-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, a 5- to 10-membered carbocyclic ring or a 5- to 10-membered heterocyclic ring is optionally substituted with 1 to 4 R ^A4 , and each R ^A4 is independently halo or C _1-4 alkyl.

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb, X is a bond. In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, X is -CR ^8a R ^8b- .

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb, Z is -CR ^9a R ^9b- .

In some embodiments, in the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb, Z is -CR ^10a =CR ^10b -, each R ^10a and R ^10b is independently H, halo, C _1-4 haloalkyl or C _1-6 alkyl. In some embodiments, Z is -CR ^10a =CR ^10b - and each of R ^10a and R ^10b , together with the carbon atom to which each is attached, is (i) a 5- to 10-membered carbocyclic ring, (ii) 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, (iii) 6-10 membered aromatic ring, or (iv) 1 selected from N, O and S form a 5-10 membered heteroaromatic ring containing from 3 to 3 heteroatoms, a 5-10 membered carbocyclic ring, a 5-10 membered heterocyclic ring, a 6-10 membered aromatic ring, or a 5 membered The to 10-membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A4 , each R ^A4 is independently halo, oxo, cyano or C _1-4 alkyl. In some embodiments, Z is -CR ^10a =CR ^10b -, and each R ^10a and R ^10b , together with the carbon atom to which each is attached, is (i) a 6-10 membered aromatic ring, or (ii) N , O and S form a 5- to 10-membered heteroaromatic ring containing 1 to 3 heteroatoms, wherein the 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring contains 1 to 4 R optionally substituted with ^A4 , and each R ^A4 is independently halo or C _1-4 alkyl. In some embodiments, Z is -CR ^10a =CR ^10b - and each of R ^10a and R ^10b , together with the carbon atom to which each is attached, is (i) a 5- to 10-membered carbocyclic ring or (ii) form a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, the 5-10 membered carbocyclic ring or the 5-10 membered heterocyclic ring is 1 optionally substituted with 4 to 4 R ^A4 , each R ^A4 is independently halo or C _1-4 alkyl.

In some embodiments, the compound of Formula I, II, III, or IV has Formula VI:

[Formula VI]

;

m is 0, 1, 2, 3 or 4;

each R ² is independently C _1-6 alkyl, C _3-6 cycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH ₂ -S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S( O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ;

two R ² at the same carbon atom, together with the carbon atom to which they are both attached, are (i) a 3- to 7-membered carbocyclic ring or (ii) one or two selected from N, O and S form a 4 to 7 membered heterocyclic ring containing heteroatoms, the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, the compound of Formula I, Ia, II, IIa, III, IIIa, IV or IVa has Formula VIa:

[Formula VIa]

;

m is 0, 1, 2, 3 or 4;

each R ² is independently C _1-6 alkyl or C _3-6 cycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH ₂ -S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S( O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ;

two R ² at the same carbon atom, together with the carbon atom to which they are both attached, are (i) a 3- to 7-membered carbocyclic ring or (ii) one or two selected from N, O and S forming a 4 to 7 membered heterocyclic ring containing heteroatoms, the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring optionally substituted with 1 to 3 R ^A2 ; each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, the compound of Formula I, Ib, II, IIb, III, IIIb, IV or IVb has Formula VIb:

[Formula VIb]

;

m is 0, 1, 2, 3 or 4;

each R ² is independently C _1-6 alkyl, C _3-6 cycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH ₂ -S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S( O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ;

two R ² at the same carbon atom, together with the carbon atom to which they are both attached, are (i) a 3- to 7-membered carbocyclic ring or (ii) one or two selected from N, O and S form a 4 to 7 membered heterocyclic ring containing heteroatoms, the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, L is -CR ^3a R ^3b- , -C(O)-, -SO ₂ - , ^{-CR 3a} R 3b-CR ^3c R ^3d-- or -N(R ^a )-. In some embodiments, L is -CR ^3a R ^3b- , -C(O)-, -CR ^3a R ^3b -CR ^3c R ^3d- , or -SO ₂ . In some embodiments, L is -CR ^3a R ^3b- , -C(O)- or -CR ^3a R ^3b -CR ^3c R ^3d- . In some embodiments, L is -CR ^3a R ^3b- or -CR ^3a R ^3b -CR ^3c R ^3d- . In some embodiments, L is -C(O)-. In some embodiments, L is -SO ₂ -. In some embodiments, L is -CR ^3a R ^3b- CR ^3c R ^3d- . In some embodiments, L is -N(R ^a )-. In some embodiments, L is -CR ^3a R ^3b- .

In some embodiments, a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or —OC _1-4 alkyl; (i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, represent (i) a 3- to 7-membered carbocyclic ring or (ii) N, O and form a 3-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, the 3-7 membered carbocyclic ring or the 3-7 membered heterocyclic ring having 1 to 3 members optionally substituted with R ^A2 , and each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e . In some embodiments, R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl, or —OC _1-4 alkyl; (i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, represent (i) a 3- to 7-membered carbocyclic ring or (ii) N, O and form a 3-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, the 3-7 membered carbocyclic ring or the 3-7 membered heterocyclic ring may contain 1 or 2 optionally substituted with R ^A2 , and each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl, or —OC _1-4 alkyl; (i) either R ^3a and R ^3b or (ii) R ^3c and R ^3d , taken together with the carbon atom to which they are attached, form a 3-membered carbocyclic ring, wherein the 3-membered carbocyclic ring is one or optionally substituted with two R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl, or —OC _1-4 alkyl; Either (i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, forms a 3-membered carbocyclic ring. In some embodiments, R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl, or —OC _1-4 alkyl. In some embodiments, R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-3 alkyl, C _1-4 haloalkyl, or —OC _1-3 alkyl. In some embodiments, R ^3a , R ^3b , R ^3c and R ^3d are independently H or C _1-3 alkyl. In some embodiments, R ^3a , R ^3b , R ^3c and R ^3d are each H.

In some embodiments, a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, L is -CR ^3a R ^3b- or -CR ^3a R ^3b- CR ^3c R ^3d- and R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or —OC _1-4 is alkyl; (i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, represent (i) a 3- to 7-membered carbocyclic ring or (ii) N, O and form a 3-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, the 3-7 membered carbocyclic ring or the 3-7 membered heterocyclic ring having 1 to 3 members optionally substituted with R ^A2 , and each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e . In some embodiments, L is -CR ^3a R ^3b- or ^{-CR 3a} R 3b-CR ^3c R ^3d- and R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or -OC _1-4 alkyl; (i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, represent (i) a 3- to 7-membered carbocyclic ring or (ii) N, O and form a 3-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, the 3-7 membered carbocyclic ring or the 3-7 membered heterocyclic ring may contain 1 or 2 optionally substituted with R ^A2 , and each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, L is -CR ^3a R ^3b- or ^{-CR 3a} R 3b-CR ^3c R ^3d- and R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or -OC _1-4 alkyl; (i) either R ^3a and R ^3b or (ii) R ^3c and R ^3d , taken together with the carbon atom to which they are attached, form a 3-membered carbocyclic ring, wherein the 3-membered carbocyclic ring is one or optionally substituted with two R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, L is -CR ^3a R ^3b- or ^{-CR 3a} R 3b-CR ^3c R ^3d- and R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or -OC _1-4 alkyl; Either (i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, forms a 3-membered carbocyclic ring. In some embodiments, L is -CR ^3a R ^3b- or ^{-CR 3a} R 3b-CR ^3c R ^3d- and R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or -OC _1-4 alkyl. In some embodiments, R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-3 alkyl, C _1-3 haloalkyl, or —OC _1-3 alkyl. In some embodiments, L is -CR ^3a R ^3b- or ^{-CR 3a} R 3b-CR ^3c R ^3d- and R ^3a , R ^3b , R ^3c and R ^3d are independently H or C _1-3 alkyl. In some embodiments, R ^3a , R ^3b , R ^3c and R ^3d are each H.

In some embodiments, a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, L is -CR ^3a R ^3b- CR ^3c R ^3d- and R ^3a , R ^3b , R ^3c , and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or —OC _1-4 alkyl; (i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, represent (i) a 3- to 7-membered carbocyclic ring or (ii) N, O and form a 3-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, the 3-7 membered carbocyclic ring or the 3-7 membered heterocyclic ring having 1 to 3 members optionally substituted with R ^A2 , and each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e . In some embodiments, L is -CR ^3a R ^3b- CR ^3c R ^3d- and R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or — OC _1-4 alkyl; (i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, represent (i) a 3- to 7-membered carbocyclic ring or (ii) N, O and form a 3-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, the 3-7 membered carbocyclic ring or the 3-7 membered heterocyclic ring may contain 1 or 2 optionally substituted with R ^A2 , and each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, L is -CR ^3a R ^3b- CR ^3c R ^3d- and R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or — OC _1-4 alkyl; (i) either R ^3a and R ^3b or (ii) R ^3c and R ^3d , taken together with the carbon atom to which they are attached, form a 3-membered carbocyclic ring, wherein the 3-membered carbocyclic ring is one or optionally substituted with two R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, L is -CR ^3a R ^3b- CR ^3c R ^3d- and R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or — OC _1-4 alkyl; Either (i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, forms a 3-membered carbocyclic ring. In some embodiments, L is -CR ^3a R ^3b- CR ^3c R ^3d- and R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or — OC _1-4 alkyl. In some embodiments, R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-3 alkyl, C _1-3 haloalkyl, or —OC _1-3 alkyl. In some embodiments, L is ^{—CR 3a} R 3b-CR ^3c R ^3d- and R ^3a , R ^3b , R ^3c and R ^3d are independently H or C _1-3 alkyl. In some embodiments, L is ^{-CR 3a} R 3b-CR ^3c R ^3d- and R ^3a , R ^3b , R ^3c and R ^3d are each H.

In some embodiments, a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, L is -CR ^3a R ^3b- , R ^3a and R ^3b are independently H, C _1-6 alkyl, C _1-4 haloalkyl or —OC _1-4 alkyl; (i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, represent (i) a 3- to 7-membered carbocyclic ring or (ii) N, O and form a 3-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, the 3-7 membered carbocyclic ring or the 3-7 membered heterocyclic ring having 1 to 3 members optionally substituted with R ^A2 , and each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e . In some embodiments, L is -CR ^3a R ^3b- and R ^3a and R ^3b are independently H, C _1-6 alkyl, C _1-4 haloalkyl, or —OC _1-4 alkyl; (i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, represent (i) a 3- to 7-membered carbocyclic ring or (ii) N, O and form a 3-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, the 3-7 membered carbocyclic ring or the 3-7 membered heterocyclic ring may contain 1 or 2 optionally substituted with R ^A2 , and each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, L is -CR ^3a R ^3b- and R ^3a and R ^3b are independently H, C _1-6 alkyl, C _1-4 haloalkyl, or —OC _1-4 alkyl; (i) either R ^3a and R ^3b or (ii) R ^3c and R ^3d , taken together with the carbon atom to which they are attached, form a 3-membered carbocyclic ring, wherein the 3-membered carbocyclic ring is one or optionally substituted with two R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, L is -CR ^3a R ^3b- and R ^3a and R ^3b are independently H, C _1-6 alkyl, C _1-4 haloalkyl, or —OC _1-4 alkyl; Either (i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, forms a 3-membered carbocyclic ring. In some embodiments, L is —CR ^3a R ^3b— and R ^3a and R ^3b are independently H, C _1-6 alkyl, C _1-4 haloalkyl, or —OC _1-4 alkyl. In some embodiments, L is —CR ^3a R ^3b— and R ^3a and R ^3b are independently H, C _1-3 alkyl, C _1-3 haloalkyl, or —OC _1-3 alkyl. In some embodiments, L is -CR ^3a R ^3b- and R ^3a and R ^3b are independently H or C _1-3 alkyl. In some embodiments, L is -CR ^3a R ^3b- and R ^3a and R ^3b are each H.

In some embodiments, the compound of Formula I, II, III, IV, or VI has Formula VII:

[Formula VII]

.

In some embodiments, the compound of Formula I, Ia, II, IIa, III, IIIa, IV, IVa, VI, or VIa has Formula VIIa:

[Formula VIIa]

.

In some embodiments, the compound of Formula I, Ib, II, IIb, III, IIIb, IV, IVb, VI, or VIb has Formula VIIb:

[Formula VIIb]

.

In some embodiments, a compound of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, and VIIb wherein R ¹ is H, C _6-10 aryl or C _6-10 heteroaryl, C _6-10 aryl or C _6-10 heteroaryl is optionally substituted with 1 to 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl- OC _1-4 alkyl.

In some embodiments, R ¹ is H, phenyl, pyridyl, pyridazine, pyrazine or pyrimidine, wherein phenyl, pyridyl, pyridazine, pyrazine or pyrimidine is optionally substituted with 1 to 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _{1 - 4} alkyl-OC _1-4 alkyl. In some embodiments, R ¹ is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, wherein phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine is optional with 1, 2, 3, or 4 R ^A1 substituted with and each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl. In some embodiments, R ¹ is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine optionally substituted with 1, 2, 3 or 4 R ^A1 , and each R ^A1 is independently halo, C _1-4 alkyl, C _1-4 haloalkyl or -OC _1-4 alkyl. In some embodiments, R ¹ is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine optionally substituted with 1, 2, 3 or 4 R ^A1 , and each R ^A1 is independently halo, C _1-4 alkyl or -OC _1-4 alkyl. In some embodiments, R ¹ is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine optionally substituted with 1, 2, 3 or 4 R ^A1 , and each R ^A1 is independently halo or C _1-4 alkyl. In some embodiments, R ¹ is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine optionally substituted with 1, 2, 3 or 4 R ^A1 , and each R ^A1 is independently halo or - OC _1-4 alkyl. In some embodiments, R ¹ is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine substituted with 1, 2, 3, or 4 halogen. In some embodiments, R ¹ is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine substituted with 2 or 3 halogens. In some embodiments, R ¹ is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine substituted with 2 or 3 halogens selected from chloro and fluoro.

In some embodiments, R ¹ is H, phenyl or pyridyl, wherein phenyl or pyridyl is optionally substituted with 1 to 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl. In some embodiments, R ¹ is phenyl or pyridyl, wherein phenyl or pyridyl is optionally substituted with 1, 2, 3, or 4 R ^A1 , each R ^A1 is independently halo, C _{1 - 6} alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl. In some embodiments, R ¹ is phenyl or pyridyl optionally substituted with 1, 2, 3 or 4 R ^A1 , and each R ^A1 is independently halo, C _1-4 alkyl, C _{1 - 4} haloalkyl or -OC _1-4 alkyl. In some embodiments, R ¹ is phenyl or pyridyl optionally substituted with 1, 2, 3 or 4 R ^A1 , each R ^A1 is independently halo, C _1-4 alkyl, or —OC _{1 -4} alkyl. In some embodiments, R ¹ is phenyl or pyridyl optionally substituted with 1, 2, 3, or 4 R ^A1 , and each R ^A1 is independently halo or C _1-4 alkyl. In some embodiments, R ¹ is phenyl or pyridyl optionally substituted with 1, 2, 3 or 4 R ^A1 , and each R ^A1 is independently halo or —OC _1-4 alkyl. In some embodiments, R ¹ is phenyl or pyridyl substituted with 1, 2, 3, or 4 halogen. In some embodiments, R ¹ is phenyl or pyridyl substituted with 2 or 3 halogens. In some embodiments, R ¹ is phenyl or pyridyl substituted with 2 or 3 halogens selected from chloro and fluoro.

In some embodiments, a compound of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, and VIIb wherein R ¹ is H or C _6-10 aryl, C _6-10 aryl is optionally substituted with 1 to 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _{1 -4} haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl. In some embodiments, R ¹ is H or phenyl; phenyl is optionally substituted with 1 to 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _{1 -4} alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl. In some embodiments, R ¹ is phenyl optionally substituted with 1, 2, 3 or 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl , C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl. In some embodiments, R ¹ is phenyl optionally substituted with 1, 2, 3 or 4 R ^A1 , each R ^A1 is independently halo, C _1-4 alkyl, C _1-4 haloalkyl or -OC _1-4 alkyl. In some embodiments, R ¹ is phenyl optionally substituted with 1, 2, 3, or 4 R ^A1 , each R ^A1 is independently halo, C _1-4 alkyl, or —OC _1-4 alkyl to be. In some embodiments, R ¹ is phenyl optionally substituted with 1, 2, 3, or 4 R ^A1 , and each R ^A1 is independently halo or C _1-4 alkyl. In some embodiments, R ¹ is phenyl optionally substituted with 1, 2, 3, or 4 R ^A1 , and each R ^A1 is independently halo or —OC _1-4 alkyl. In some embodiments, R ¹ is phenyl substituted with 1, 2, 3, or 4 halogen. In some embodiments, R ¹ is phenyl substituted with 2 or 3 halogens. In some embodiments, R ¹ is phenyl substituted with 2 or 3 halogens selected from chloro and fluoro.

,

,

,

,

,

및

로 이루어진 군으로부터 선택된다. 일부 실시형태에서, R¹은In some embodiments, R ¹ is

,

,

,

,

,

and

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

,

및

로 이루어진 군으로부터 선택된다. 일부 실시형태에서, R¹은

,

,

및

로 이루어진 군으로부터 선택된다.

,

and

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

,

,

and

is selected from the group consisting of

In some embodiments, R ¹ is pyridyl optionally substituted with 1, 2, 3 or 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 halo alkyl, C _3-6 cycloalkyl, cyano, —OC _1-4 alkyl, —OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl. In some embodiments, R ¹ is pyridyl optionally substituted with 1, 2, 3 or 4 R ^A1 , each R ^A1 is independently halo, C _1-4 alkyl, C _1-4 halo alkyl or -OC _1-4 alkyl. In some embodiments, R ¹ is pyridyl optionally substituted with 1, 2, 3 or 4 R ^A1 , each R ^A1 is independently halo, C _1-4 alkyl, or —OC _1-4 is alkyl. In some embodiments, R ¹ is pyridyl optionally substituted with 1, 2, 3, or 4 R ^A1 , and each R ^A1 is independently halo or C _1-4 alkyl. In some embodiments, R ¹ is pyridyl optionally substituted with 1, 2, 3, or 4 R ^A1 , and each R ^A1 is independently halo or —OC _1-4 alkyl. In some embodiments, R ¹ is pyridyl substituted with 1, 2, 3, or 4 halogen. In some embodiments, R ¹ is pyridyl substituted with 2 or 3 halogens. In some embodiments, R ¹ is pyridyl substituted with 2 or 3 halogens selected from chloro and fluoro.

In some embodiments, the compound of Formula I, II, III, IV, VI, or VII has Formula VIII:

[Formula VIII]

;

In the above formula, p is 2 or 3.

In some embodiments, the compound of Formula I, Ia, II, IIa, III, IIIa, IV, IVa, VI, VIa, VII, or VIIa has Formula VIIIa:

[Formula VIIIa]

;

In the above formula, p is 2 or 3.

In some embodiments, the compound of Formula I, Ib, II, IIb, III, IIIb, IV, IVb, VI, VIb, VII, or VIIb has Formula VIIIb:

[Formula VIIIb]

;

In the above formula, p is 2 or 3.

In some embodiments, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, for compounds of VIIIa or VIIIb, each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _{3 -6} cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl. In some embodiments, each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cyclo alkyl or C _1-4 alkyl-OC _1-4 alkyl. In some embodiments, each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cyclo alkyl or C _1-4 alkyl-OC _1-4 alkyl. In some embodiments, each R ^A1 is independently halo, C _1-4 alkyl, C _1-4 haloalkyl, or —OC _1-4 alkyl. In some embodiments, each R ^A1 is independently halo, C _1-4 alkyl, or —OC _1-4 alkyl. In some embodiments, each R ^A1 is independently halo, C _1-4 alkyl, cyano, or —OC _1-4 alkyl. In some embodiments, each R ^A1 is independently halo, cyano, or C _1-4 alkyl. In some embodiments, each R ^A1 is independently halo or C _1-4 alkyl. In some embodiments, each R ^A1 is independently halo, cyano, or -OC _1-4 alkyl. In some embodiments, each R ^A1 is independently halo or -OC _1-4 alkyl. In some embodiments, each R ^A1 is independently halogen. In some embodiments, each R ^A1 is independently chloro or fluoro.

In some embodiments, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, For compounds of VIIIa or VIIIb, R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a and R ^9b are each independently H, C _1-6 alkyl, C _1-4 haloalkyl, halo, hydroxyl, cyano, -OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl. In some embodiments, R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a and R ^9b are each independently H, C ₁ -C ₆ alkyl, halo, or cyano. In some embodiments, R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a and R ^9b are each independently H, halo or C ₁ -C ₄ alkyl. In some embodiments, R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a and R ^9b are each independently H, fluoro, chloro, or C ₁ -C ₄ alkyl. In some embodiments, each of R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a and R ^9b is independently H or cyano. In some embodiments, R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a and R ^9b are each independently H or C _1-4 haloalkyl.

In some embodiments, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, For the compound of VIIIa or VIIIb, any one of (i) R ^4a and R ^4b , (ii) R ^5a and R ^5b , (iii) R ^8a and R ^8b , or (iv) R ^9a and R ^9b is that they are together with the attached carbon atoms form (i) a 3 to 7 membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, O and S and a 3-7 membered carbocyclic ring or a 4-7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e . In some embodiments, any one of (i) R ^4a and R ^4b , (ii) R ^5a and R ^5b , (iii) R ^8a and R ^8b , or (iv) R ^9a and R ^9b is the carbon to which they are attached together with the atoms form (i) a 3-7 membered carbocyclic ring or (ii) a 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S; 7-7 membered carbocyclic ring or 4-7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, any one of (i) R ^4a and R ^4b , (ii) R ^5a and R ^5b , (iii) R ^8a and R ^8b , or (iv) R ^9a and R ^9b is the carbon to which they are attached taken together with the atoms form a 3- to 7-membered carbocyclic ring, wherein the 3- to 7-membered carbocyclic ring is optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo, halo , cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, any one of (i) R ^4a and R ^4b , (ii) R ^5a and R ^5b , (iii) R ^8a and R ^8b , or (iv) R ^9a and R ^9b is the carbon to which they are attached together with the atoms form a 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, a 3-7 membered carbocyclic ring or a 4-7 membered heteroatom The click ring is optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, any one of (i) R ^4a and R ^4b , (ii) R ^5a and R ^5b , (iii) R ^8a and R ^8b , or (iv) R ^9a and R ^9b is the carbon to which they are attached Together with the atoms form (i) a 3-7 membered carbocyclic ring or (ii) a 3-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S. In some embodiments, any one of (i) R ^4a and R ^4b , (ii) R ^5a and R ^5b , (iii) R ^8a and R ^8b , or (iv) R ^9a and R ^9b is the carbon to which they are attached taken together with the atoms form a 3-membered carbocyclic ring optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo, halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, any one of (i) R ^4a and R ^4b , (ii) R ^5a and R ^5b , (iii) R ^8a and R ^8b , or (iv) R ^9a and R ^9b is the carbon to which they are attached Together with the atoms, a 3- to 7-membered carbocyclic ring is formed. In some embodiments, R ^4a and R ^4b , taken together with the carbon atom to which they are attached, form a 3-membered carbocyclic ring optionally substituted with 1 to 3 R ^A3 , and each R ^A3 is independently oxo , halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, R ^5a and R ^5b , taken together with the carbon atom to which they are attached, form a 3-membered carbocyclic ring optionally substituted with 1 to 3 R ^A3 , and each R ^A3 is independently oxo , halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, R ^8a and R ^8b , taken together with the carbon atom to which they are attached, form a 3-membered carbocyclic ring optionally substituted with 1 to 3 R ^A3 , and each R ^A3 is independently oxo , halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, R ^9a and R ^9b , taken together with the carbon atom to which they are attached, form a 3-membered carbocyclic ring optionally substituted with 1 to 3 R ^A3 , and each R ^A3 is independently oxo , halo, cyano, C _1-6 alkyl or C _3-6 cycloalkyl. In some embodiments, R ^4a and R ^4b together with the carbon atom to which they are attached form a 3-membered carbocyclic ring. In some embodiments R ^5a and R ^5b together with the carbon atom to which they are attached form a 3-membered carbocyclic ring. In some embodiments, R ^8a and R ^8b together with the carbon atom to which they are attached form a 3-membered carbocyclic ring. In some embodiments, R ^9a and R ^9b together with the carbon atom to which they are attached form a 3-membered carbocyclic ring.

In some embodiments, for compounds of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

In some embodiments, for compounds of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, each R ² is independently C _1-6 alkyl, C _3-6 cycloalkyl, halo, Cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C( O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or - S(O) _n- R ^a- ; two R ² at the same carbon atom, together with the carbon atom to which they are both attached, form a 3- to 7-membered carbocyclic ring, wherein the 3- to 7-membered carbocyclic ring has 1-3 optionally substituted with R ^A2 , and each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, for compounds of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, each R ² is independently C _1-6 alkyl, C _3-6 cycloalkyl, halo, Cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C( O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or - S(O) _n- R ^a- ; R ^2a and R ^2b or two R ² at the same carbon atom, together with the carbon atom to which they are both attached, form a 3 to 5 membered carbocyclic ring and a 3 to 5 membered carbocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, for compounds of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, each R ² is independently C _1-6 alkyl, C _3-6 cycloalkyl, halo, Cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C( O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or - S(O) _n- R ^a- ; two R ² at the same carbon atom, together with the carbon atom to which they are both attached, form a 3-membered carbocyclic ring, the 3-membered carbocyclic ring optionally substituted with 1 to 3 R ^A2 . and each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e .

In some embodiments, for a compound of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIb, each R ² is independently C _1-6 alkyl, C _3-6 cycloalkyl, halo, Cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C( O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or - S(O) _n- R ^a- ; Two R ² at the same carbon atom, together with the carbon atom to which they are both attached, form a 3-membered carbocyclic ring.

In some embodiments, a compound of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, each R ² is independently C _1-6 alkyl, C _3-6 cycloalkyl, halo, cyano , -CH ₂ R ^a- , -CH ₂ OR ^a , -OR ^a , or -NHR ^a . In some embodiments, each R ² is independently C _1-6 alkyl, C _3-6 cycloalkyl, halo, cyano, —CH ₂ R ^a- , —CH ₂ OR ^a , or —OR ^a . In some embodiments, each R ² is independently C _1-6 alkyl, C _3-6 cycloalkyl or halo. In some embodiments, each R ² is independently halo. In some embodiments, each R ² is independently -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )-, -S(O) _n- R ^a- or -OC(O)-NHR ^a . In some embodiments, each R ² is independently -OR ^a , -NHR ^a , -C(O)-NH(R ^a ), -NR ^e- C(O)R ^a , or -NR ^e- S(O) _n R ^a . In some embodiments, each R ² is independently -OR ^a or -OC(O)-NHR ^a . In some embodiments, each R ² is independently -S(O) _n- NH(R ^a ) or -S(O) _n- R ^a- . In some embodiments, each R ² is independently halo, cyano, -NHR ^a- or -OR ^a . In some embodiments, each R ² is -NHR ^a . In some embodiments, each R ² is independently halo, cyano or —OR ^a . In some embodiments, each R ² is cyano. In some embodiments, each R ² is independently —OR ^a . In some embodiments, each R ² is independently —OR ^a , and each R ^a is independently selected from 1 to 2 substituents independently selected from the group consisting of halo, cyano and —OC ₁ -C ₄ alkyl. optionally substituted C ₃ -C ₆ cycloalkyl. In some embodiments, each R ² is independently —OR ^a , and each R ^a is independently selected from 1 to 2 substituents independently selected from the group consisting of halo, cyano, —OC ₁ -C ₄ alkyl. optionally substituted C ₁ -C ₆ alkyl. In some embodiments, each R ² is independently —OR ^a , and each R ^a is independently —OC _1-4 alkyl or C ₁ -C ₆ alkyl optionally substituted with halo. In some embodiments, each R ² is independently —OR ^a , and each R ^a is independently C ₁ -C ₆ alkyl optionally substituted with —OC _1-4 alkyl.

In some embodiments, a compound of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, m is 2, and each R ² is independently C _1-6 alkyl, C _3-6 cycloalkyl , halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -OR ^a or -NHR ^a . In some embodiments, m is 2, each R ² is independently C _1-6 alkyl, C _3-6 cycloalkyl, halo, cyano, —CH ₂ R ^a- , —CH ₂ OR ^a , or —OR ^a . In some embodiments, m is 2, each R ² is independently C _1-6 alkyl, C _3-6 cycloalkyl or halo. In some embodiments, m is 2, each R ² is independently halo. In some embodiments, m is 2, each R ² is independently -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )-, -S(O) _n- R ^a- or -OC(O)-NHR ^a . In some embodiments, m is 2, each R ² is independently -OR ^a , -NHR ^a , -C(O)-NH(R ^a ), -NR ^e- C(O)R ^a , or -NR ^e- S(O) _n R ^a . In some embodiments, m is 2, each R ² is independently -OR ^a or -OC(O)-NHR ^a . In some embodiments, m is 2, each R ² is independently -S(O) _n- NH(R ^a ) or -S(O) _n- R ^a- . In some embodiments, m is 2, each R ² is independently halo, cyano, -NHR ^a- or -OR ^a . In some embodiments, m is 2, each R ² is independently —NHR ^a . In some embodiments, m is 2, each R ² is independently halo, cyano or —OR ^a . In some embodiments, m is 2, each R ² is cyano. In some embodiments, m is 2, each R ² is independently halo. In some embodiments, m is 2 and each R ² is independently —OR ^a . In some embodiments, m is 2, each R ² is independently —OR ^a , and each R ^a is independently 1 independently selected from the group consisting of halo, cyano and —OC ₁ -C ₄ alkyl. C ₃ -C ₆ cycloalkyl optionally substituted with to 2 substituents. In some embodiments, m is 2, each R ² is independently —OR ^a , and each R ^a is independently 1 selected from the group consisting of halo, cyano, —OC ₁ -C ₄ alkyl. C ₁ -C ₆ alkyl optionally substituted with to 2 substituents. In some embodiments, m is 2, each R ² is independently —OR ^a , and each R ^a is independently —OC _1-4 alkyl or C ₁ -C ₆ alkyl optionally substituted with halo. In some embodiments, each m is 2, R ² is independently —OR ^a , and each R ^a is independently C ₁ -C ₆ alkyl optionally substituted with —OC _1-4 alkyl.

In some embodiments, a compound of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, m is 1, and R ² is C _1-6 alkyl, C _3-6 cycloalkyl, halo, cya. no, -CH ₂ R ^a- , -CH ₂ OR ^a , -OR ^a or -NHR ^a . In some embodiments, m is 1 and R ² is C _1-6 alkyl, C _3-6 cycloalkyl, halo, cyano, —CH ₂ R ^a- , —CH ₂ OR ^a , or —OR ^a . In some embodiments, m is 1 and R ² is C _1-6 alkyl, C _3-6 cycloalkyl, or halo. In some embodiments, m is 1, R ² is halo. In some embodiments, m is 1 and R ² is -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )-, -S(O) _n- R ^a- or -OC(O)-NHR ^a . In some embodiments, m is 1 and R ² is -OR ^a , -NHR ^a , -C(O)-NH(R ^a ), -NR ^e -C(O)R ^a , or -NR ^e- S( O) _n R ^a . In some embodiments, m is 1 and R ² is -OR ^a or -OC(O)-NHR ^a . In some embodiments, m is 1 and R ² is -S(O) _n- NH(R ^a ) or -S(O) _n- R ^a- . In some embodiments, m is 1 and R ² is halo, cyano, -NHR ^a- or -OR ^a . In some embodiments, m is 1 and R ² is —NHR ^a . In some embodiments, m is 1 and R ² is halo, cyano, or —OR ^a . In some embodiments, m is 1 and R ² is cyano. In some embodiments, m is 1 and R ² is halo. In some embodiments, m is 1 and R ² is —OR ^a . In some embodiments, m is 1, R ² is —OR ^a , and R ^a is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, cyano and —OC ₁ -C ₄ alkyl. C ₃ -C ₆ cycloalkyl. In some embodiments, m is 1 and R ² is —OR ^a ; R ^a is C ₁ -C ₆ alkyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, -OC ₁ -C ₄ alkyl. In some embodiments, m is 1 and R ² is —OR ^a ; R ^a is -OC _1-4 alkyl or C ₁ -C ₆ alkyl optionally substituted with halo. In some embodiments, each m is 1, R ² is —OR ^a , and each R ^a is C ₁ -C ₆ alkyl optionally substituted with —OC _1-4 alkyl.

In some embodiments, a compound of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, m is 1 or 2, and each R ² is independently halo or —OR ^a , and each R ^a is independently H or C ₁ -C ₆ alkyl. In some embodiments, m is 1 or 2, each R ² is independently halo or —OR ^a , and each R ^a is independently H or C ₁ -C ₃ alkyl. In some embodiments, m is 1 or 2, each R ² is independently halo or —OR ^a , and each R ^a is independently H or methyl. In some embodiments, m is 1 or 2, each R ² is independently halo or —OR ^a , and each R ^a is H. In some embodiments, m is 1 or 2, each R ² is independently halo or —OR ^a , and each R ^a is methyl.

In some embodiments, a compound of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, m is 1, R ² is halo or —OR ^a , R ^a is H or C ₁ -C ₆ alkyl. In some embodiments, m is 1, R ² is halo or —OR ^a , and R ^a is H or C ₁ -C ₃ alkyl. In some embodiments, m is 1, R ² is halo or —OR ^a , and R ^a is H or methyl. In some embodiments, m is 1, R ² is halo or —OR ^a , and R ^a is H. In some embodiments, m is 1, R ² is halo or —OR ^a , and R ^a is methyl.

In some embodiments, a compound of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, m is 2, each R ² is independently halo or —OR ^a , and each R ^a is independently H or C ₁ -C ₆ alkyl. In some embodiments, m is 2, each R ² is independently halo or —OR ^a , and each R ^a is independently H or C ₁ -C ₃ alkyl. In some embodiments, m is 2, each R ² is independently halo or —OR ^a , and each R ^a is independently H or methyl. In some embodiments, m is 2, each R ² is independently halo or —OR ^a , and each R ^a is H. In some embodiments, m is 2, each R ² is independently halo or —OR ^a , and each R ^a is methyl.

In some embodiments, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, In the compounds of VIIIa and VIIIb, each R ^a is independently H, C _1-6 alkyl or C _3-6 cycloalkyl; C _1-6 alkyl or C _3-6 cycloalkyl contains 1 or 2 heteroatoms selected from halo, cyano, -OC _1-4 alkyl, 5-10 membered carbocyclic ring, N, O and S independently from the group consisting of a 5-10 membered heterocyclic ring, a 6-10 membered aromatic ring, and a 5-10 membered heteroaromatic ring containing 1 or 3 heteroatoms selected from N, O and S 5-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring optionally substituted with 0-4 selected substituents is optionally substituted with 1 to 4 R ^A5 , each R ^A5 is independently oxo, halo, cyano, C _1-6 alkyl, C _1-6 cycloalkyl or —OR ^e .

In some embodiments, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, In the compounds of VIIIa, and VIIIb, each R ^a is independently H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, which is halo, cyano, —OC ₁ -C ₄ alkyl, 5-10 members. optionally substituted with 1 to 2 substituents independently selected from the group consisting of a membered carbocyclic ring and a 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S .

In some embodiments, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, In the compounds of VIIIa, and VIIIb, each R ^a is independently H, C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl, which is independently from the group consisting of halo, cyano and -OC ₁ -C ₄ alkyl It is optionally substituted with 1 to 2 substituents selected from

In some embodiments, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, In the compounds of VIIIa, and VIIIb, each R ^a is independently C ₃ -C optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano and -OC ₁ -C ₄ alkyl ₆ cycloalkyl.

In some embodiments, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, In the compounds of VIIIa, and VIIIb, each R ^a is independently C ₁ -C ₆ optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, -OC ₁ -C ₄ alkyl is alkyl.

In some embodiments, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, In the compounds of VIIIa, and VIIIb, each R ^a is independently —OC _1-4 alkyl or C _1-6 alkyl optionally substituted with halo.

In some embodiments, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, In the compounds of VIIIa and VIIIb, each R ^a is independently a 5- to 10-membered carbocyclic ring, a 5- to 10-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S; 6 to 10 membered aromatic ring, or 5 to 10 membered heteroaromatic ring containing 1 or 3 heteroatoms selected from N, O and S, 5 to 10 membered carbocyclic ring, 5 to 10 membered The heterocyclic ring, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A4 , each R ^A4 is independently oxo, halo, cyano, C _1-6 alkyl, C _1-6 cycloalkyl or —OR ^e .

Compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa and VIIIb in some embodiments of, each R ^e is independently H, C _1-4 alkyl or C _3-6 cycloalkyl, and each C _1-4 alkyl or C _3-6 cycloalkyl is independently optionally substituted. In some embodiments, each R ^e is independently H, C _1-4 alkyl or C _3-6 cycloalkyl. In some embodiments, each R ^e is independently H or C _1-4 alkyl, wherein C _1-4 alkyl is optionally substituted with halo or cyano. In some embodiments, each R ^e is independently H or C _3-6 cycloalkyl, and each C _3-6 cycloalkyl is optionally substituted with halo or cyano. In some embodiments, each R ^e is independently H or C _1-4 alkyl. In some embodiments, each R ^e is independently H or C _3-6 cycloalkyl. In some embodiments, each R ^e is H. In some embodiments, each R ^e is independently C _1-4 alkyl. In some embodiments, each R ^e is independently C _3-6 cycloalkyl.

In some embodiments, for compounds of Formulas VIII, VIIIa, and VIIIb, p is 2 or 3 and each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cyclo alkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl. In some embodiments, p is 2 or 3 and each R ^A1 is independently halo, C _1-4 alkyl, C _1-4 haloalkyl, or —OC _1-4 alkyl. In some embodiments, p is 2 or 3 and each R ^A1 is independently halo, C _1-4 alkyl, or —OC _1-4 alkyl. In some embodiments, p is 2 or 3 and each R ^A1 is independently halo or C _1-4 alkyl. In some embodiments, p is 2 or 3 and each R ^A1 is independently halo or -OC _1-4 alkyl. In some embodiments, p is 2 or 3 and each R ^A1 is independently halogen. In some embodiments, p is 2 or 3 and each R ^A1 is independently selected from chloro and fluoro.

In some embodiments, for compounds of Formulas VIII, VIIIa, and VIIIb, p is 2 and each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl. In some embodiments, p is 2 and each R ^A1 is independently halo, C _1-4 alkyl, C _1-4 haloalkyl, or —OC _1-4 alkyl. In some embodiments, p is 2 and each R ^A1 is independently halo, C _1-4 alkyl, or —OC _1-4 alkyl. In some embodiments, p is 2 and each R ^A1 is independently halo or C _1-4 alkyl. In some embodiments, p is 2 and each R ^A1 is independently halo or -OC _1-4 alkyl. In some embodiments, p is 2 and each R ^A1 is independently halogen. In some embodiments, p is 2 and each R ^A1 is independently selected from chloro and fluoro.

In some embodiments, for compounds of Formulas VIII, VIIIa, and VIIIb, p is 3 and each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl. In some embodiments, p is 3 and each R ^A1 is independently halo, C _1-4 alkyl, C _1-4 haloalkyl, or —OC _1-4 alkyl. In some embodiments, p is 3 and each R ^A1 is independently halo, C _1-4 alkyl, or —OC _1-4 alkyl. In some embodiments, p is 3 and each R ^A1 is independently halo or C _1-4 alkyl. In some embodiments, p is 3 and each R ^A1 is independently halo or -OC _1-4 alkyl. In some embodiments, p is 3 and each R ^A1 is independently halogen. In some embodiments, p is 3 and each R ^A1 is independently selected from chloro and fluoro.

In some embodiments of the compound of Formula IV, IVa, or IVb:

[Formula IV]

[Formula IVa]

[Formula IVb]

X is -CR ^8a R ^8b- ;

W ¹ is a bond or -CR ^4a R ^4b- ;

W ² is -CR ^5a R ^5b- or -CR ^6a =CR ^6b- ;

Z is -CR ^9a R ^9b- ;

L is -CH ₂ -;

R ^2a , R ^2b , R ^12a and R ^12b are independently H, C _1-6 alkyl, halo, —OR ^a— or —CH ₂ OR ^a ;

R ^a is H or C _1-6 alkyl;

R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a , R ^9b are independently H, hydroxyl, C _1-6 alkyl or —OC _1-4 alkyl;

both R ^6a and R ^6b are H;

R ¹ is C ^6-10 aryl optionally substituted with 1 to 4 R _A1 , and each R ^A1 is independently fluoro or chloro.

In some embodiments, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, The compound of VIIIa or VIIIb is

,

,

,

,

,

' 및

로 이루어진 군으로부터 선택된 화합물, 또는 이들의 약제학적으로 허용 가능한 염이다.

,

,

,

,

,

' and

A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

In some embodiments, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, The compound of VIIIa or VIIIb is

및

로 이루어진 군으로부터 선택된 화합물, 또는 이들의 약제학적으로 허용 가능한 염이다.

and

A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

In some embodiments, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, The compound of VIIIa or VIIIb is

및

로 이루어진 군으로부터 선택된 화합물, 또는 이들의 약제학적으로 허용 가능한 염이다.

and

A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

III. Compositions and kits

The compounds provided herein are usually administered in the form of pharmaceutical compositions. As such, also provided herein are pharmaceutical compositions comprising one or more compounds provided herein or a pharmaceutically acceptable salt, isomer, or mixture thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. do. A compound provided herein may be the sole active ingredient or one of the active ingredients of a pharmaceutical composition. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner known in the pharmaceutical art. See, eg, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985)]; and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.)].

In one aspect, a compound provided herein (eg, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, Provided herein is a pharmaceutical composition comprising a compound of VII, VIIa, VIIb, VIII, VIIIa or VIIIb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

In some embodiments, the pharmaceutical compositions provided herein comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) ) of an additional therapeutic agent, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4). species), or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition may be administered in either a single dose or multiple doses. The pharmaceutical composition can be administered by a variety of methods including, for example, the rectal route, the buccal route, the intranasal route, and the transdermal route. In some embodiments, the pharmaceutical composition may be administered by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

One mode of administration is parenterally, for example by injection. Forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or sterile aqueous solutions, and similar pharmaceutical vehicles. of aqueous or oily suspensions or emulsions.

Oral administration may be another route of administration for a compound provided herein. Administration can be via, for example, capsules or enteric coated tablets. In preparing a pharmaceutical composition comprising at least one compound provided herein, or a pharmaceutically acceptable salt, isomer or mixture thereof, the active ingredient (eg, a compound provided herein) is usually diluted with an excipient and/or , enclosed in a carrier, which may be in the form of a capsule, sachet, paper or other container. When an excipient serves as a diluent, it may be in the form of a solid, semi-solid or liquid substance, which acts as a vehicle, carrier or medium for the active ingredient. Thus, pharmaceutical compositions can be formulated as tablets, pills, powders, lozenges, cachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (either as solid or in a liquid medium), for example containing up to 10% by weight of the active compound. It may be in the form of ointments containing ointments, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

Some examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methyl cellulose or any combination thereof. The pharmaceutical composition may contain lubricants such as talc, magnesium stearate and mineral oil; wetting agent; emulsifying and suspending agents; preservatives such as methyl and propylhydroxy-benzoates; sweetener; and spices; or any combination thereof.

Pharmaceutical compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, can be prepared for rapid release of an active ingredient (eg, a compound provided herein) following administration to a subject by using procedures known in the art. It may be formulated to provide release, sustained release or delayed release. Controlled release drug delivery systems for oral administration include dissolution systems and osmotic pump systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are described in US Pat. Nos. 3,845,770; US Pat. No. 4,326,525; US Pat. No. 4,902,514; and U.S. Patent No. 5,616,345. Another formulation for use in the methods of the present disclosure uses a transdermal delivery device (“patch”). Such transdermal patches can be used to provide continuous or discontinuous infusion of a controlled amount of a compound provided herein. The construction and use of transdermal patches for the delivery of medicaments are well known in the art. See, for example, US Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches may be configured for continuous, pulsed or on-demand delivery of the medicament.

To prepare a solid composition such as a tablet, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof. can be formed When this preformulation composition is referred to as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

Tablets or pills of the compounds described herein may be coated or otherwise formulated to provide a dosage form that provides the benefit of sustained action, or to protect against the acid conditions of the stomach. For example, a tablet or pill may contain an inner dosage component and an outer dosage component, the latter in the form of a shell over the former. The two components function to resist disintegration in the stomach and can be separated by an enteric layer that allows the inner component to pass intact into the duodenum or to delay release. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

Pharmaceutical compositions for inhalation or insufflation may include solutions and suspensions and powders in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by the oral or nasal respiratory route for local or systemic effect. In another embodiment, the composition in a pharmaceutically acceptable solvent may be nebulized by the use of an inert gas. The nebulized solution may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a facemask tent or intermittent positive pressure respirator. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

In one aspect, a compound provided herein (eg, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, Provided herein is a kit comprising a compound of VII, VIIa, VIIb, VIII, VIIIa or VIIIb), or a pharmaceutically acceptable salt, stereoisomer, prodrug or solvate thereof, and suitable packaging. In some embodiments, the kit further comprises instructions for use. In some embodiments, the kit comprises a compound provided herein (e.g., Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa , VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a disease or condition described herein. labels and/or instructions for use of the compound in

In some embodiments, the kit includes one or more (eg, 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents. , or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein is an article of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, in a suitable container. In some embodiments, the container may be a vial, bottle, ampoule, preloaded syringe, or intravenous bag.

IV. Way

In one embodiment, a therapeutically effective amount of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof, or Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb , VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or a human at risk of having an infection comprising administering to the human a pharmaceutical composition of a compound of VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof A method of treating HIV (eg, HIV-1 and/or HIV-2) infection is provided.

In some embodiments, the method further comprises administering to the human a therapeutically effective amount of one, two, three or four additional therapeutic agents. In certain embodiments, the additional therapeutic agent or therapeutic agents are anti-HIV agents. In certain embodiments, the additional therapeutic agent or therapeutic agents is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor , gpl20 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAb (broadly neutralizing HIV antibody), TLR7 agonists, pharmacokinetic enhancers, other drugs to treat HIV, or combinations thereof to be. In one embodiment, the additional therapeutic agent or therapeutic agents is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-(( S )-1-(3-(4-chloro-3-(methylsulfonami) Figure)-l-(2,2,2-trifluoroethyl)-lH-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l- yne -l -yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b S ,4a R )-5,5-difluoro-3-(trifluoro methyl)-3b, 4,4a ,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2- c ]pyrazol-l-yl)acetamide, or a pharmaceutical thereof is an acceptable salt.

In another embodiment, for the treatment of HIV (eg, HIV-1 and/or HIV-2) infection in a human having or at risk of having an infection, Formula I, Ia, Ib, II, IIa, IIb, A compound of III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof, or Formula I , Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or The use of a pharmaceutical composition of a pharmaceutically acceptable salt thereof is provided.

In another embodiment, for use in medical treatment, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII , VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof, or Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Provided is a pharmaceutical composition of a compound of Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof.

In another embodiment, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, A compound of VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof, or Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb , V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof.

In another embodiment, for use in a method of treating an HIV infection in a human having or at risk of having an infection, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb , V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, a compound of VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof, or Formula I, Ia, Ib, II, IIa, IIb, A pharmaceutical composition of a compound of III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof is provided

In another embodiment, for use in a method of treating an HIV infection in a human having or at risk of having an infection, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb , V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, a compound of VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof, or Formula I, Ia, Ib, II, IIa, IIb, A pharmaceutical composition of a compound of III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof provided, the method further comprising administering to the human one, two, three or four additional therapeutic agents.

In another embodiment, for use in a method of treating an HIV infection in a human having or at risk of having an infection, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb , V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, a compound of VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof, or Formula I, Ia, Ib, II, IIa, IIb, A pharmaceutical composition of a compound of III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof Provided, wherein the method comprises an HIV protease inhibitor, an HIV nonnucleoside or nonnucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gpl20 inhibitor, a CCR5 inhibitor, one, two, three or four additional therapeutic agents selected from the group consisting of a latent reversing agent, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof It further comprises the step of administering to a human. In one embodiment, the one, two, three or four additional therapeutic agents is an HIV protease inhibitor, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, a latent reversing agent, an HIV capsid inhibitors, HIV bNAb, TLR7 agonists, and combinations thereof.

In another embodiment, for use in a method of treating an HIV infection in a human having or at risk of having an infection, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb , V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, a compound of VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof, or Formula I, Ia, Ib, II, IIa, IIb, A pharmaceutical composition of a compound of III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof provided, the method further comprising administering to the human a therapeutically effective amount of tenofovir disoproxil and emtricitabine.

In another embodiment, for use in a method of treating an HIV infection in a human having or at risk of having an infection, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb , V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, a compound of VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof, or Formula I, Ia, Ib, II, IIa, IIb, A pharmaceutical composition of a compound of III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof provided, the method further comprising administering to the human a therapeutically effective amount of tenofovir alafenamide and emtricitabine.

In another embodiment, for use in a method of treating an HIV infection in a human having or at risk of having an infection, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb , V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, a compound of VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof, or Formula I, Ia, Ib, II, IIa, IIb, A pharmaceutical composition of a compound of III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof provided, the method further comprising administering to the human a therapeutically effective amount of tenofovir disoproxil.

In another embodiment, for use in a method of treating an HIV infection in a human having or at risk of having an infection, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb , V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, a compound of VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof, or Formula I, Ia, Ib, II, IIa, IIb, A pharmaceutical composition of a compound of III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof Provided, the method further comprises administering to the human a therapeutically effective amount of tenofovir alafenamide.

In another embodiment, in the treatment of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, Methods of using the compounds of VIII, VIIIa or VIIIb are provided. In particular, formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb A compound of, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for treating the proliferation of the HIV virus in a mammal (eg, a human), treating AIDS, or , a method of delaying the onset of symptoms of AIDS or ARC.

In another embodiment, Formula I, Ia, Ib, II, for use in a method of treating the proliferation of the HIV virus, treating AIDS, or delaying the development of symptoms of AIDS or ARC in a mammal (eg, a human); A compound of IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof , and a composition comprising a pharmaceutically acceptable excipient is provided.

In one embodiment, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, A compound of VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof, or Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa A pharmaceutical composition of a compound of , VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof, is provided for use in preventing HIV infection.

For example, in one embodiment, formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof, or Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb , VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or a pharmaceutical composition of a compound of VIIIb, or a pharmaceutically acceptable salt thereof, for use in pre-exposure prophylaxis (PrEP), i.e., when an individual is exposed to a virus to prevent the HIV infection from becoming established and/or to keep the virus from establishing a permanent infection and/or to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectable levels in the blood given prior to exposure of an individual to the HIV virus.

In another embodiment, Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb for the manufacture of a medicament for the treatment of an HIV infection in a human having or at risk of having an infection. , V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof.

In other embodiments, formula I, la, lb, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb as a research tool , a compound of VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof.

In another embodiment, a composition effective for treating HIV infection; and a packaging material comprising a label indicating that the composition can be used to treat infection by HIV. Exemplary compositions include Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or a compound of VIIIb, or a pharmaceutically acceptable salt thereof.

In another embodiment, a method of inhibiting replication of HIV is disclosed. The method comprises administering the virus to an effective amount of the formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, and exposure to a compound of VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a salt thereof.

In another embodiment, formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, The use of a compound of VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb is disclosed.

In another embodiment, formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII for inhibiting replication of HIV , VIIa, VIIb, VIII, VIIIa or VIIIb, or a salt thereof.

V. administration

A compound of the present disclosure (also referred to herein as an active ingredient) may be administered by any route suitable for the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, intravaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. It will be understood that the preferred route may vary depending on, for example, the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

A compound of the present disclosure may be administered to a subject according to an effective dosing regimen for a desired period or duration, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. have. In some embodiments, the compound is administered on a daily or intermittent schedule for the life of the individual.

The specific dosage level of a compound of the present disclosure for any particular subject will depend on the activity, age, weight, general health, sex, diet, time of administration, route and excretion rate, drug combination, and treatment of the particular compound employed. will depend on a variety of factors, including the severity of the particular disease in the recipient subject. For example, a dosage may be expressed as the number of milligrams (mg/kg) of a compound described herein per kilogram of the subject's body weight. A dosage of about 0.1 to 150 mg/kg may be appropriate. In some embodiments, about 0.1 to 100 mg/kg may be appropriate. In other embodiments, a dosage of 0.5 to 60 mg/kg may be appropriate. Normalization according to a subject's body weight is widely used, as occurs when using drugs in both pediatric and adult humans, or when converting an effective dosage in a non-human subject, such as a dog, into a dosage suitable for a human subject. It is particularly useful when adjusting the dosage between subjects of different sizes.

Daily dosage may also be described as the total amount of a compound described herein administered per dose or daily. A compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb The daily dose of , or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof is about 1 mg to 4,000 mg, about 2,000 to 4,000 mg/day, about 1 to 2,000 mg/day, about 1 to 1,000 mg per day, about 10-500 mg/day, about 20-500 mg/day, about 50-300 mg/day, about 75-200 mg/day, or about 15-150 mg/day.

The dosage or frequency of administration of a compound of the present disclosure may be adjusted over the course of treatment based on the judgment of the administering physician.

A compound of the present disclosure may be administered to a subject (eg, a human) in a therapeutically effective amount. In some embodiments, the compound is administered once daily.

The compounds provided herein can be administered by any useful route and means, such as oral or parenteral (eg, intravenous) administration. A therapeutically effective amount of the compound may range from about 0.00001 mg/kg body weight daily to about 10 mg/kg body weight daily, such as from about 0.0001 mg/kg body weight daily to about 10 mg/kg body weight daily, or such as from about 0.001 mg/kg body weight daily to about 1 mg/kg body weight daily, or such as from about 0.01 mg/kg body weight daily to about 1 mg/kg body weight daily, or such as from about 0.05 mg/kg body weight daily to about 0.5 mg/kg body weight daily. In some embodiments, a therapeutically effective amount of a compound provided herein is from about 0.3 mg to about 30 mg daily, or from about 30 mg to about 300 mg daily, or from about 0.3 μg to about 30 mg daily, or from about 30 μg to about daily 300 μg.

A compound of the present disclosure may be combined with one or more additional therapeutic agents at any dosage of a compound of the present disclosure (eg, 1 mg to 1000 mg of compound). A therapeutically effective amount may be from about 0.1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or such as from about 100 mg per dose to about 400 mg per dose, or such as about 150 mg per dose. to about 350 mg per dose, or such as from about 200 mg per dose to about 300 mg per dose, or such as from about 0.01 mg per dose to about 1000 mg per dose, or such as from about 0.01 mg per dose to about 100 mg per dose, or such as about 0.1 mg per dose to about 100 mg per dose, or such as about 1 mg per dose to about 100 mg per dose, or such as about 1 mg per dose to about 10 mg per dose, or such as about 1 mg per dose to about 1 mg per dose. about 1000 mg of sugar. Other Treatments of Compounds of Formulas I, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb A therapeutically effective amount is about 1 mg per dose, or about 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 per dose. mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or about 100 mg. Another therapeutically effective amount of a compound of the present disclosure is about 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, per dose; 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg , 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or about 1000 mg.

In some embodiments, the methods described herein comprise administering to the subject an initial daily dose of a compound described herein from about 1 mg to 500 mg and increasing the dose in increments until clinical efficacy is achieved. Increments of about 5 mg, 10 mg, 25 mg, 50 mg or 100 mg may be used to increase the dose. The dosage may be increased daily, every other day, twice a week, once a week, once every two weeks, once every three weeks, or once every month.

When administered orally, the total daily dosage for a human subject is from about 1 mg to 1,000 mg, from about 10 to 500 mg/day, from about 50 to 300 mg/day, from about 75 to 200 mg/day, or from about 100 to 150 mg/daily. In some embodiments, the total daily dose to the human subject is about 100 mg/day, 200 mg/day, 300 mg/day, 400 mg/day, 500 mg/day, 600 mg/day, 700 administered as a single dose. mg/day, 800 mg/day, 900 mg/day or 1000 mg/day. In some embodiments, the total daily dose to the human subject is about 200 mg/day, 300 mg/day, 400 mg/day, 500 mg/day, 600 mg/day, 700 mg/day, or 800 administered as a single dose. mg/day. In some embodiments, the total daily dose to a human subject may be about 300 mg/day, 400 mg/day, 500 mg/day, or 600 mg/day administered as a single dose.

In some embodiments, the total daily dosage to a human subject may be about 100 mg/day administered as a single dose. In some embodiments, the total daily dosage to a human subject may be about 150 mg/day administered as a single dose. In some embodiments, the total daily dosage to a human subject may be about 200 mg/day administered as a single dose. In some embodiments, the total daily dosage to a human subject may be about 250 mg/day administered as a single dose. In some embodiments, the total daily dosage to a human subject may be about 300 mg/day administered as a single dose. In some embodiments, the total daily dosage to a human subject may be about 350 mg/day administered as a single dose. In some embodiments, the total daily dosage to a human subject may be about 400 mg/day administered as a single dose. In some embodiments, the total daily dosage to a human subject may be about 450 mg/day administered as a single dose. In some embodiments, the total daily dose to a human subject may be about 500 mg/day administered as a single dose. In some embodiments, the total daily dosage to a human subject may be about 550 mg/day administered as a single dose. In some embodiments, the total daily dosage to a human subject may be about 600 mg/day administered as a single dose. In some embodiments, the total daily dosage to a human subject may be about 650 mg/day administered as a single dose. In some embodiments, the total daily dose to a human subject may be about 700 mg/day administered as a single dose. In some embodiments, the total daily dosage to a human subject may be about 750 mg/day administered as a single dose. In some embodiments, the total daily dosage to a human subject may be about 800 mg/day administered as a single dose. In some embodiments, the total daily dosage to a human subject may be about 850 mg/day administered as a single dose. In some embodiments, the total daily dosage to a human subject may be about 900 mg/day administered as a single dose. In some embodiments, the total daily dosage to a human subject may be about 950 mg/day administered as a single dose. In some embodiments, the total daily dosage to a human subject may be about 1000 mg/day administered in a single dose.

A single dose may be administered hourly, daily, weekly or monthly. For example, a single dose may be administered once every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or once every 24 hours. A single dose may also be administered once every 1, 2, 3, 4, 5, 6, or once every 7 days. A single dose may also be administered once every 1 week, 2 weeks, 3 weeks, or once every 4 weeks. In certain embodiments, a single dose may be administered once weekly. A single dose may also be administered once monthly. In some embodiments, a compound disclosed herein is administered once daily in a method disclosed herein. In some embodiments, a compound disclosed herein is administered twice daily in a method disclosed herein.

The frequency of administration of a compound of the present disclosure will be determined by the needs of the individual patient and may be, for example, once daily or twice daily or more. Administration of the compound continues for as long as necessary to treat HBV infection, HIV infection, cancer, hyperproliferative disease, or any other indication described herein. For example, the compound may be administered to a person infected with HBV for a period of 20 days to 180 days, or for example, for a period of 20 days to 90 days, or for example, for a period of 30 days to 60 days. .

Administration can be intermittent by a period of several days or more days while the patient is receiving a daily dose of a compound of the present disclosure, followed by a period of several days or more days while the patient is not receiving a daily dose of the compound. For example, a patient may receive a dose of the compound every other day, or three times weekly. As another example, the patient receives a dose of the compound daily for a period of 1 to 14 days, then the patient does not receive a dose of the compound for a period of 7 to 21 days, and then the patient receives the daily dose of the compound for a subsequent period ( For example, 1 to 14 days). Alternating periods of administration of the compound followed by no administration of the compound may be repeated as clinically necessary to treat the patient.

A compound of the present disclosure or a pharmaceutical composition thereof may be administered once, twice, three times or four times daily using any suitable mode described above. In addition, administration or treatment with the compound may continue for multiple days; For example, often treatment will continue for at least 7, 14 or 28 days for one treatment cycle. Treatment cycles are known in cancer chemotherapy, frequently alternating between cycles with rest periods of about 1 to 28 days, often about 7 days or about 14 days. In other embodiments, the treatment cycle may also be continuous.

VI. combination therapy

In certain embodiments, a method of treating or preventing HIV infection in a human having or at risk of having an HIV infection is provided, comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to one or more and administering to a human being in combination with a therapeutically effective amount of one or more (eg, one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, there is provided a method of treating an HIV infection in a human having or at risk of having an HIV infection, the method comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to one or more ( e.g., one, two, three, one or two, or one to three) additional therapeutic agents, in combination with a therapeutically effective amount, to the human.

In one embodiment, a compound disclosed herein, or a pharmaceutically thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents Pharmaceutical compositions comprising an acceptable salt, and a pharmaceutically acceptable carrier, diluent, or excipient are provided.

In certain embodiments, the present disclosure provides a method of treating an HIV infection, the method comprising a therapeutically effective amount in combination with one or more additional therapeutic agents suitable for treating an HIV infection in a patient in need thereof in a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In a further embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and/or may be selected from different classes of therapeutic agents.

Administration of HIV Combination Therapy

In certain embodiments, a compound disclosed herein is administered in combination with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic agents is generally such that a therapeutically effective amount of a compound disclosed herein and one or more additional therapeutic agents is present in the body of both patients with a compound disclosed herein and one or more additional therapeutic agents. It refers to the simultaneous or sequential administration of therapeutic agents. When administered sequentially, the combination may be administered in two or more administrations.

Co-administration includes administration of a unit dose of a compound disclosed herein before or after administration of a unit dose of one or more additional therapeutic agents. For example, a compound disclosed herein may be administered within seconds, minutes, or hours following administration of the one or more additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed by administration of a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes. In other embodiments, a unit dose of a compound disclosed herein is administered first, followed by administration of a unit dose of one or more additional therapeutic agents after a period of several hours (eg, 1 to 12 hours). In another embodiment, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein after a period of several hours (eg, 1 to 12 hours).

In certain embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents in unit dosage form for simultaneous administration to a patient, eg, in a solid dosage form for oral administration.

In certain embodiments, the compound of formula (I) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the purification comprises an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase It may contain other active ingredients for treating HIV, such as agent inhibitors, pharmacokinetic enhancers, and combinations thereof.

In certain embodiments, such tablets are suitable for once daily administration.

HIV Combination Therapy

In the above embodiments, the additional therapeutic agent may be an anti-HIV agent. HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing agents (eg CRISPR/Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), cell therapy (e.g., chimeric antigen receptor T-cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapy), latent reversing agents targeting HIV capsid, compounds, immune based therapies, phosphatidylinositol 3- Kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide Isomerase inhibitor, complement C5a receptor antagonist, DNA methyltransferase inhibitor, HIV vif gene modulator, Vif dimerization antagonist, HIV-1 viral infectious factor inhibitor, TAT protein inhibitor, HIV-1 Nef modulator, Hck tyrosine kinase modulator, combination Lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, CD4 modulators, CD4 antagonists, HIV Ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, CCR5 chemokine antagonists, CCR5 gene modulators, dendritic ICAM-3 grabbing non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, hyaluronidase inhibitors , Nef antagonist, Nef inhibitor, protease-activated receptor-1 antagonist, TNF alpha ligand inhibitor, PDE4 inhibitor, complement factor H Modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetics Enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

In some embodiments, the additional therapeutic agent is a combination drug for HIV, other drugs for the treatment of HIV, an HIV protease inhibitor, an HIV reverse transcriptase inhibitor, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, HIV selected from the group consisting of input (fusion) inhibitors, HIV maturation inhibitors, latent reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof do.

HIV Combination Drugs

Examples of combination drugs include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate and emtricitabine); BIKTARVY® (bictegravir, emtricitabine and tenofovir alafenamide); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); SYMTUZA® (darunavir, tenofovir alafenamide hemifumarate, emtricitabine and cobicistat); SYMFITM (efavirenz, lamivudine and tenofovir disoproxil fumarate); CIMDU™ (lamivudine and tenofovir disoproxil fumarate); tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat and elvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir and lamivudine); TRIZIVIR® (abacavir sulfate, zidovudine and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; Dapivirine + levonorgestrel, dolutegravir + lamivudine, dolutegravir + emtricitabine + tenofovir alafenamide, elsulfavirin + emtricitabine + tenofovir disoproxil, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine and lamivudine.

other HIV drugs

Examples of other drugs to treat HIV include acemannan, alisporivir, astrodrimer, BanLec, CC-11050, deferiprone, gamimmune, grifitcin, methenkephaline, naltrexone, prolastin, REP 9, RPI-MN, Vorapaxar, VSSP, H1 virus, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, MK-8527, BlockAide, PSC-RANTES, ABX- 464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV -90111, TEV-90113, RN-18, Immuglo, and VIR-576.

HIV protease inhibitors

Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfina Vir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122 , TMB-607 and TMC-310911.

HIV reverse transcriptase inhibitors

Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include dapivirine, delavirdin, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine , TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, and elsulfavirin (VM-1500).

Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, azbudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, Tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX® and VIDEX EC® (didanosine, ddl), ABBA Kavir, Abacavir Sulfate, Allovudine, Apricitabine, Sensavudine, Didanosine, Elbucitabine, Pestinavir, Fosalbudin Tidoxil, CMX-157, Dapivirine, Doravirine, Etravirine, OCR-5753 , tenofovir disoproxil orotate, pozivudine tidoxil, islatravir, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, lovafovir etalafenamide (GS-9131), GS-9148 , MK-8504, MK-8591, MK-858, VM-2500 and KP-1461.

HIV integrase inhibitors

Examples of HIV integrase inhibitors include elvitegravir, curcumin, a derivative of curcumin, chicoric acid, a derivative of chicoric acid, 3,5-dicaffeoylquinic acid, a derivative of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid , aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, raltegravir, dolutegravir, JTK- 351, bictegravir, AVX-15567, BMS-986197, cabotegravir (long-acting injection), diketoquinoline-4-1 derivative, integrase-LEDGF inhibitor, resin (ledgin), M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, Stilbendisulfonic Acid, T-169, VM-3500 and Carbo including tegravir.

Examples of HIV non-catalytic site or allosteric integrase inhibitors (NCINIs) include CX-05045, CX-05168 and CX-14442.

HIV entry inhibitors

Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 adhesion inhibitors, DS-003 (BMS-599793), gp120 inhibitors and CXCR4 inhibitors.

Examples of CCR5 inhibitors include aflaviroc, vicriviroc, maraviroc, cenicriviroc, leronrimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120/CD4 or CCR5 bispecific antibody, B-07, MB-66, polypeptide C25P, TD-0680 and vMIP (Haimipu).

Examples of gp41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV -3, ITV-4, PIE-12 trimer and cifuvirtide.

Examples of CD4 adhesion inhibitors include ivalizumab and CADA analogs.

Examples of gp120 inhibitors include Radha-108(receptol) 3B3-PE38, BanLec, bentonite-based nanodrugs, postemsavir tromethamine, IQP-0831 and BMS-663068.

Examples of CXCR4 inhibitors include plerixapor, ALT-1188, N15 peptide and vMIP (Haimipu).

HIV maturation inhibitor

Examples of HIV maturation inhibitors include BMS-955176, BMS-986197, GSK-3640254 and GSK-2838232.

Latent reversing agent

Examples of latent reversing agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade and ixazomib citrate, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors. , ionomycin, PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide and hydroxamic acid), IL-15 modulating antibody, JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors; Examples include the ragazole analogs, APH-0812 and GSK-343.

Examples of HDAC inhibitors include romidepsin, vorinostat and panobinostat.

Examples of PKC activators include indolactam, prostratin, ingenol B and DAG-lactone.

capsid inhibitor

Examples of capsid inhibitors include capsid polymerization inhibitors or capsid disruption compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, GS-6207, AVI-621, AVI-101, AVI-201 , AVI-301 and AVI-CAN1-15 series.

Immune-Based Therapy

Examples of immune-based treatments include toll-like receptor modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15 modulators; DermaVir; interleukin-7; Plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; polymer polyethyleneimine (PEI); Gefon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15/Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, NKTR-262, NKTR-214, normferon, peginterferon alpha-2a, peginterferon alpha-2b , recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulator, RIG-I modulator, NOD2 modulator, SB-9200 and IR-103.

Examples of TLR agonists: besatolimod (GS-9620), GS-986, IR-103, repitolimod, tilsotolimod, lintatolimod, DSP-0509, AL-034, G-100, covitoli Mod, AST-008, Motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, Telatolimod. RO-7020531.

Phosphatidylinositol 3-kinase (PI3K) inhibitors

Examples of PI3K inhibitors include idelarisib, alfelisib, bupalisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilarisib , puquitinib mesylate, rigocertib, rigocertib sodium, sonorisib, tacelisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423 , EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR -260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.

Alpha-4/beta-7 antagonists

Examples of integrin alpha-4/beta-7 antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

HIV Antibodies, Bispecific Antibodies, and “Antibody-Like” Therapeutic Proteins

Examples of HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bispecific antibodies, trispecific antibodies, multivalent antibodies, bnAB (broadly neutralizing HIV-1 antibody), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41, antibody-mobilizing molecules targeting HIV, anti-CD63 monoclonal antibody, CD3 bispecific antibody , CD16 bispecific antibody, anti-GB virus C antibody, anti-GP120/CD4, CCR5 bispecific antibody, anti-Nef single domain antibody, anti-Rev antibody, camel-derived anti-CD18 antibody, camel-derived anti-ICAM -1 antibody, DCVax-001, gp140 targeted antibody, gp41 based antibody for the treatment of HIV, human recombinant mAb (PGT-121), ivalizumab, Immuglo, MB-66.

Examples of targeting HIV in this way include babituximab, UB-421, C2F5, 2G12, C4E10, C2F5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC117-LS, 3BNC60, D1D2, 10-1074, 10-1074 -LS, GS-9722, DH411-2, BG18, PGT145, PGT121, PGT122, PGT-151, PGT-133, PGT-135, PGT-128, MDX010 (ipilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45-46, PG9, PG16, 8ANC195, 2Dm2m, 4Dm2m, 6Dm2m, VRC -01, VRC-01-LS, PGDM1400, A32, 7B2, 10E8, 10E8VLS, 3810109, 10E8v4, 10E8.4/iMab, VRC-01/PGDM-1400/10E8v4, IMC-HIV, iMab㎥6, 10E8v4/PGT121 - VRC01, eCD4-Ig, IOMA, CAP256-VRC26.25, DRVIA7, SAR-441236, VRC-07-523, VRC07-523LS, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12 and VRC07 includes Examples of HIV bispecific antibodies include MGD014, TMB-bispecific.

Examples of bnAB delivered in vivo, such as AAV8-VRC07; mRNA encoding anti-HIV antibody VRC01.

Pharmacokinetic enhancers

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

additional treatment

Examples of additional therapeutic agents include WO 2004/096286 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (Gilead) Sciences), International Publication No. WO 2012/003498 (Gilead Sciences), International Publication No. WO 2012/145728 (Gilead Sciences), International Publication No. WO 2013/006738 (Gilead Sciences), International Publication No. WO 2013/159064 (Gilead Sciences) , International Publication No. WO 2014/100323 (Gilead Sciences), U.S. Patent Application Publication No. US 2013/0165489 (University of Pennsylvania), U.S. Patent Application Publication No. US 2014/0221378 (Japan Tobacco), U.S. Patent Application Publication No. US 2014/0221380 (Japan Tobacco), International Publication No. WO 2009/062285 (Boehringer Ingelheim), International Publication No. WO 2010/130034 (Boehringer Ingelheim), International Publication No. WO 2013/006792 (Pharma Resources), US Patent Application Publication No. US 20140221356 ( Gilead Sciences), US Patent Application Publication No. 20100143301 (Gilead Sciences) and International Publication No. WO 2013/091096 (Boehringer Ingelheim).

HIV vaccine

Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines using viral vectors such as arenavirus, lymphocytic choriomeningitis virus (LCMV), pichinde virus, modified vaccinia ankara virus (MVA), adenovirus. Virus, adeno-associated virus (AAV), vesicular stomatitis virus (VSV) and chimpanzee adenovirus (ChAd), DNA vaccine, CD4-derived peptide vaccine, vaccine combination, BG505 SOSIP.664 gp140, rgp120 (AIDSVAX), ALVAC HIV , (vCP1521)/AIDSVAX B/E(gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad4-Env145NFL, Ad5-ENVA-48, HB-500, DCVax -001 (CDX-2401), Vacc-4x, Vacc-C5, Vacc-CRX, VVX-004, VAC-3S, Multiclad DNA Recombinant Adenovirus-5 (rAd5), rAd5 gag-pol env A/B/C Vaccine, Pennvax-G, Pennvax-GP/MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvant vaccine, TatImmune, GTU- multiHIV (FIT-06), gp140 [delta] V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIVAX , HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env clad C +Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-C MDR, DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV + MVA Mosaic vaccine + gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines (eg pseudovirion vaccine), CombiVICHvac, LFn-p24 B/C fusion vaccine, GTU based DNA vaccine, HIV gag/pol/nef/env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptide vaccine, dendritic cell vaccine , gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), I i-key/MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO -5, Multiclad Env vaccine, MVA vaccine, Pennvax-GP, pp71 deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x + romidepsin, variant gp120 polypeptide vaccine, rAd5 gag-pol env A/B/C vaccine, DNA.HTI, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP + VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60-mer based vaccine, PD-201401, env (A, B, C, A/E)/gag(C) DNA vaccine, gp120(A,B,C,A/E) protein vaccine, PDPHV-201401 , Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE adjuvant), HIV p24gag prime-boost plasmid DNA vaccine, arenavirus vector based immunotherapy (Vaxwave, TheraT), MVA-BN HIV-1 vaccine therapy, MVA.tHIVconsv4, MVA.tHIVconsv3, UBI HIV gp120, mRNA based prophylactic vaccine, TBL-1203HI, VRC-HIVRGP096-00-VP, VAX-3S, and HIV MAG DNA vaccine.

HIV Combination Therapy

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is selected from ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF +FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; prolastin; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; Etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; sutabudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; Tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine and zidovudine; abacavir; and one, two, three, four or more additional therapeutic agents selected from abacavir sulfate.

It will be understood by those of ordinary skill in the art that the additional therapeutic agents listed above may be included in more than one of the classes listed above. A particular class is not intended to limit the functionality of such compounds listed in that class.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibitory compound. In a further embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two HIV nucleosides or nucleotide inhibitors of reverse transcriptase.

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with an HIV capsid inhibitor and/or a nucleoside reverse transcriptase translocation inhibitor. In some embodiments, the compounds disclosed herein are used in combination with lenacapavir and/or islatravir. In some embodiments, the compounds disclosed herein are used in combination with lenacapavir. In some embodiments, the compounds disclosed herein are used in combination with islatravir.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifuma Late, tenofovir alafenamide or tenofovir alafenamide hemifumarate.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir in combination with alafenamide hemifumarate.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide and the in combination with a first additional therapeutic agent selected from the group consisting of nofovir alafenamide hemifumarate and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, comprises tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafen in combination with a first additional therapeutic agent and a second additional therapeutic agent selected from the group consisting of amide hemifumarate, wherein the second additional therapeutic agent is emtricitabine.

A compound as disclosed herein (eg, any compound of Formula I) may be combined with one or more additional therapeutic agents in any dosage of a compound of Formula I (eg, 1 mg to 500 mg of a compound). can be

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, comprises 5 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide; and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is 5 to 10 mg, 5 to 15 mg, 5 to 20 mg, 5 to 25 mg, 25 to 30 mg, 20 to 30 mg, 15 to 30 mg, or 10 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, comprises 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, comprises 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. A compound disclosed herein (eg, a compound of Formula I) can be administered in any dosage (eg, from 1 mg to 500 mg of a compound) of the compound, such that each combination of dosages is specifically and individually listed. may be combined with the formulations provided herein.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, comprises 200 to 400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is 200 to 250 mg, 200 to 300 mg, 200 to 350 mg, 250 to 350 mg, 250 to 400 mg, 350 to 400 mg, 300 to 400 mg, or 250 to 400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, comprises 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of tenofovir disoproxil. mg of emtricitabine. A compound disclosed herein (eg, a compound of Formula I) can be administered in any dosage (eg, from 1 mg to 500 mg of a compound) of the compound, such that each combination of dosages is specifically and individually listed. may be combined with the formulations provided herein.

In one embodiment, a compound disclosed herein, or a pharmaceutical thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents A kit comprising an acceptable salt is provided.

Contraceptive (contraceptive) combination therapy

Treatments (contraceptives) used for contraception are cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethinodiol, etonogestrel, levomefolate, levo Norgestrel, Linestrenol, Medroxyprogesterone Acetate, Mestranol, Mifepristone, Misoprostol, Nomegestrol Acetate, Norelgestromin, Noretindrone, Noretinodrel, Norgestimate, Ormel roxifen, segestersone acetate, ulipristal acetate, and any combination thereof.

Gene therapy and cell therapy

Gene therapy and cell therapy include genetic manipulation to silence genes; genetic approaches that directly kill infected cells; implantation of immune cells designed to replace most of the patient's own immune system to enhance the immune response against infected cells, activate the patient's own immune system to kill infected cells, or detect and kill infected cells; Includes genetic approaches to modify cellular activity to further alter the endogenous immune responsiveness to infection.

An example of dendritic cell therapy includes AGS-004.

Examples of CCR5 gene editing drugs, such as SB-728T.

Examples of CCR5 gene inhibitors, such as Cal-1.

CD4-positive T cells expressing C34-CCR5/C34-CXCR4.

AGT-103-transduced autologous T cell therapy.

AAV-eCD4-Ig gene therapy.

gene editing agent

The genome editing system is selected from the group consisting of a CRISPR/Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonuclease system and a meganuclease system.

An example of an HIV targeting CRISPR/Cas9 system includes EBT-101.

CAR-T cell therapy

A population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen-binding domain. The HIV antigen comprises an HIV envelope protein or portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, a CD4 inducible binding site on gp120, an N glycan on gp120, V2 of gp120, a membrane proximal region on gp41. Immune effector cells are T cells or NK cells. In some embodiments, the T cell is a CD4+ T cell, a CD8+ T cell, or a combination thereof. Cells may be autologous or allogeneic.

Examples of HIV CAR-T include VC-CAR-T, anti-CD4 CART cell therapy, autologous hematopoietic stem cells genetically engineered to express CD4 CAR, and C46 peptide.

TCR-T cell therapy

TCR-T cells are engineered to target HIV-derived peptides present on the surface of virus-infected cells.

VII. Example

Exemplary chemical entities of the present disclosure are provided in the specific examples below. One of ordinary skill in the art will recognize that starting materials can be appropriately selected to obtain a variety of compounds of the invention, so that ultimately the desired substituents will be transferred through the scheme, with or without protection as required, to yield the desired product. Alternatively, it may be necessary or desirable to ultimately use, in place of the desired substituent, an appropriate group that may be passed through the scheme and substituted with the desired substituent as necessary. Moreover, those skilled in the art will recognize that the transformations shown in the schemes below can be performed in any order suitable for the functionality of the particular pendant group.

The examples provided herein illustrate the synthesis of the compounds disclosed herein, as well as the intermediates used to prepare the compounds. It should be understood that the individual steps described herein may be combined. It should also be understood that individual batches of compounds may be combined and then carried out in the next synthetic step.

In the following description of the examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice specific embodiments of the present disclosure. Other embodiments may be utilized and other logical and other changes may be made without departing from the scope of the present disclosure. Accordingly, the following description is not intended to limit the scope of the present disclosure.

Example 1: ((6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8, Preparation of 10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (1):

Step 1. Synthesis of tert-butyl 3-amino-3-cyanoazepane-1-carboxylate ( 1a ) :

tert-butyl 3-oxoazepane-1-carboxylate (3.5 g, 16.4 mmol), potassium cyanide (1.60 g, 24.6 mmol) in ammonium hydroxide (19.5 mL), ethanol (20 mL) and water (6.5 mL), Ammonium chloride (1.32 g, 24.6 mmol) was heated at 60° C. overnight. The reaction mixture was concentrated to about 30 mL and extracted with dichloromethane (3x). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and purified by CombiFlash (80 g, ethyl acetate/hex) to afford the title compound. MS ( m/z ) 239.82 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl 3-((tert-butoxycarbonyl)amino)-3-cyanoazepane-1-carboxylate ( 1b ) :

To a solution of tert-butyl 3-amino-3-cyano-azepane-1-carboxylate ( la , 3.3 g, 13.8 mmol) in ethyl acetate (20 mL) saturated sodium carbonate (5 mL) and di-tert-butyl Dicarbonate (4.51 g, 20.7 mmol) was added. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was extracted with dichloromethane (3x), dried (MgSO ₄ ), filtered and concentrated. Purification of the residue via CombiFlash (80 g, ethyl acetate/hexanes) afforded the title compound and recovery of the starting material. MS ( m/z ) 339.9 [M+H] ⁺ .

Step 3: Synthesis of tert-butyl 3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylate ( 1c ) :

To a solution of tert-butyl 3-((tert-butoxycarbonyl)amino)-3-cyanoazepane-1-carboxylate ( 1b , 0.952 g, 2.81 mmol) in dichloromethane (14.0 mL) at 0° C. Bis(cyclopentadienyl) zirconium(IV) chloride hydride (1.45 g, 5.61 mmol) was added. The reaction mixture was stirred at 0° C. for 20 h. Additional bis(cyclopentadienyl)zirconium(IV) chloride hydride (1.45 g, 5.61 mmol) was added and the reaction mixture was allowed to warm to room temperature over 3 hours. The reaction mixture was adsorbed to silica gel, loaded onto a dry load cartridge and purified by CombiFlash (120 g, 0-30% EtOAc/Hex) to afford the title compound. MS ( m/z ) 342.73 [M+H] ⁺ .

Step 4: tert-Butyl 3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)vinyl)-3-((tert-part Toxycarbonyl)amino)azepane-1-carboxylate ( 1d ) of the synthesis:

Methyl 3-(benzyloxy)-6-((dimethoxyphosphoryl)methyl)-4-oxo-4H-pyran-2-carboxylate (prepared according to WO2018102485) in THF (15 mL) at -78°C (0.826 g, 2.16 mmol) was added dropwise 1.0 M lithium diisopropylamide (2.30 mL, 2.30 mmol) in THF/hexanes. The reaction mixture was stirred for 60 min, then tert-butyl 3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylate ( 1c , 0.370 g, 1.08) in THF (5.0 mL). mmol) was added. The reaction mixture was stirred at -78 °C for 0.5 h, then warmed to -40 °C. After 1 h, the reaction mixture was stirred at 0° C. for 4 h. The reaction mixture was quenched with 1 N HCl, brine was added and extracted with ethyl acetate (2x). The combined organic layers were dried (MgSO ₄ ), filtered, concentrated and purified by CombiFlash (120 g, 0-60% EtOAc/Hex) to afford the title compound. MS ( m/z ) 598.88 [M+H] ⁺ .

Step 5: tert-Butyl 3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)ethyl)-3-((tert-part Toxycarbonyl)amino)azepane-1-carboxylate ( 1e ) of the synthesis:

tert-Butyl 3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)vinyl)-3-(() in THF (20 mL) tert-Butoxycarbonyl)amino)azepane-1-carboxylate ( 1d , 490 mg, 0.80 mmol) and 20% palladium hydroxide on carbon, wet (114 mg) were stirred under a hydrogen atmosphere (1 atm) for 1 hour. did. The reaction mixture was filtered through a pad of Celite, washed with ethyl acetate and concentrated to tert-butyl 3-((tert-butoxycarbonyl)amino)-3-(2-(5-hydroxy-6-( Methoxycarbonyl)-4-oxo-4H-pyran-2-yl)ethyl)azepane-1-carboxylate was obtained, which was used in the next step without further purification.

tert-Butyl 3-((tert-butoxycarbonyl)amino)-3-(2-(5-hydroxy-6-(methoxycarbonyl)-4-oxo-4H-pyran-2- from above yl)ethyl)azepane-1-carboxylate (0.427 g) was dissolved in DMF (8 mL) and benzyl bromide (193 μL, 1.63 mmol) and potassium carbonate (0.451 g, 3.26 mmol) were added. The reaction mixture was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with 5% LiCl solution (3x) and brine, dried (MgSO ₄ ) and filtered. Concentration and purification (40 g, 0-60% EtOAc/Hex) afforded the title compound. MS ( m/z ) 600.83 [M+H] ⁺ .

Step 6: 11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine Synthesis of -1,10-dione ( 1f ):

tert-Butyl 3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)ethyl)-3-( A solution of (tert-butoxycarbonyl)amino)azepane-1-carboxylate ( 1e , 0.252 g, 0.410 mmol) and trifluoroacetic acid (2.0 mL) was stirred at 0° C. for 2 h, then at room temperature. Warm over 4 hours. The reaction mixture was concentrated and dried under high vacuum overnight.

Dissolve methyl 6-(2-(3-aminoazepan-3-yl)ethyl)-3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylate from above in ethanol (10 mL) and heated at 90° C. for 5 hours. The reaction mixture was concentrated and purified via CombiFlash (24 g, 0-20% MeOH/CH ₂ Cl ₂ ) to afford the title compound. MS ( m/z ) 351.28 [M+H] ⁺ .

Step 7: 11-(benzyloxy)-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2 Synthesis of -cd]indolizine-1,10-dione :

11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2- in anhydrous methanol (6.3 mL) cd] In a solution of indolizine-1,10-dione ( 1f , 260 mg, 0.626 mmol) 3-chloroperoxybenzoic acid (0.432 g, 2.51 mmol) followed by N-iodosuccinimide (0.564 g, 2.51 mmol) ) was added. The reaction mixture was heated at 70° C. for 15 minutes. The reaction mixture was diluted with dichloromethane and washed with 10% sodium sulfite. The aqueous layer was back extracted and the combined organic layers were dried (MgSO ₄ ), filtered and concentrated. Purification via CombiFlash (40 g, 0% - 10% MeOH/CH ₂ Cl ₂ ) afforded the title compound. MS ( m/z ) 477.14 [M+H] ⁺ .

Step 8: 11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro Synthesis of -2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 1g ) :

11-(benzyloxy)-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9, in DMSO (6.5 mL) 2,4,6-trifluorobenzyl amine (355 mg, 2.20 mmol), N,N-diisopropyl in a solution of 1,2-cd]indolizine-1,10-dione (210 mg, 0.441 mmol) Ethylamine (384 μL, 2.20 mmol) and tetrakis(triphenylphosphine)palladium (25.5 mg, 0.022 mmol) were added. The reaction mixture was degassed under vacuum and backfilled with CO (3x). The reaction mixture was slowly sparged with CO using a 22 gauge needle connected to a gas bag filled CO and heated at 80° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 0.05 N HCl, saturated sodium bicarbonate solution and brine, dried (MgSO ₄ ) and concentrated. The residue was purified by CombiFlash (40 g, 0% to -100% EtOAc/Hex) to give the desired product. MS ( m/z ) 538.15 [M+H] ⁺ .

Step 9: (6aR)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8, 10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 1h-1 ) and (6aS)-11-(benzyl) oxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano Cleavage of [1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 1h-2 ) :

Racemic 11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro Split -2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (119 mg) using chiral SFC (IB, 30% MeOH) did.

(6aR)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octa Hydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide: peak 1, MS ( m/z ) 538.16 [M+H] ⁺ .

(6aS)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octa Hydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide: peak 2, MS ( m/z ) 538.18 [M+H] ⁺ .

Step 10: (6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10- Synthesis of octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 1 ) :

(6aR)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6 in dichloromethane (1.5 mL), 7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 1h-1 , 37 mg, 0.069 mmol ) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was aged in the freezer for 30 hours. The reaction mixture was concentrated and purified by Gilson HPLC (Gemini 5 - 100% ACN/H ₂ O + 0.1% TFA) to afford the title compound after lyophilization. MS ( m/z ) 448.24 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 7.07 - 6.79 (m, 2H), 4.73 - 4.54 (m, 2H), 4.35 (dt, J = 13.4, 8.0 Hz, 1H), 3.98 - 3.73 (m, 3H), 3.49 (ddd, J = 18.8, 11.2, 7.7 Hz, 1H), 3.19 (ddd, J = 13.2, 7.0, 3.4 Hz, 1H), 2.31 - 2.07 (m, 3H), 2.07 - 1.85 (m, 3H), 1.79 (dd, J = 15.6, 6.9 Hz, 1H), 1.39 - 1.23 (m, 1H).

Example 2: (6aS)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10 Preparation of -octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (2):

(6aS)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro- 2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 2 ) is (6aR)-11-(benzyloxy)-1 in step 10 , 10-dioxo-N- (2,4,6-trifluorobenzyl) -1,3,4,5,6,7,8,10-octahydro-2,6a-methano [1,4 ]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 1h-1 ) instead of (6aS)-11-(benzyloxy)-1,10-dioxo-N-(2) ,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2 (6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluoro except using -cd]indolizine-9-carboxamide ( 1h-2 ) benzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9- Carboxamide ( 1 ) was prepared in a similar manner. MS ( m/z ) 448.19 [M+H] ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ 10.79 (t, J = 5.0 Hz, 1H), 8.77 (s, 1H), 6.75 - 6.59 (m, 2H), 4.65 (qd, J = 14.4, 5.4 Hz) , 2H), 4.44 (dt, J = 13.7, 8.1 Hz, 1H), 4.10 (dd, J = 18.9, 8.3 Hz, 1H), 3.81 - 3.61 (m, 2H), 3.53 (ddd, J = 19.0, 11.5) , 7.7 Hz, 1H), 3.14 (ddd, J = 13.7, 7.2, 3.3 Hz, 1H), 2.15 (dddd, J = 31.2, 18.6, 11.4, 5.4 Hz, 4H), 1.83 (dddd, J = 23.1, 16.1) , 12.3, 5.0 Hz, 3H), 1.42 - 1.26 (m, 1H).

Example 3: (6aR)-N-(2,4-difluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octa Preparation of hydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (3):

(6aR)-N-(2,4-difluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2, 6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 3 ) is 2,4,6-trifluorobenzylamine in step 8 instead of 2 (6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4 except using ,4-trifluorobenzyl amine Similar to ,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 1 ) manufactured in this way. MS ( m/z ) 430.30 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 7.44 (q, J = 8.4 Hz, 1H), 7.02 - 6.88 (m, 2H), 4.68 - 4.54 (m, 2H), 4.37 (dt, J = 13.6, 7.9 Hz, 1H), 3.99 - 3.74 (m, 3H), 3.57 - 3.44 (m, 1H), 3.24 - 3.13 (m, 1H), 2.29 - 2.06 (m, 3H), 2.04 - 1.86 (m, 3H) , 1.86 - 1.72 (m, 1H), 1.32 (q, J = 12.7, 12.2 Hz, 1H).

Example 4: (6aS)-N-(2,4-difluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octa Preparation of hydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (4):

(6aS)-N-(2,4-difluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2, 6a-Methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 4 ) replaces 2,4,6-trifluorobenzylamine in step 8 with 2 ,4-trifluorobenzyl amine and (6aR)-11-(benzyloxy)-N-(2,4-difluorobenzyl)-1,10-dioxo-1,3,4,5 in step 10 Instead of ,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 1h-1 ) (6aS)-11-(benzyloxy)-N-(2,4-difluorobenzyl)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro- (6aR)-11-hydroxy except using 2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 1h-2 ) -1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1 ,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 1 ) was prepared similarly. MS ( m/z ) 430.31 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 7.44 (q, J = 8.3 Hz, 1H), 7.05 - 6.87 (m, 2H), 4.68 - 4.55 (m, 2H), 4.37 (dt, J = 13.5, 8.0 Hz, 1H), 3.98 - 3.75 (m, 3H), 3.51 (ddd, J = 18.7, 11.5, 7.7 Hz, 1H), 3.24 - 3.14 (m, 1H), 2.30 - 2.09 (m, 3H), 2.09 - 1.86 (m, 3H), 1.81 (dd, J = 15.8, 6.5 Hz, 1H), 1.39 - 1.25 (m, 1H).

Example 5: (6aR)-N-(3-chloro-2-fluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10- Preparation of octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (5):

(6aR)-N-(3-chloro-2-fluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2 ,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 5 ) in step 8 instead of 2,4,6-trifluorobenzylamine (6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3 except using 3-chloro-2-fluorobenzyl amine ,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 1 ) was prepared in a similar manner to MS ( m/z ) 446.30 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 7.43 - 7.38 (m, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 4.69 (dd, J = 15.4, 5.3 Hz, 2H), 4.37 (dt, J = 13.7, 8.1 Hz, 1H), 3.98 - 3.74 (m, 3H), 3.58 - 3.44 (m, 1H), 3.20 (ddd, J = 12.3, 7.0 , 3.7 Hz, 1H), 2.31 - 2.09 (m, 3H), 2.08 - 1.86 (m, 3H), 1.86 - 1.73 (m, 1H), 1.32 (q, J = 12.8, 12.4 Hz, 1H).

Example 6: (6aS)-N-(3-chloro-2-fluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10- Preparation of octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (6):

(6aS)-N-(3-chloro-2-fluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2 ,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 6 ) was replaced with 2,4,6-trifluorobenzylamine in step 8 Using 3-chloro-2-fluorobenzyl amine and in step 10 (6aR)-11-(benzyloxy)-N-(2,4-difluorobenzyl)-1,10-dioxo-1,3 , 4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 1h- 1 ) instead of (6aS)-11-(benzyloxy)-N-(3-chloro-2-fluorobenzyl)-1,10-dioxo-1,3,4,5,6,7,8, (6aR) except for using 10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 1h-2 ) -11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a -Methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 1 ) was prepared in a similar manner. MS ( m/z ) 446.30 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 7.43 - 7.38 (m, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 4.69 (dd, J = 15.4, 5.3 Hz, 2H), 4.37 (dt, J = 13.7, 8.1 Hz, 1H), 3.98 - 3.74 (m, 3H), 3.58 - 3.44 (m, 1H), 3.20 (ddd, J = 12.3, 7.0 , 3.7 Hz, 1H), 2.31 - 2.09 (m, 3H), 2.08 - 1.86 (m, 3H), 1.86 - 1.73 (m, 1H), 1.32 (q, J = 12.8, 12.4 Hz, 1H).

Example 7: ((6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8, Preparation of 10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (7):

Step 1: Methyl 11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazo nino[9,1,2-cd]indolizine-9-carboxylate ( 7a ) of the synthesis:

7-Benzyloxy-5-iodo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7- in anhydrous tetrahydrofuran (2.0 mL) and anhydrous methanol (2.0 mL) To a solution of diene-6,9-dione (0.169 g, 0.355 mmol) was added N,N-diisopropylethylamine (185 μL, 1.06 mmol) and tetrakis(triphenylphosphine)palladium (0.021, 0.018 mmol) added. The reaction mixture was degassed under vacuum and backfilled with CO (3x). The reaction mixture was sparged with CO using an 18 gauge needle connected to a gas bag filled CO and heated at 65° C. for 18 hours. Additional methanol (4.0 mL) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.029 g, 0.0355 mmol) were added, and the reaction mixture was stirred in a CO atmosphere (1 atm) heated for 24 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 0.05 N HCl, saturated sodium bicarbonate solution, brine, dried (MgSO ₄ ) and concentrated. The crude product was purified by CombiFlash (40 g, 0% to -100% EtOAc/Hept) to give the desired product. MS ( m/z ) 409.1 [M+H] ⁺ .

Step 2: 11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino [9,1,2-cd]indolizine-9-carboxylic acid ( 7b ) of the synthesis:

Methyl 11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a- in THF (1.0 mL) and methanol (0.5 mL) A solution of methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxylate ( 7a ) (46 mg, 0.113 mmol) and lithium hydroxide (5M, 68 μL, 0.338 mmol) was heated at 45 °C for 2 h. The reaction mixture was acidified with 1 M HCl and extracted with ethyl acetate (3x). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated to give the desired product, which was used in the next step without further purification. MS ( m/z ) 395.05 [M+H] ⁺ .

Step 3: 11-(benzyloxy)-1,10-dioxo-N'-(2-(2,4,6-trifluorophenyl)ethanethioyl)-1,3,4,5,6, 7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carbohydrazide ( 7d ) of the synthesis:

11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4 in anhydrous THF (2.0 mmol) In a solution of ]diazonino[9,1,2-cd]indolizine-9-carboxylic acid ( 7b ) (44 mg, 0.112 mmol) at 0° C. with N-methyl morpholine (49 μL, 0.446 mmol) and isobutyl Chloroformate (19 μL, 0.145 mmol) was added. The reaction mixture was stirred for 2 hours. 2-(2,4,6-trifluorophenyl)ethanethiohydrazide, TFA salt ( 7c ) (55.9 mg, 0.167 mmol) was added followed by N-methyl morpholine (49 μL, 0.446 mmol). The reaction mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, dried (MgSO ₄ ), filtered and concentrated. The reaction product was used in the next step without further purification. MS ( m/z ) 596.93 [M+H] ⁺ .

Step 4: 11-(benzyloxy)-9-(5-(2,4,6-trifluorobenzyl)-1,3,4-thiadiazol-2-yl)-3,4,5,6 ,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione ( 7e ) of the synthesis:

11-(benzyloxy)-1,10-dioxo-N'-(2-(2,4,6-trifluorophenyl)ethanethioyl)-1,3,4,5,6,7,8 ,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carbohydrazide ( 7d ) (approximately 0.0033 mmol) was mixed with acetic acid (1.5 mL) and heated at 100° C. for 7 h. The reaction mixture was concentrated, purified by Gilson HPLC (Gemini, 5 - 100% ACN/H 2 O + 0.1% TFA) and lyophilized to afford the desired product. MS ( m/z ) 489.36 [M+H] ⁺ .

Step 5: 11-Hydroxy-9-(5-(2,4,6-trifluorobenzyl)-1,3,4-thiadiazol-2-yl)-3,4,5,6,7 , 8-hexahydro-2,6a-methano [1,4] diazonino [9,1,2-cd] indolizine-1,10-dione ( 7 ) of the synthesis:

7-benzyloxy-5-[5-[(2,4,6-trifluorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-10,15 in toluene (1.0 mL) -diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7-diene-6,9-dione ( 7e ) (1.5 mg, 0.0026 mmol) and a solution of trifluoroacetic acid (0.5 mL) Stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and purified by Gilson HPLC (Gemini, 5 - 100% ACN/H ₂ O + 0.1% TFA) to afford the desired product after lyophilization. MS ( m/z ) 579.04 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 7.05 - 6.88 (m, 2H), 4.52 (s, 2H), 4.38 (dt, J = 13.3, 8.1 Hz, 1H), 4.05 (dd, J = 18.5, 7.6 Hz, 1H), 3.96 (d, J = 14.2 Hz, 1H), 3.86 (d, J = 14.1 Hz, 1H), 3.67 (ddd, J = 18.7, 10.9, 8.0 Hz, 1H), 3.23 (dq, J = 9.9, 3.5 Hz, 1H), 2.47 - 2.18 (m, 3H), 1.99 (ddd, J = 32.1, 14.1, 6.8 Hz, 3H), 1.83 (dd, J = 13.7, 5.7 Hz, 1H), 1.33 (q, J = 11.2, 10.7 Hz, 1H).

Example 8: (6aS,8S)-8-fluoro-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5, 6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (8-1) and (6aR ,8R)-8-fluoro-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8, Preparation of 10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (8-2):

Step 1. 11-(benzyloxy)-8-fluoro-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2 -cd]indolizine-1,10-dione ( 8a ) of the synthesis:

11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a- prepared according to the preparation of intermediate 1f in Example 1 in THF (3 mL) under Ar (g) In a solution of methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione (0.050 g, 0.143 mmol) N -fluorobenzenesulfonimide (0.135 g, 0.428) mmol) was added. The reaction mixture was cooled to -78 °C and a 1.0 M solution of LiHMDS in THF (0.428 mL, 0.428 mmol) was added dropwise. After stirring for 0.5 h, the reaction was allowed to warm to room temperature and allowed to stir overnight. It was quenched by addition of methanol and the solution was concentrated. The residue was purified by column chromatography (0-20% MeOH/CH ₂ Cl ₂ ) to 11-(benzyloxy)-8-fluoro-3,4,5,6,7,8-hexahydro-2 ,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione was provided. MS ( m/z ) 369.26 [M+H] ⁺ .

Step 2. 11-(benzyloxy)-8-fluoro-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[ 9,1,2-cd]indolizine-1,10-dione ( 8b ) of the synthesis:

11-(benzyloxy)-8-fluoro-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9 in anhydrous methanol (0.5 mL) ,1,2-cd]indolizine-1,10-dione (0.022 g, 0.059 mmol) in a solution of 77% m -CPBA (meta-chloroperbenzoic acid) (0.053 g, 0.237 mmol) and N -iodosuccinic The imide (0.053 g, 0.237 mmol) was added. The reaction mixture was heated at 80° C. for 24 h and cooled to room temperature. The solution was diluted with CH ₂ Cl ₂ and washed with 10% aqueous Na ₂ SO ₃ solution. The aqueous phase was extracted with CH ₂ Cl ₂ , and the combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (0-10% MeOH/CH ₂ Cl ₂ ) to 11-(benzyloxy)-8-fluoro-9-iodo-3,4,5,6,7,8 - Hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione was provided. MS ( m/z ) 495.10 [M+H] ⁺ .

Step 3. 11-(Benzyloxy)-8-fluoro-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8 , 10-octahydro-2,6a-methano [1,4] diazonino [9,1,2-cd] indolizine-9-carboxamide ( 8c ) of the synthesis:

11-(benzyloxy)-8-fluoro-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]dia in DMSO (1 mL) In a solution of zonino[9,1,2-cd]indolizine-1,10-dione (0.026 g, 0.053 mmol), 2,4,6-trifluorobenzylamine (0.042 g, 0.263 mmol), i - Pr ₂ NEt (0.046 mL, 0.263 mmol) and Pd(PPh ₃ ) ₄ (0.003 g, 0.003 mmol) were added. The reaction flask was evacuated and backfilled with CO (g) three times, then heated to 80° C. for 4 hours under 1 atm of CO (g). After cooling to room temperature, the reaction was diluted with EtOAc and washed with 0.05 N HCl (1x), saturated aqueous NaHCO ₃ (1x) and brine (1x). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (0-100% EtOAc/heptane) to 11-(benzyloxy)-8-fluoro-1,10-dioxo-N-(2,4,6-trifluoro) benzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9- Carboxamide was given. MS ( m/z ) 556.17 [M+H] ⁺ .

Step 4. (6aS,8S)-8-fluoro-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6 ,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 8-1 ) and (6aR,8R)-8-fluoro-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6, 7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 8-2 ) of the synthesis:

rac- (6aR,8S)-11-(benzyloxy)-8-fluoro-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5, 6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide as two separate enantiomers It was separated into its individual enantiomers by preparative SFC on an AD-H column using 40% MeOH cosolvent to provide. Each separated enantiomer was dissolved in 1:1 toluene/TFA (2 mL). The reaction mixture was allowed to stir at room temperature for 2 h and concentrated. The residue was dissolved in MeCN and preparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2) eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30 min. mm). The combined fractions were lyophilized to provide the title compound. The absolute three-dimensional form is not confirmed.

Peak 1: MS ( m/z ) 466.24 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.83 (t, J = 5.7 Hz, 1H), 7.30 - 7.16 (m, 2H), 6.84 - 6.69 (m, 1H), 4.61 (dd, J = 14.5) , 5.8 Hz, 1H), 4.52 (dd, J = 14.6, 5.5 Hz, 1H), 4.19 (dt, J = 12.8, 7.4 Hz, 1H), 3.86 (d, J = 14.3 Hz, 1H), 3.68 (d) , J = 14.2 Hz, 1H), 3.05 (dt, J = 12.3, 5.7 Hz, 1H), 2.44 (d, J = 2.9 Hz, 1H), 2.38 (s, 1H), 2.16 - 2.00 (m, 2H) , 1.83 (dd, J = 15.6, 8.1 Hz, 2H), 1.74 - 1.65 (m, 1H), 1.24 (s, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -109.31 (ddd, J = 15.5, 9.3, 6.4 Hz), -112.48 (t, J = 7.2 Hz), -167.67 (ddd, J = 50.1, 35.0, 24.1 Hz).

Peak 2: MS ( m/z ) 466.27 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (t, J = 5.7 Hz, 1H), 7.31 - 7.13 (m, 2H), 6.85 - 6.63 (m, 1H), 4.60 (dd, J = 14.6) , 5.9 Hz, 1H), 4.51 (dd, J = 14.5, 5.5 Hz, 1H), 4.19 (dt, J = 14.0, 7.4 Hz, 1H), 3.86 (d, J = 14.3 Hz, 1H), 3.67 (d) , J = 14.2 Hz, 1H), 3.04 (dt, J = 12.5, 5.8 Hz, 1H), 2.44 (d, J = 3.0 Hz, 1H), 2.40 - 2.29 (m, 1H), 2.16 - 1.98 (m, 2H), 1.90 - 1.77 (m, 2H), 1.69 (d, J = 16.1 Hz, 1H), 1.33 - 1.18 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -109.31 (tt, J = 9.4, 6.4 Hz), -112.48 (t, J = 7.2 Hz), -167.67 (ddd, J = 50.0, 35.1, 24.2 Hz) ).

Example 9: (6aS,8R)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6, 7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (9-1), (6aR,8R )-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro -2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (9-2), (6aS,8S)-8,11-dihydr Roxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[ 1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (9-3) and (6aR,8S)-8,11-dihydroxy-1,10-dioxo -N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[ Preparation of 9,1,2-cd]indolizine-9-carboxamide (9-4):

Step 1. 11-(benzyloxy)-8-hydroxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2 -cd]indolizine-1,10-dione ( 9a ) of the synthesis:

11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a- prepared according to the preparation of intermediate 1f in Example 1 in THF (5 mL) under Ar (g) A solution of methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione (0.100 g, 0.285 mmol) was cooled to -78°C. A 1.0 M solution of LiHMDS in THF (0.856 mL, 0.856 mmol) was added dropwise. After 10 min, a solution of 2-(benzenesulfonyl)-3-phenyl-oxaziridine (0.164 g, 0.628 mmol) in THF (1 mL) was added. The reaction mixture was allowed to warm to room temperature and allowed to stir for 3 hours. It was quenched by addition of methanol and the solution was concentrated. The residue was purified by column chromatography (0-20% MeOH/CH ₂ Cl ₂ ) to 11-(benzyloxy)-8-hydroxy-3,4,5,6,7 as a mixture of diastereomers, 8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione was provided. MS ( m/z ) 367.27 [M+H] ⁺ .

Step 2. 11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[ 9,1,2-cd]indolizine-1,10-dione ( 9b ) of the synthesis:

11-(benzyloxy)-8-hydroxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9 in anhydrous methanol (1 mL) ,1,2-cd]indolizine-1,10-dione (0.057 g, 0.155 mmol) in a solution of 77% m -CPBA (0.139 g, 0.620 mmol) and N -iodosuccinimide (0.140 g, 0.620) mmol) was added. The reaction mixture was heated at 80° C. for 1 h and cooled to room temperature. The solution was diluted with CH ₂ Cl ₂ and washed with 10% aqueous Na ₂ SO ₃ solution. The aqueous phase was extracted with CH ₂ Cl ₂ , and the combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (0-10% MeOH/CH ₂ Cl ₂ ) to 11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8 - Hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione was provided. MS ( m/z ) 493.11 [M+H] ⁺ .

Step 3. 11-(benzyloxy)-8-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8 , 10-octahydro-2,6a-methano [1,4] diazonino [9,1,2-cd] indolizine-9-carboxamide ( 9c ) of the synthesis:

11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]dia in DMSO (2 mL) In a solution of zonino[9,1,2-cd]indolizine-1,10-dione (0.052 g, 0.105 mmol), 2,4,6-trifluorobenzylamine (0.084 g, 0.524 mmol), i - Pr ₂ NEt (0.091 mL, 0.524 mmol) and Pd(PPh ₃ ) ₄ (0.006 g, 0.005 mmol) were added. The reaction flask was evacuated and backfilled with CO (g) three times, then heated to 80° C. for 4 hours under 1 atm of CO (g). After cooling to room temperature, the reaction was diluted with EtOAc and washed with 0.05 N HCl (1x), saturated aqueous NaHCO ₃ (1x) and brine (1x). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (0-100% EtOAc/heptane) to 11-(benzyloxy)-8-hydroxy-1,10-dioxo-N-(2,4,6-trifluoro) benzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9- Carboxamide was given. MS ( m/z ) 554.21 [M+H] ⁺ .

Step 4. (6aS,8R)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7 ,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (9-1) , (6aR,8R)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8 , 10-octahydro-2,6a-methano [1,4] diazonino [9,1,2-cd] indolizine-9-carboxamide (9-2) , (6aS,8S)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8 , 10-octahydro-2,6a-methano [1,4] diazonino [9,1,2-cd] indolizine-9-carboxamide (9-3) , (6aR,8S)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8 , 10-octahydro-2,6a-methano [1,4] diazonino [9,1,2-cd] indolizine-9-carboxamide (9-4) Synthesis of:

11-(benzyloxy)-8-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10- Octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide was sequentially numbered from peaks 1 to 4 according to the order of elution. It was separated into its individual stereoisomers by preparative SFC on an AD-H column using 50% i -PrOH (containing 0.1% NH ₃ ) cosolvent to give 4 distinct peaks. Among them, peak 1 and peak 4 are enantiomers; Peak 2 and Peak 3 are enantiomers. The absolute three-dimensional form is not confirmed.

The separated stereoisomers were each dissolved in 1:1 toluene/TFA (2 mL). The reaction mixture was allowed to stir at room temperature for 2 h and concentrated. The residue was dissolved in MeCN and preparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2) eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30 min. mm). The combined fractions were lyophilized to provide the title compound. The absolute three-dimensional form is not confirmed.

Peak 1: MS ( m/z ) 464.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.52 (t, J = 5.7 Hz, 1H), 7.23 (t, J = 8.6 Hz, 2H), 6.85 (s, 1H), 5.60 (dd, J = 9.4, 7.0 Hz, 1H), 4.66 (dd, J = 14.6, 5.9 Hz, 1H), 4.55 (dd, J = 14.5, 5.5 Hz, 1H), 4.16 (dt, J = 13.8, 7.3 Hz, 1H), 3.83 (s, 2H), 3.09 - 3.00 (m, 1H), 2.61 (dd, J = 12.2, 7.1 Hz, 1H), 2.02 - 1.90 (m, 2H), 1.88 - 1.76 (m, 3H), 1.70 - 1.55 (m, 1H), 1.21 - 1.07 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -108.99 (td, J = 9.3, 4.4 Hz), -112.44 (t, J = 7.2 Hz).

Peak 2: MS ( m/z ) 464.26 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.88 (t, J = 5.7 Hz, 1H), 7.32 - 7.16 (m, 2H), 5.68 (d, J = 6.7 Hz, 1H), 4.62 (dd, J = 14.5, 5.8 Hz, 1H), 4.54 (dd, J = 14.6, 5.6 Hz, 1H), 4.18 (dt, J = 14.3, 7.4 Hz, 1H), 3.81 (d, J = 14.2 Hz, 1H), 3.65 (d, J = 14.1 Hz, 1H), 3.03 (dt, J = 12.1, 5.7 Hz, 1H), 2.25 (dd, J = 13.5, 6.9 Hz, 1H), 2.21 - 2.07 (m, 2H), 2.04 (d, J = 13.4 Hz, 1H), 1.89 - 1.76 (m, 2H), 1.73 - 1.59 (m, 1H), 1.30 - 1.14 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -109.24 (ddd, J = 15.5, 9.2, 6.2 Hz), -112.44 (t, J = 7.2 Hz).

Peak 3: MS ( m/z ) 464.26 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.88 (t, J = 5.7 Hz, 1H), 7.32 - 7.13 (m, 2H), 5.68 (d, J = 6.7 Hz, 1H), 4.62 (dd, J = 14.5, 5.8 Hz, 1H), 4.54 (dd, J = 14.5, 5.6 Hz, 1H), 4.18 (dt, J = 14.1, 7.4 Hz, 1H), 3.81 (d, J = 14.2 Hz, 1H), 3.65 (d, J = 14.1 Hz, 1H), 3.03 (dt, J = 12.3, 5.5 Hz, 1H), 2.25 (dd, J = 13.4, 6.8 Hz, 1H), 2.21 - 2.07 (m, 2H), 2.04 (d, J = 13.4 Hz, 1H), 1.90 - 1.76 (m, 2H), 1.73 - 1.59 (m, 1H), 1.31 - 1.13 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -109.24 (ddd, J = 15.6, 9.5, 6.3 Hz), -112.44 (t, J = 7.1 Hz).

Peak 4: MS ( m/z ) 464.22 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.52 (t, J = 5.6 Hz, 1H), 7.23 (t, J = 8.7 Hz, 2H), 6.86 (s, 1H), 5.61 (dd, J = 9.4, 7.1 Hz, 1H), 4.66 (dd, J = 14.5, 6.0 Hz, 1H), 4.56 (dd, J = 14.7, 5.5 Hz, 1H), 4.17 (dt, J = 14.5, 7.6 Hz, 1H), 3.84 (s, 2H), 3.06 (dt, J = 12.5, 5.7 Hz, 1H), 2.62 (dd, J = 12.2, 7.0 Hz, 1H), 2.03 - 1.90 (m, 2H), 1.87 - 1.78 (m, 3H), 1.69 - 1.55 (m, 1H), 1.23 - 1.08 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -108.87 - -109.12 (m), -112.44 (t, J = 7.3 Hz).

Example 10: (6aS,8R)-N-(2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7, 8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (10-1), (6aR,8R)- N-(2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a -methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (10-2), (6aS,8S)-N-(2,4-difluoro benzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazo nino[9,1,2-cd]indolizine-9-carboxamide (10-3) and (6aR,8S)-N-(2,4-difluorobenzyl)-8,11-dihydroxy -1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd] Preparation of indolizine-9-carboxamide (10-4):

Step 1. 11-(benzyloxy)-N-(2,4-difluorobenzyl)-8-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10 -octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 10a ) of the synthesis:

11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8-hexahydro prepared according to the preparation of intermediate 9b in Example 9 in DMSO (3.7 mL) 2,4-difluorobenzyl in a solution of -2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione (0.091 g, 0.185 mmol) Amine (0.149 g, 1.04 mmol), i -Pr ₂ NEt (0.161 mL, 0.924 mmol) and Pd(PPh ₃ ) ₄ (0.011 g, 0.009 mmol) were added. The reaction flask was evacuated and backfilled with CO (g) three times, then heated to 80° C. for 4 hours under 1 atm of CO (g). After cooling to room temperature, the reaction was diluted with EtOAc and washed with 0.05 N HCl (1x), saturated aqueous NaHCO ₃ (1x) and brine (1x). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (0-100% EtOAc/heptane) to 11-(benzyloxy)-N-(2,4-difluorobenzyl)-8-hydroxy-1,10-dioxo -1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxa mid was provided. MS ( m/z ) 536.16 [M+H] ⁺ .

Step 2. (6aS,8R)-N-(2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8 , 10-octahydro-2,6a-methano [1,4] diazonino [9,1,2-cd] indolizine-9-carboxamide ( 10-1 ), (6aR,8R)-N-(2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8, 10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 10-2 ), (6aS,8S)-N-(2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8, 10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 10-3 ) and (6aR,8S)-N-(2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8, 10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 10-4 ) of the synthesis:

11-(benzyloxy)-N-(2,4-difluorobenzyl)-8-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro -2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide was eluted with four sequentially numbered peaks 1 to 4 according to the order of elution. It was separated into its individual stereoisomers by preparative SFC on an AD-H column using 50% i -PrOH (containing 0.1% NH ₃ ) cosolvent to give distinct peaks. Among them, peak 1 and peak 4 are enantiomers; Peak 2 and Peak 3 are enantiomers. The absolute conformation is not identified and assigned.

The separated stereoisomers were each dissolved in 1:1 toluene/TFA (2 mL). The reaction mixture was allowed to stir at room temperature for 2 h and concentrated. The residue was dissolved in MeCN and preparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2) eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30 min. mm). The combined fractions were lyophilized to provide the title compound. The absolute conformation is not identified and assigned.

Peak 1: MS ( m/z ) 446.23 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.44 (t, J = 5.8 Hz, 1H), 7.45 (td, J = 8.6, 6.6 Hz, 1H), 7.33 - 7.19 (m, 1H), 7.09 ( td, J = 8.6, 2.6 Hz, 1H), 5.61 (dd, J = 9.4, 7.1 Hz, 1H), 4.60 (qd, J = 15.0, 5.7 Hz, 2H), 4.18 (dt, J = 14.1, 7.4 Hz) , 1H), 3.85 (s, 2H), 3.07 (dt, J = 12.5, 5.7 Hz, 1H), 2.63 (dd, J = 12.2, 7.0 Hz, 1H), 2.04 - 1.92 (m, 2H), 1.89 - 1.77 (m, 3H), 1.71 - 1.55 (m, 1H), 1.22 - 1.08 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -112.03 (p, J = 8.1 Hz), -114.77 (q, J = 8.9 Hz).

Peak 2: MS ( m/z ) 446.27 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.80 (t, J = 5.8 Hz, 1H), 7.44 (td, J = 8.7, 6.6 Hz, 1H), 7.26 (ddd, J = 10.6, 9.3, 2.6) Hz, 1H), 7.08 (td, J = 8.5, 2.6 Hz, 1H), 5.68 (d, J = 6.7 Hz, 1H), 4.63 - 4.52 (m, 2H), 4.19 (dt, J = 13.2, 7.5 Hz) , 1H), 3.83 (d, J = 14.2 Hz, 1H), 3.68 (dd, J = 14.1, 1.4 Hz, 1H), 3.05 (ddd, J = 13.3, 6.6, 4.7 Hz, 1H), 2.28 (dd, J = 13.5, 6.9 Hz, 1H), 2.20 (dd, J = 15.5, 6.4 Hz, 1H), 2.15 - 2.08 (m, 1H), 2.06 (d, J = 13.5 Hz, 1H), 1.91 - 1.77 (m) , 2H), 1.73 - 1.62 (m, 1H), 1.30 - 1.16 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -112.32 (p, J = 7.7 Hz), -114.96 (q, J = 8.8 Hz).

Peak 3: MS ( m/z ) 446.26 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.80 (t, J = 5.9 Hz, 1H), 7.50 - 7.37 (m, 1H), 7.26 (td, J = 10.0, 2.6 Hz, 1H), 7.08 ( td, J = 8.5, 2.5 Hz, 1H), 5.68 (d, J = 6.8 Hz, 1H), 4.64 - 4.51 (m, 2H), 4.19 (dt, J = 14.1, 7.5 Hz, 1H), 3.83 (d) , J = 14.2 Hz, 1H), 3.68 (d, J = 14.1 Hz, 1H), 3.05 (dt, J = 12.3, 5.5 Hz, 1H), 2.28 (dd, J = 13.5, 6.8 Hz, 1H), 2.20 (dd, J = 15.4, 6.4 Hz, 1H), 2.16 - 2.09 (m, 1H), 2.06 (d, J = 13.4 Hz, 1H), 1.92 - 1.78 (m, 2H), 1.74 - 1.62 (m, 1H) ), 1.30 - 1.15 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -112.32 (p, J = 7.6 Hz), -114.96 (q, J = 8.5 Hz).

Peak 4: MS ( m/z ) 446.24 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.43 (t, J = 5.8 Hz, 1H), 7.44 (td, J = 8.7, 6.6 Hz, 1H), 7.26 (td, J = 9.9, 2.6 Hz, 1H), 7.08 (td, J = 8.5, 2.7 Hz, 1H), 5.61 (dd, J = 9.4, 7.1 Hz, 1H), 4.59 (qd, J = 14.9, 5.8 Hz, 2H), 4.17 (dt, J) = 14.2, 7.4 Hz, 1H), 3.84 (s, 2H), 3.05 (dd, J = 12.8, 5.9 Hz, 1H), 2.62 (dd, J = 12.2, 7.1 Hz, 1H), 2.03 - 1.92 (m, 2H), 1.89 - 1.76 (m, 3H), 1.69 - 1.57 (m, 1H), 1.22 - 1.08 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -112.03 (p, J = 8.2 Hz), -114.77 (q, J = 8.9 Hz).

Example 11: (6aR,7S,8S)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4, 5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (11-1); (6aS,7S,8S)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6, 7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (11-2), (6aR,7R ,8R)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8, 10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (11-3) and (6aS,7R,8R)- 7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro Preparation of -2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (11-4):

Step 1. tert-Butyl 3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)-1,2-dihydroxyethyl) -3-((tert-butoxycarbonyl)amino)azepane-1-carboxylate ( 11a ) of the synthesis:

tert-Butyl (E)-3-(2-(5-(benzyloxy)-6-(methoxycarbo) prepared according to the preparation of intermediate 1d in Example 1 in 1:1 acetone/water (14.3 mL) nyl)-4-oxo-4H-pyran-2-yl)vinyl)-3-((tert-butoxycarbonyl)amino)azepane-1-carboxylate (0.595 g, 0.994 mmol) in a solution of A solution of NMO (0.233 g, 1.99 mmol) and 2.5% OsO ₄ in 0.125 mL, 0.010 mmol) was added. The reaction mixture was stirred at room temperature for 24 h, quenched with saturated aqueous sodium thiosulfate and NaHCO ₃ and stirred for 1 h. The mixture was concentrated and CH ₂ Cl ₂ was added. The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2x). The combined organic phases were dried over Na ₂ SO ₄ , filtered, concentrated and purified by column chromatography (0-80% EtOAc/hexanes) tert-butyl 3-(2-(5-(benzyloxy)-6) -(Methoxycarbonyl)-4-oxo-4H-pyran-2-yl)-1,2-dihydroxyethyl)-3-((tert-butoxycarbonyl)amino)azepane-1-carboxyl rate was provided. MS ( m/z ) 632.87 [M+H] ⁺ .

Step 2. 11-(benzyloxy)-7,8-dihydroxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9, 1,2-cd]indolizine-1,10-dione ( 11b ) of the synthesis:

tert-Butyl 3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl) in CH ₂ Cl ₂ (20 mL) at 0° C. To a solution of -1,2-dihydroxyethyl)-3-((tert-butoxycarbonyl)amino)azepane-1-carboxylate (0.519 g, 0.821 mmol) trifluoroacetic acid (4.00 mL, 50.5) mmol) was added. The reaction mixture was stirred for 2 h, warmed to room temperature, concentrated and dried under high vacuum for 1 h. The residue was dissolved in ethanol (20 mL) and heated at 90° C. for 3 h. The reaction mixture was cooled to room temperature, concentrated and purified by column chromatography to give 11-(benzyloxy)-7,8-dihydroxy-3,4,5,6,7,8-hexahydro-2, 6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione was provided. MS ( m/z ) 383.26 [M+H] ⁺ .

Step 3. 11-(benzyloxy)-7,8-dihydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]dia Zonino[9,1,2-cd]indolizine-1,10-dione ( 11c ) of the synthesis:

11-(benzyloxy)-7,8-dihydroxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazo in anhydrous methanol (2 mL) In a solution of nino[9,1,2-cd]indolizine-1,10-dione (0.100 g, 0.261 mmol) 77% m -CPBA (0.234 g, 1.05 mmol) and N -iodosuccinimide (0.235) g, 1.05 mmol) was added. The reaction mixture was heated at 80° C. for 0.5 h and cooled to room temperature. The solution was diluted with CH ₂ Cl ₂ and washed with 10% aqueous Na ₂ SO ₃ solution. The aqueous phase was extracted with CH ₂ Cl ₂ , and the combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (0-10% MeOH/CH ₂ Cl ₂ ) to obtain 11-(benzyloxy)-7,8-dihydroxy-9-iodo-3,4,5,6, 7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione was provided. MS ( m/z ) 509.09 [M+H] ⁺ .

Step 4. 11-(benzyloxy)-7,8-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6, 7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 11d ) of the synthesis:

11-(benzyloxy)-7,8-dihydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1, in DMSO (2 mL) 4] 2,4,6-trifluorobenzylamine (0.043 g, 0.266 mmol) in a solution of 4]diazonino[9,1,2-cd]indolizine-1,10-dione (0.027 g, 0.053 mmol) , i -Pr ₂ NEt (0.046 mL, 0.266 mmol) and Pd(PPh ₃ ) ₄ (0.003 g, 0.003 mmol) were added. The reaction flask was evacuated and backfilled with CO (g) three times, then heated to 80° C. for 4 hours under 1 atm of CO (g). After cooling to room temperature, the reaction was diluted with EtOAc and washed with 0.05 N HCl (1x), saturated aqueous NaHCO ₃ (1x) and brine (1x). The organic phase was dried over Na ₂ SO ₄ , filtered, concentrated and purified by column chromatography (0-20% MeOH/CH ₂ Cl ₂ ) 11-(benzyloxy)-7,8-dihydroxy- 1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1, 4]diazonino[9,1,2-cd]indolizine-9-carboxamide was provided. MS ( m/z ) 570.21 [M+H] ⁺ .

Step 5. (6aR,7S,8S)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5 , 6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 11-1 ), (6aS,7S,8S)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5, 6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 11-2 ), (6aR,7R,8R)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5, 6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 11-3 ) and (6aS,7R,8R)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5, 6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 11-4 ) of the synthesis:

11-(benzyloxy)-7,8-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8 , 10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide sequentially from peaks 1 to 4 according to the order of elution It was separated into its individual stereoisomers by preparative SFC on an IB column using 40% MeOH cosolvent to give 4 distinct peaks numbered as . Among them, peak 1 and peak 4 are enantiomers; Peak 2 and Peak 3 are enantiomers. The absolute conformation is not identified and assigned.

The separated stereoisomers were each dissolved in 1:1 toluene/TFA (2 mL). The reaction mixture was allowed to stir at room temperature for 2 h and concentrated. The residue was dissolved in MeCN and preparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2) eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30 min. mm). The combined fractions were lyophilized to provide the title compound. The absolute conformation is not identified and assigned.

Peak 1: MS ( m/z ) 480.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.86 (t, J = 5.7 Hz, 1H), 7.22 (t, J = 8.6 Hz, 2H), 5.74 (s, 1H), 5.53 (s, 1H) , 4.57 (qd, J = 14.6, 5.7 Hz, 2H), 4.20 (dt, J = 13.7, 6.9 Hz, 1H), 4.06 (s, 1H), 3.79 (d, J = 14.6 Hz, 1H), 3.65 ( d, J = 14.6 Hz, 1H), 3.03 (dt, J = 12.6, 6.0 Hz, 1H), 2.49 - 2.43 (m, 1H), 2.17 - 2.06 (m, 1H), 2.00 (dd, J = 15.5, 7.1 Hz, 1H), 1.86 - 1.75 (m, 2H), 1.78 - 1.59 (m, 1H), 1.25 (d, J = 15.5 Hz, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -109.28 (ddd, J = 15.6, 9.3, 6.2 Hz), -112.43 (t, J = 7.2 Hz).

Peak 2: MS ( m/z ) 480.21 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.50 (t, J = 5.7 Hz, 1H), 7.23 (t, J = 8.6 Hz, 2H), 6.98 (s, 1H), 5.10 (d, J = 8.0 Hz, 1H), 4.65 (dd, J = 14.6, 5.8 Hz, 1H), 4.55 (dd, J = 14.6, 5.4 Hz, 1H), 4.15 (dt, J = 13.5, 6.9 Hz, 1H), 4.06 ( d, J = 7.9 Hz, 1H), 3.83 - 3.70 (m, 2H), 3.05 (dt, J = 12.8, 6.0 Hz, 1H), 2.32 - 2.25 (m, 1H), 1.86 - 1.74 (m, 2H) , 1.75 - 1.69 (m, 1H), 1.69 - 1.59 (m, 1H), 1.50 (dd, J = 15.1, 7.2 Hz, 1H), 1.34 - 1.26 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -108.87 - -109.08 (m), -112.43 (t, J = 7.4 Hz).

Peak 3: MS ( m/z ) 480.22 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.51 (t, J = 5.7 Hz, 1H), 7.28 - 7.18 (m, 2H), 6.99 (s, 1H), 5.10 (d, J = 8.0 Hz, 1H), 4.66 (dd, J = 14.7, 5.8 Hz, 1H), 4.56 (dd, J = 14.6, 5.5 Hz, 1H), 4.21 - 4.11 (m, 1H), 4.07 (d, J = 8.2 Hz, 1H) ), 3.81 - 3.72 (m, 2H), 3.10 - 3.02 (m, 1H), 2.33 - 2.25 (m, 1H), 1.88 - 1.70 (m, 3H), 1.70 - 1.59 (m, 1H), 1.51 (dd , J = 14.6, 7.5 Hz, 1H), 1.32 - 1.24 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -108.87 - -109.07 (m), -112.43 (t, J = 7.2 Hz).

Peak 4: MS ( m/z ) 480.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.86 (t, J = 5.7 Hz, 1H), 7.28 - 7.13 (m, 2H), 5.74 (s, 1H), 5.53 (s, 1H), 4.57 ( qd, J = 14.5, 5.7 Hz, 2H), 4.20 (dt, J = 13.4, 6.8 Hz, 1H), 4.06 (s, 1H), 3.79 (d, J = 14.5 Hz, 1H), 3.65 (d, J) = 14.6 Hz, 1H), 3.03 (dt, J = 13.0, 6.1 Hz, 1H), 2.17 - 2.06 (m, 1H), 2.00 (dd, J = 15.4, 7.3 Hz, 1H), 1.85 - 1.74 (m, 2H), 1.74 - 1.61 (m, 1H), 1.35 - 1.24 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -109.28 (ddd, J = 9.4, 6.5, 3.0 Hz), -112.43 (t, J = 7.1 Hz).

Example 12: (6aS,8R)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5, 6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (12-1), (6aR ,8S)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8, 10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (12-2), (6aS,8S)-11- Hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2 ,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (12-3) and (6aR,8R)-11-hydroxy-8-methyl oxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[ Preparation of 1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (12-4):

Step 1. 11-(benzyloxy)-9-iodo-8-methoxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[ 9,1,2-cd]indolizine-1,10-dione ( 12a ) of the synthesis:

11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8- prepared according to the preparation of intermediate 9b in Example 9 in DMF (1 mL) at room temperature In a solution of hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione (0.035 g, 0.071 mmol), 60% sodium hydride (0.004 g, 0.107 mmol) was added. After 5 min, iodomethane (0.009 mL, 0.142 mmol) was added. The reaction was stirred for 2 h, quenched with MeOH, concentrated and purified by column chromatography (0-10% MeOH/CH ₂ Cl ₂ ). The impure residue was purified again by column chromatography (20-100% EtOAc/hexanes) to 11-(benzyloxy)-9-iodo-8-methoxy-3,4,5,6,7,8- Hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione was provided. MS ( m/z ) 507.10 [M+H] ⁺ .

Step 2. 11-(benzyloxy)-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8 , 10-octahydro-2,6a-methano [1,4] diazonino [9,1,2-cd] indolizine-9-carboxamide ( 12b ) of the synthesis:

11-(benzyloxy)-9-iodo-8-methoxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]dia in DMSO (1 mL) In a solution of zonino[9,1,2-cd]indolizine-1,10-dione (0.016 g, 0.032 mmol) 2,4,6-trifluorobenzylamine (0.026 g, 0.160 mmol), i - Pr ₂ NEt (0.028 mL, 0.160 mmol) and Pd(PPh ₃ ) ₄ (0.002 g, 0.002 mmol) were added. The reaction flask was evacuated and backfilled with CO (g) three times, then heated to 80° C. for 4 hours under 1 atm of CO (g). After cooling to room temperature, the reaction was diluted with EtOAc and washed with 0.05 N HCl (1x), saturated aqueous NaHCO ₃ (1x) and brine (1x). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (0-10% MeOH/CH ₂ Cl ₂ ) to 11-(benzyloxy)-8-methoxy-1,10-dioxo-N- as two separable stereoisomers. (2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1 ,2-cd]indolizine-9-carboxamide was provided.

Peak 1 (Note): MS ( m/z ) 568.15 [M+H] ⁺ .

Peak 2 (part): MS ( m/z ) 568.18 [M+H] ⁺ .

Step 3. (6aS,8R)-11-Hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6 ,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 12-1 ), (6aR,8S)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6, 7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 12-2 ), (6aS,8S)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6, 7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 12-3 ) and (6aR,8R)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6, 7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 12-4 ) of the synthesis:

11-(benzyloxy)-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10- The major diastereomer of octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (peak 1 from 12b ) was separated into two distinct was separated into its individual stereoisomers by preparative SFC on an AD-H column using 40% MeOH cosolvent to give peaks of The separated stereoisomers were each dissolved in 1:1 toluene/TFA (2 mL). The reaction mixture was allowed to stir at room temperature for 2 h and concentrated. The residue was dissolved in MeCN and preparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2) eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30 min. mm). The combined fractions were lyophilized to provide the title compound. The absolute conformation is not identified and assigned.

Peak 1: MS ( m/z ) 478.19 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.83 (t, J = 5.6 Hz, 1H), 7.32 - 7.13 (m, 2H), 5.68 (d, J = 5.6 Hz, 1H), 4.63 (dd, J = 14.4, 6.1 Hz, 1H), 4.47 (dd, J = 14.4, 5.1 Hz, 1H), 4.18 (dt, J = 13.6, 7.1 Hz, 1H), 3.81 (d, J = 14.2 Hz, 1H), 3.63 (d, J = 14.3 Hz, 1H), 3.39 (s, 3H), 3.02 (dt, J = 12.7, 5.7 Hz, 1H), 2.27 (d, J = 13.5 Hz, 1H), 2.13 - 2.02 (m) , 3H), 1.87 - 1.76 (m, 2H), 1.72 - 1.61 (m, 1H), 1.31 - 1.24 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -109.34 (tt, J = 9.7, 6.4 Hz), -112.45 (t, J = 7.3 Hz).

Peak 2: MS ( m/z ) 478.18 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.83 (t, J = 5.6 Hz, 1H), 7.26 - 7.16 (m, 2H), 5.68 (d, J = 5.6 Hz, 1H), 4.63 (dd, J = 14.5, 6.0 Hz, 1H), 4.47 (dd, J = 14.5, 5.2 Hz, 1H), 4.18 (dt, J = 13.8, 7.1 Hz, 1H), 3.81 (d, J = 14.2 Hz, 1H), 3.63 (d, J = 14.3 Hz, 1H), 3.39 (s, 3H), 3.02 (dt, J = 12.5, 5.7 Hz, 1H), 2.27 (d, J = 13.5 Hz, 1H), 2.13 - 2.03 (m) , 3H), 1.86 - 1.76 (m, 2H), 1.71 - 1.62 (m, 1H), 1.31 - 1.24 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -109.34 (ddd, J = 9.0, 6.4, 2.9 Hz), -112.45 (t, J = 7.2 Hz).

11-(benzyloxy)-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10- The minor diastereomer of octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (peak 2 from 12b ) was separated into two separate was separated into its individual stereoisomers by preparative SFC on an OJ-H column using 20% EtOH cosolvent to give the peak of The separated stereoisomers were each dissolved in 1:1 toluene/TFA (2 mL). The reaction mixture was allowed to stir at room temperature for 2 h and concentrated. The residue was dissolved in MeCN and preparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2) eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30 min. mm). The combined fractions were lyophilized to provide the title compound. The absolute conformation is not identified and assigned.

Peak 1: MS ( m/z ) 478.12 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.66 (t, J = 5.6 Hz, 1H), 7.22 - 7.14 (m, 2H), 5.37 (t, J = 7.6 Hz, 1H), 4.55 (dd, J = 14.3, 6.2 Hz, 1H), 4.41 (dd, J = 14.5, 5.1 Hz, 1H), 4.16 (dt, J = 14.2, 7.6 Hz, 1H), 3.85 - 3.74 (m, 2H), 3.27 (s) , 3H), 3.09 - 3.00 (m, 1H), 2.76 (dd, J = 12.4, 7.2 Hz, 1H), 1.89 - 1.72 (m, 5H), 1.67 - 1.56 (m, 1H), 1.16 - 1.05 (m) , 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -109.64 (ddd, J = 9.4, 6.4, 3.0 Hz), -112.09 (t, J = 7.1 Hz).

Peak 2: MS ( m/z ) 478.13 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.67 (t, J = 5.6 Hz, 1H), 7.25 - 7.17 (m, 2H), 5.37 (t, J = 7.6 Hz, 1H), 4.56 (dd, J = 14.2, 6.1 Hz, 1H), 4.42 (dd, J = 14.4, 5.0 Hz, 1H), 4.17 (dt, J = 14.0, 7.6 Hz, 1H), 3.87 - 3.74 (m, 2H), 3.28 (s) , 3H), 3.09 - 3.01 (m, 1H), 2.77 (dd, J = 12.3, 7.2 Hz, 1H), 1.94 - 1.75 (m, 5H), 1.69 - 1.52 (m, 1H), 1.21 - 1.00 (m , 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -109.64 (tt, J = 9.0, 6.1 Hz), -112.09 (t, J = 7.2 Hz).

Example 13: (6aR,7S,8S)-11-hydroxy-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3, 4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (13-1 ), (6aS,7R,8R)-11-hydroxy-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4, 5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (13-2); (6aR,7R,8R)-11-hydroxy-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5, 6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (13-3) and (6aS ,7S,8S)-11-hydroxy-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6, Preparation of 7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (13-4):

Step 1. 11-(benzyloxy)-7,8-dimethoxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1 ,2-cd]indolizine-1,10-dione ( 13a ) of the synthesis:

11-(benzyloxy)-7,8-dihydroxy-3,4,5,6,7,8-hexahydro prepared according to the preparation of intermediate 11b in Example 11 in DMF (20 mL) at room temperature -2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione (0.250 g, 0.654 mmol) in a solution of 60% sodium hydride (0.063 g, 1.63 mmol) was added. After 5 min, iodomethane (0.163 mL, 2.61 mmol) was added. The reaction was stirred for 2 h, quenched with MeOH, concentrated and purified by column chromatography (0-100% EtOAc/heptane followed by 0-10% MeOH/CH ₂ Cl ₂ ) to 11-(benzyloxy) -7,8-dimethoxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1 , provided 10-dione. MS ( m/z ) 411.28 [M+H] ⁺ .

Step 2. 11-(benzyloxy)-9-iodo-7,8-dimethoxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazo nino[9,1,2-cd]indolizine-1,10-dione ( 13b ) of the synthesis:

11-(benzyloxy)-7,8-dimethoxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino in anhydrous methanol (1 mL) In a solution of [9,1,2-cd]indolizine-1,10-dione (0.036 g, 0.088 mmol), 77% m -CPBA (0.079 g, 0.351 mmol) and N -iodosuccinimide (0.079 g) , 0.351 mmol) was added. The reaction mixture was heated at 80° C. for 1 h and cooled to room temperature. The solution was diluted with CH ₂ Cl ₂ and washed with 10% aqueous Na ₂ SO ₃ solution. The aqueous phase was extracted with CH ₂ Cl ₂ , and the combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (0-10% MeOH/CH ₂ Cl ₂ ) to 11-(benzyloxy)-9-iodo-7,8-dimethoxy-3,4,5,6,7 ,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione was provided. MS ( m/z ) 537.08 [M+H] ⁺ .

Step 3. 11-(benzyloxy)-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7 ,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 13c ) of the synthesis:

11-(benzyloxy)-9-iodo-7,8-dimethoxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4 in DMSO (1.4 mL) 2,4,6-trifluorobenzylamine (0.052 g, 0.322 mmol) in a solution of ]diazonino[9,1,2-cd]indolizine-1,10-dione (0.034 g, 0.064 mmol), i -Pr ₂ NEt (0.056 mL, 0.322 mmol) and Pd(PPh ₃ ) ₄ (0.004 g, 0.003 mmol) were added. The reaction flask was evacuated and backfilled with CO (g) three times, then heated to 80° C. for 4 hours under 1 atm of CO (g). After cooling to room temperature, the reaction was diluted with EtOAc and washed with 0.05 N HCl (1x), saturated aqueous NaHCO ₃ (1x) and brine (1x). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (0-100% EtOAc/heptane) to 11-(benzyloxy)-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-tri) fluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine- 9-carboxamide was given. MS ( m/z ) 598.15 [M+H] ⁺ .

Step 4. (6aR,7S,8S)-11-hydroxy-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4 , 5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (13-1) , (6aS,7R,8R)-11-hydroxy-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5 , 6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (13-2), ( 6aR,7R,8R)-11-hydroxy-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6 ,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (13-3) and (6aS, 7S,8S)-11-hydroxy-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7 Synthesis of ,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (13-4):

11-(benzyloxy)-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8, 10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide sequentially from peak 1 to peak 4 according to the order of elution It was separated into its individual stereoisomers by preparative SFC on an IA column using 50% i -PrOH (containing 0.1% NH ₃ ) cosolvent to give 4 distinct peaks, numbered. The separated stereoisomers were each dissolved in 1:1 toluene/TFA (2 mL). The reaction mixture was allowed to stir at room temperature for 2 h and concentrated. The residue was dissolved in MeCN and preparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2) eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30 min. mm). The combined fractions were lyophilized to provide the title compound. The absolute conformation is not identified and assigned.

Peak 1: MS ( m/z ) 508.22 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.80 (t, J = 5.6 Hz, 1H), 7.32 - 7.13 (m, 2H), 5.76 (s, 1H), 5.52 (s, 1H), 4.61 ( dd, J = 14.5, 5.9 Hz, 1H), 4.51 (dd, J = 14.5, 5.4 Hz, 1H), 4.20 (dt, J = 13.0, 6.3 Hz, 1H), 4.05 (s, 1H), 3.79 (s) , 2H), 3.53 (s, 3H), 3.40 (s, 3H), 3.04 (dt, J = 12.8, 5.8 Hz, 1H), 2.21 - 2.07 (m, 1H), 1.94 - 1.73 (m, 4H), 1.42 - 1.22 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -109.24 (tt, J = 9.4, 6.3 Hz), -112.28 - -112.58 (m).

Peak 2: MS ( m/z ) 508.24 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.80 (t, J = 5.6 Hz, 1H), 7.23 (t, J = 8.6 Hz, 2H), 5.76 (s, 1H), 5.52 (s, 1H) , 4.61 (dd, J = 14.5, 5.9 Hz, 1H), 4.51 (dd, J = 14.5, 5.4 Hz, 1H), 4.26 - 4.15 (m, 1H), 4.05 (s, 1H), 3.79 (s, 2H) ), 3.53 (s, 3H), 3.40 (s, 3H), 3.04 (dt, J = 12.7, 5.9 Hz, 1H), 2.15 (dd, J = 15.5, 10.0 Hz, 1H), 1.92 - 1.75 (m, 4H), 1.40 - 1.25 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -109.24 (tt, J = 9.4, 6.3 Hz), -112.45 (t, J = 7.3 Hz).

Peak 3: MS ( m/z ) 508.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.35 (t, J = 5.6 Hz, 1H), 7.26 - 7.09 (m, 2H), 4.89 (d, J = 7.4 Hz, 1H), 4.46 (qd, J = 14.4, 5.5 Hz, 2H), 4.14 (dt, J = 14.3, 7.4 Hz, 1H), 4.02 - 3.81 (m, 3H), 3.48 (s, 3H), 3.39 (s, 3H), 3.09 - 3.00 (m, 1H), 2.15 - 1.99 (m, 1H), 1.89 - 1.76 (m, 2H), 1.75 - 1.61 (m, 1H), 1.54 (dd, J = 15.3, 6.5 Hz, 1H), 1.26 - 1.09 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -109.66 (tt, J = 9.5, 6.2 Hz), -112.01 (t, J = 7.0 Hz).

Peak 4: MS ( m/z ) 508.21 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.35 (t, J = 5.6 Hz, 1H), 7.31 - 7.09 (m, 2H), 4.90 (d, J = 7.3 Hz, 1H), 4.47 (qd, J = 14.4, 5.7 Hz, 2H), 4.15 (dt, J = 14.1, 7.4 Hz, 1H), 3.98 - 3.82 (m, 3H), 3.48 (s, 3H), 3.40 (s, 3H), 3.10 - 3.02 (m, 1H), 2.13 - 2.02 (m, 1H), 1.89 - 1.78 (m, 2H), 1.75 - 1.64 (m, 1H), 1.54 (dd, J = 15.2, 6.6 Hz, 1H), 1.28 - 1.12 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -109.66 (tt, J = 9.1, 6.3 Hz), -112.01 (t, J = 7.1 Hz).

Example 14: (6aR,8R)-N-(3-chloro-2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5, 6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (14-1) and (6aR ,8S)-N-(3-chloro-2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8, Preparation of 10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (14-2):

(6aR)-11-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-8-hydroxy-1,10-dioxo-1,3,4,5,6, Synthesis of 7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide:

(6aR)-11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1] in DMSO (10 mL) 3-chloro-2,4-difluorobenzylamine in a solution of ,4]diazonino[9,1,2-cd]indolizine-1,10-dione (0.261 g, 0.530 mmol) (intermediate 9b ) (0.471 g, 2.65 mmol), i -Pr ₂ NEt (0.462 mL, 2.65 mmol) and Pd(PPh ₃ ) ₄ (0.031 g, 0.026 mmol) were added. The reaction flask was evacuated and backfilled with CO (g) three times, then heated to 80° C. under 1 atm of CO (g) for 4 hours. After cooling to room temperature, the reaction was diluted with EtOAc and washed with 0.05 N HCl (1x), saturated aqueous NaHCO ₃ (1x) and brine (1x). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (0-100% EtOAc/heptane) to (6aR)-11-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-8-hydro Roxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd ]Indolizine-9-carboxamide was provided. MS ( m/z ) 570.15 [M+H] ⁺ .

(6aR,8R)-N-(3-chloro-2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7, 8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 14-1 ) and (6aR,8S)-N-(3-chloro-2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6, 7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 14-2 ) of the synthesis:

(6aR)-11-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-8-hydroxy-1,10-dioxo-1,3,4,5,6, 7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide to give two distinct peaks It was separated into its individual stereoisomers by preparative SFC on an IB column using 45% methanol cosolvent. The separated stereoisomers were each dissolved in 1:1 toluene/TFA (10 mL for peak 1; 6 mL for peak 2). The reaction mixture was allowed to stir at room temperature for 2 h and concentrated. The residue was dissolved in MeCN and preparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2) eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30 min. mm). The combined fractions were lyophilized to provide the title compound.

Peak 1 ( 14-1 ): MS ( m/z ) 480.31 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.84 (t, J = 5.9 Hz, 1H), 7.42 (td, J = 8.5, 6.2 Hz, 1H), 7.31 (td, J = 8.8, 1.7 Hz, 1H), 5.67 (dd, J = 6.7, 3.5 Hz, 1H), 5.34 (d, J = 3.4 Hz, 1H), 4.68 - 4.54 (m, 2H), 4.18 (dt, J = 13.0, 7.5 Hz, 1H) ), 3.82 (d, J = 14.2 Hz, 1H), 3.67 (d, J = 13.9 Hz, 1H), 3.05 (ddd, J = 13.2, 6.5, 4.6 Hz, 1H), 2.27 (dd, J = 13.4, 6.8 Hz, 1H), 2.19 (dd, J = 15.5, 6.4 Hz, 1H), 2.14 - 2.00 (m, 2H), 1.92 - 1.77 (m, 2H), 1.74 - 1.59 (m, 1H), 1.30 - 1.14 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -116.15 (td, J = 7.4, 6.1, 2.2 Hz), -118.37 (d, J = 8.2 Hz).

Peak 2 ( 14-2 ): MS ( m/z ) 480.21 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.45 (t, J = 5.9 Hz, 1H), 7.43 (td, J = 8.4, 6.2 Hz, 1H), 7.31 (td, J = 8.8, 1.7 Hz, 1H), 5.60 (dd, J = 9.4, 7.0 Hz, 1H), 4.64 (qd, J = 15.1, 5.9 Hz, 2H), 4.17 (dt, J = 13.2, 7.4 Hz, 1H), 3.84 (s, 2H) ), 3.06 (dt, J = 13.2, 5.7 Hz, 1H), 2.62 (dd, J = 12.2, 7.1 Hz, 1H), 2.02 - 1.90 (m, 2H), 1.90 - 1.76 (m, 3H), 1.70 - 1.56 (m, 1H), 1.23 - 1.08 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -115.86 (ddd, J = 8.7, 6.1, 2.4 Hz), -118.16 (d, J = 8.0 Hz).

Example 15: (6aS,8S)-8,11-dihydroxy-8-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4, Preparation of 5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (15):

Step 1. tert -Butyl ( R )-3-(( tert -Butoxycarbonyl)amino)-3-formylazepane-1-carboxylate ( 15a-1 ) and tert -Butyl ( S )-3-(( tert -Butoxycarbonyl)amino)-3-formylazepane-1-carboxylate ( 15a-2 ) of the division:

Racemic tert -butyl-3-(( tert -butoxycarbonyl)amino)-3-formylazepane-1-carboxylate was resolved using chiral SFC (15% ACN) to tert -butyl ( R ) -3-(( tert -butoxycarbonyl)amino)-3-formylazepane-1-carboxylate ( 15a-1 ) and tert -butyl ( S )-3-(( tert -butoxycarbonyl)amino )-3-formylazepane-1-carboxylate ( 15a-2 ).

Step 2. (6aS)-11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2- cd]indolizine-1,10-dione ( 15b ) of the synthesis:

The title compound is tert-butyl ( R )-3-(( tert -butoxy) instead of tert -butyl 3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylate ( 1c ) 11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a- using carbonyl)amino)-3-formylazepane-1-carboxylate ( 15a-1 ) It was synthesized in a similar manner to methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione ( 1f ).

Step 3. (6aS)-11-(benzyloxy)-3,4,5,6-tetrahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine -1,8,10(7H)-trion ( 15c ) of the synthesis:

(6aS)-11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1 in THF (100 mL) To a solution of ,2-cd]indolizine-1,10-dione ( 15b , 2.0 g, 5.7 mmol) was added dropwise LiHMDS (1.0 M in THF, 17.1 mL) at -78 °C, and the resulting dark solution was stirred for 30 min. stirred for a while. O ₂ (g) was bubbled through the reaction, allowing it to warm to room temperature while bubbling O ₂ (g) through the reaction for 20 minutes. The reaction was quenched with MeOH, concentrated and purified via combiflash (24 g, MeOH/DCM) to afford the title product.

Step 4. (6aS,8S)-11-(benzyloxy)-8-hydroxy-8-methyl-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4 ]diazonino[9,1,2-cd]indolizine-1,10-dione ( 15d ) of the synthesis:

MeLi (3.1 M in diethoxymethane, 0.32 mL), followed by MeMgBr (3.0 M in THF, 0.165 mL) was added to THF (6 mL) at -78 °C and the resulting solution was stirred for 1 h. (6aS)-11-(benzyloxy)-3,4,5,6-tetrahydro-2,6a-methano[1,4]diazonino[9,1,2-cd in THF (6 mL) ] A solution of indolizine-1,8,10(7H)-trione ( 15c , 120 mg, 0.33 mmol) was added dropwise, and the solution was stirred at -78°C for 1 hour. The reaction was quenched with water, filtered and the filter cake washed sequentially with DCM and MeOH. The filtrate was concentrated, dissolved in DMF/TFA and purified by Gilson HPLC (0-100% ACN/H ₂ O) to afford the title product as the single experimentally assigned stereoisomer.

Step 5. (6aS,8S)-11-(benzyloxy)-8-hydroxy-8-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3 , 4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 15e ) of the synthesis:

The title compound is 11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine (6aS,8S)-11-(benzyloxy)-8-hydroxy-8-methyl-3,4,5,6,7,8-hexahydro-2 instead of -1,10-dione ( 1f ), 11-(benzyloxy)-1,10-dioxo-N using 6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione ( 15d ) -(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9, 1,2-cd]indolizine-9-carboxamide ( 1 g ) was prepared in a similar manner. The reaction was purified using Gilson HPLC (5-100% ACN/H ₂ O + 0.1% TFA) to afford the title compound.

Step 6. (6aS,8S)-8,11-dihydroxy-8-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5 , 6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 15 ) of the synthesis:

(6aS,8S)-11-(benzyloxy)-8-hydroxy-8-methyl-1,10-dioxo-N-(2,4,6-) in toluene (1 mL) in TFA (1 mL) trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine It was added to a solution of -9-carboxamide ( 15e , 38 mg, 0.0067 mmol), and the resulting solution was stirred for 3 hours. The reaction was concentrated, dissolved in DMF and purified by Gilson HPLC (0-100% ACN/H2O) to afford the title product. 1H NMR (400 MHz, DMSO-d6) δ 11.68 (t, J = 5.5 Hz, 1H), 7.73 (s, 1H), 7.35 - 7.16 (m, 2H), 4.81 - 4.38 (m, 2H), 4.24 - 4.12 (m, 1H), 3.86 (d, J = 14.4 Hz, 1H), 3.74 (d, J = 14.4 Hz, 1H), 3.00 (dt, J = 13.3, 6.7 Hz, 1H), 2.41 - 2.36 (m) , 1H), 2.26 - 2.13 (m, 2H), 1.89 - 1.71 (m, 5H), 1.69 (s, 3H); MS ( m/z ) 478.2 [M+H] ⁺ .

Example 16: (6aS)-11-hydroxy-8-(hydroxymethyl)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5 Preparation of ,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (16):

Step 1. (6aS)-11-(benzyloxy)-8-(hydroxymethyl)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazo nino[9,1,2-cd]indolizine-1,10-dione ( 16a ) of the synthesis:

(6aS)-11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazo in THF (4 mL) at -78°C To a solution of nino[9,1,2-cd]indolizine-1,10-dione ( 15b , 100 mg, 0.43 mmol) was added LDA (1.0 M in THF/hexanes, 0.86 mL), and the resulting solution was Stir for 10 minutes. A solution of 1H-benzotriazole-1-methanol (2 mL) in THF was added and the solution was stirred at -78°C for 1 h. The reaction was quenched with MeOH, concentrated and purified via combiflash (12 g, MeOH/DCM) to give the desired product as a mixture of diastereomers.

Step 2. (6aS,8S)-11-(benzyloxy)-8-(hydroxymethyl)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3, 4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 16b-1 ) and (6aS,8R)-11-(benzyloxy)-8-(hydroxymethyl)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4 , 5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 16b-2 ) of the synthesis:

The title compound is 11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine (6aS)-11-(benzyloxy)-8-(hydroxymethyl)-3,4,5,6,7,8-hexahydro-2,6a-meta instead of -1,10-dione ( 1f ) 11-(benzyloxy)-1,10-dioxo-N-(2) using no[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione ( 16a ) ,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2 -cd]indolizine-9-carboxamide ( 1 g ) was prepared in a similar manner. The mixture was purified using Gilson HPLC (5-100% ACN/H ₂ O + 0.1% TFA) to afford the title compound as isolated diastereomers.

Step 3. (6aS)-11-hydroxy-8-(hydroxymethyl)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5, 6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 16 ) of the synthesis:

(6aS)-11-(benzyloxy)-8-(hydroxymethyl)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3 in toluene (0.5 mL) , 4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 16b- 2 , peak 2) was added TFA (0.5 mL), and the resulting solution was stirred for 3 hours. The reaction was concentrated and redissolved in 1:1 THF/MeOH (1 mL) and LiOH (2M in H ₂ O, 0.05 mL) was added. The solution was stirred for 1.5 h and 0.15 mL 1 N HCl was added. The reaction was concentrated, redissolved in DMF and purified by Gilson HPLC (5-100% ACN/H ₂ O) to afford the title compound. 1H NMR (400 MHz, chloroform-d) δ 11.09 (s, 1H), 6.78 - 6.57 (m, 2H), 4.75 - 4.56 (m, 3H), 4.47 (dt, J = 13.7, 6.9 Hz, 1H), 4.09 (dd, J = 10.8, 6.4 Hz, 1H), 3.90 (dd, J = 10.7, 6.3 Hz, 1H), 3.73 - 3.52 (m, 2H), 3.02 (dt, J = 12.9, 6.1 Hz, 1H) , 2.47 - 1.94 (m, 5H), 1.86 (dt, J = 14.7, 7.4 Hz, 1H), 1.83 - 1.70 (m, 1H), 1.58 (dd, J = 15.8, 7.8 Hz, 1H); MS ( m/z ) 478.2 [M+H] ⁺ .

Example 17: (6aR,8R)-8,11-dihydroxy-8-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4, Preparation of 5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (17):

The title compound is tert-butyl ( S )-3-(( tert ) in place of ( R )-3-(( tert -butoxycarbonyl)amino)-3-formylazepane-1-carboxylate ( 15a-1 ) -Butoxycarbonyl)amino)-3-formylazepane-1-carboxylate ( 15a-2 ) using (6aS,8S)-8,11-dihydroxy-8-methyl-1,10-di Oxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino [9,1,2-cd]indolizine-9-carboxamide ( 15 ) was prepared in a similar manner, and stereochemistry was assigned experimentally. 1H NMR (400 MHz, DMSO-d6) δ 11.68 (t, J = 5.5 Hz, 1H), 7.73 (s, 1H), 7.35 - 7.16 (m, 2H), 4.81 - 4.38 (m, 2H), 4.24 - 4.12 (m, 1H), 3.86 (d, J = 14.4 Hz, 1H), 3.74 (d, J = 14.4 Hz, 1H), 3.00 (dt, J = 13.3, 6.7 Hz, 1H), 2.41 - 2.36 (m) , 1H), 2.26 - 2.13 (m, 2H), 1.89 - 1.71 (m, 5H), 1.69 (s, 3H); MS ( m/z ) 478.1 [M+H] ⁺ .

Example 18: (6aR)-11-hydroxy-8-(hydroxymethyl)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5 Preparation of ,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (18):

Step 1. (6aR)-11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2- cd]indolizine-1,10-dione ( 18a ) of the synthesis:

The title compound is tert-butyl ( S )-3-(( tert -butoxy) instead of tert -butyl 3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylate ( 1c ) 11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a- using carbonyl)amino)-3-formylazepane-1-carboxylate ( 15a-2 ) It was synthesized in a similar manner to methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione ( 1f ).

Step 2. (6aR)-11-hydroxy-8-(hydroxymethyl)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5, 6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide ( 18 ) of the synthesis:

The title compound is (6aS)-11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2- (6aR)-11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1, instead of cd]indolizine-1,10-dione ( 15b ) 4]diazonino[9,1,2-cd]indolizine-1,10-dione ( 18a ) using (6aS)-11-hydroxy-8-(hydroxymethyl)-1,10-dione Oxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino Prepared analogously to [9,1,2-cd]indolizine-9-carboxamide ( 16 ). 1H NMR (400 MHz, methanol-d4) δ 6.96 - 6.86 (m, 2H), 4.72 - 4.56 (m, 2H), 4.37 (dt, J = 14.6, 7.8 Hz, 1H), 4.26 (tt, J = 8.3) , 3.8 Hz, 1H), 4.00 - 3.90 (m, 1H), 3.87 (d, J = 18.4 Hz, 1H), 3.83 - 3.72 (m, 1H), 3.25 - 3.11 (m, 1H), 2.37 (dd, J = 13.0, 8.3 Hz, 1H), 2.26 (dd, J = 13.0, 8.8 Hz, 1H), 2.07 - 1.87 (m, 4H), 1.78 (d, J = 14.7 Hz, 1H), 1.32 (dq, J) = 15.7, 7.7 Hz, 1H); MS ( m/z ) 478.1 [M+H] ⁺ .

Example 19: (1R,11S,14S)-N-[(2,4-difluorophenyl)methyl]-3,7-dihydroxy-14-methoxy-11-methyl-6,9-di of oxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide (19-1, 19-2 and 19-3) Produce:

Step 1: Synthesis of methyl (3S,7S)-3-amino-7-methyl-1,2,4,7-tetrahydroazepine-3-carboxylate bis TFA salt:

O1-Benzyl O3-methyl (3S,7S)-3-(benzyloxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1,3-dicarboxylate (5 g, 11.0 mmol) was heated in TFA (25 mL) at 100° C. for 4 h. The reaction was cooled to room temperature, concentrated and the resulting residue co-evaporated with EtOAc (8x20 mL) and used directly in the next step. LCMS-ESI+ (m/z): H+ calculated for C9H16N2O2, theoretical: 184.12, observed: 185.02.

Step 2: O1-tert-Butyl O3-methyl (3S,7S)-3-(tert-butoxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1,3-dica Synthesis of carboxylates:

Methyl (3S,7S)-3-amino-7-methyl-1,2,4,7-tetrahydroazepine-3-carboxylate bis TFA salt (4.556 g, 11.1 mol) was mixed with EtOAc (84.0 mL) at room temperature was dissolved in Saturated aqueous sodium carbonate solution (13.2 mL) was added followed by di-tert-butyl dicarbonate (7.235 g, 33.2 mmol). The resulting mixture was heated to 70° C. overnight. The reaction was cooled to room temperature, diluted with EtOAc, washed with water, brine, dried over sodium sulfate, filtered, concentrated and purified by normal phase chromatography. LCMS-ESI+ (m/z): H+ calculated for C19H32N2O6, theoretical: 384.23, observed: 384.746.

Step 3: tert-Butyl (3S,7S)-3-(tert-butoxycarbonylamino)-3-(hydroxymethyl)-7-methyl-4,7-dihydro-2H-azepine-1- Synthesis of carboxylates:

O1-tert-Butyl O3-methyl (3S,7S)-3-(tert-butoxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1,3-dicarboxylate ( 3.756 g, 9,77 mmol) was dissolved in THF (97.0 mL) and cooled to 0°C. The resulting mixture was flushed with nitrogen prior to addition of 1.0 M LAH in THF (12.7 mL, 12.7 mmol). The reaction was stirred at 0° C. for 10 min, then removed from the cooling bath and stirred at room temperature for 30 min. The reaction was cooled back to 0° C. and quenched dropwise with saturated Rochelle salt. The mixture was then diluted with EtOAc and the organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated and used directly in the next step. LCMS-ESI+ (m/z): H+ calculated for C18H32N2O5, theoretical: 356.23, observed: 356.837.

Step 4: Synthesis of tert-butyl (3S,7S)-3-(tert-butoxycarbonylamino)-3-formyl-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate :

tert-Butyl (3S,7S)-3-(tert-butoxycarbonylamino)-3-(hydroxymethyl)-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate ( 3.48 g, 9.76 mmol) was dissolved in DCM (65 mL) and cooled to 0 °C. Dess-Martin periodinane (6.21 g, 14.6 mmol) was added in portions. After addition, the reaction was warmed to room temperature and stirred overnight. The reaction was cooled back to 0° C., 1 N sodium thiosulfate (80 mL) was added, and saturated sodium bicarbonate (80 mL) was added. The mixture was stirred vigorously for 30 minutes. The layers were separated and the aqueous layer was extracted with DCM (x2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting product was purified by normal phase chromatography (80 g silica gel 0-40% EtOAc/hexanes). LCMS-ESI+ (m/z): H+ calculated for C18H30N2O5, theoretical: 354.22, observed: 355.016.

Step 5: tert-Butyl (3R,7S)-3-[(E)-2-(5-benzyloxy-6-methoxycarbonyl-4-oxo-pyran-2-yl)vinyl]-3-( Synthesis of tert-butoxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate:

Methyl 3-benzyloxy-6-(dimethoxyphosphorylmethyl)-4-oxo-pyran-2-carboxylate (1.96 g, 5.12 mmol) was dissolved in THF (25 mL) and cooled to -78°C. 1.0 M LDA in THF/hexanes (5.12 mL, 5.12 mmol) was added dropwise. The resulting mixture was stirred at -78 °C for 45 min. Then tert-Butyl (3S,7S)-3-(tert-butoxycarbonylamino)-3-formyl-7-methyl-4,7-dihydro-2H-azepine-1 in THF (9 mL) A solution of -carboxylate (1.21 g, 3.4 mmol) was added to the cold mixture. The newly formed mixture was stirred at −78° C. for 10 min, then warmed to −10° C. in 1 hour and stirred at −10° C. for an additional 60 min. The reaction was slowly quenched with saturated ammonium chloride. The mixture was diluted with EtOAc, washed with saturated ammonium chloride, brine, dried over sodium sulfate, filtered, concentrated and purified by normal phase chromatography. LCMS-ESI+ (m/z): H+ calculated for C33H42N2O9, theoretical: 610.29, observed: 610.897.

Step 6: tert-Butyl (3S,7S)-3-[2-(5-benzyloxy-6-methoxycarbonyl-4-oxo-pyran-2-yl)ethyl]-3-(tert-butoxy Synthesis of carbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate:

tert-Butyl (3R,7S)-3-[(E)-2-(5-benzyloxy-6-methoxycarbonyl-4-oxo-pyran-2-yl)vinyl]- in toluene (32.5 mL) A solution of 3-(tert-butoxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate (650 mg, 1.06 mmol) was purged with nitrogen. poly(methylhydrosiloxane) (0.64 g, 10.6 mmol) followed by chloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]copper(I) (78 mg, 0.16 mmol) and 2.0M sodium tert-butoxide in THF (0.16 mL, 0.319 mmol) were added under nitrogen. The reaction was then stirred under a nitrogen balloon for 1 hour. The reaction was quenched with water and stirred vigorously for 30 min, brine (20 mL) was added, stirred for an additional 10 min, and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purified by normal phase chromatography. LCMS-ESI+ (m/z): H+ calculated for C33H44N2O9, theoretical: 612.30, observed: 612.746.

Step 7: (1S,11S)-7-benzyloxy-11-methyl-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-6,9 - Synthesis of dione:

tert-Butyl (3S,7S)-3-[2-(5-benzyloxy-6-methoxycarbonyl-4-oxo-pyran-2-yl)ethyl]-3-(tert-butoxycarbonylamino )-7-Methyl-4,7-dihydro-2H-azepine-1-carboxylate (0.41 g, 0.669 mmol) was dissolved in DCM (16 mL), cooled to 0° C. and TFA was added to the side of the flask. was added dropwise slowly. The newly formed mixture was stirred at 0° C. for 30 min, then at room temperature for 2 h. The reaction was concentrated, co-evaporated with DCM (3x5 mL) and further dried on a vacuum line for 3 h. The residue was then dissolved in EtOH (40 mL) and heated to 90° C. for 2 h. The reaction was cooled to room temperature, concentrated and purified by normal phase chromatography. LCMS-ESI+ (m/z): H+ calculated for C22H22N2O3, theoretical: 362.16, observed: 363.30.

Step 8: (1S,11S)-7-benzyloxy-5-iodo-11-methyl-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-tri Synthesis of ene-6,9-dione:

(1S,11S)-7-benzyloxy-11-methyl-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12- in MeOH (34 mL) at room temperature To a solution of triene-6,9-dione (640 mg, 1.77 mmol) was added MCPBA (792 mg, 3.53 mmol) and NIS (795 mg, 3.53 mmol). The resulting mixture was heated to 80° C. for 20 minutes. The reaction was cooled to room temperature, diluted with DCM, washed with 1 N sodium thiosulfate, saturated NaHCO ₃ , dried over sodium sulfate, filtered, concentrated and purified by normal phase chromatography. LCMS-ESI+ (m/z): H+ calculated for C22H21IN2O3, theoretical: 488.06, observed: 489.139.

Step 9: (1S,11S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-11-methyl-6,9-dioxo-10,15-diazatetracyclo[ 6.6.1.11,10.04,15] Synthesis of hexadeca-4,7,12-triene-5-carboxamide:

(1S,11S)-7-benzyloxy-5-iodo-11-methyl-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4 in DMSO (12 mL) at room temperature, (2,4-difluorophenyl)methanamine (418 mg, 2.92 mmol) in a solution of 7,12-triene-6,9-dione (285 mg, 0.584 mmol) followed by DIPEA (377 mg, 2.92 mmol) ), tetrakis(triphenylphosphine)palladium(0) (33.7 mg, 0.0292 mmol) and PdCl ₂ dppf (21.4 mg, 0.0292 mmol) were added. The resulting mixture was degassed and flushed with CO 3 times, then heated to 85° C. under a CO balloon for 3 hours. The reaction was cooled to room temperature, diluted with EtOAc, washed with water, saturated NH ₄ Cl, brine, dried over sodium sulfate, filtered, concentrated and purified by normal phase chromatography. LCMS-ESI+ (m/z): H+ calculated for C30H27F2N3O4, theoretical: 531.20, observed: 532.203.

Step 10: (1R,11S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-11-methyl-6,9,14-trioxo-10,15-diazatetra Synthesis of cyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide:

(1S,11S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-11-methyl-6,9-dioxo-10,15-diazatetracyclo[6.6.1.11 ,10.04,15]hexadeca-4,7,12-triene-5-carboxamide (210 mg, 0,395 mmol) was dissolved in 1,4-dioxane (4 mL). Selenium dioxide (263 mg, 2.37 mmol) was added. The resulting mixture was heated at 100° C. for 6 hours. The reaction was cooled to room temperature, filtered through celite, concentrated and purified by normal phase chromatography. LCMS-ESI+ (m/z): H+ calculated for C30H25F2N3O5, theoretical: 545.18, observed: 546.174.

Step 11: (1R,11S,14S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-14-hydroxy-11-methyl-6,9-dioxo-10, Synthesis of 15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide:

(1R,11S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-11-methyl-6,9,14-trioxo-10,15- in MeOH (5 mL) A solution of diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide (189 mg, 0.346 mmol) was cooled to 0 °C and CeCl3.7H2O ( 129 mg, 0.346 mmol), followed by sodium borohydride (15.27 mg, 0.4 mmol). The reaction was stirred for 5 min and then quenched with water. The reaction was extracted with DCM and the organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated and purified by normal phase chromatography. LCMS-ESI+ (m/z): H+ calculated for C30H27F2N3O5, theoretical: 547.19, observed: 548.124.

Step 12: (1R,11S,14S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-14-methoxy-11-methyl-6,9-dioxo-10, Synthesis of 15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide:

(1R,11S,14S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-14-hydroxy-11-methyl-6,9-dioxo in DMF (3.6 mL) A solution of -10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide (100 mg, 0.183 mmol) was cooled to 0 °C and , NaH (60% dispersion in mineral oil) (9.5 mg, 0.237 mmol) was added and the newly formed mixture was stirred for 10 min, followed by a solution of iodomethane (28.5 mg, 0.20 mmol) in DMF (1 mL) was added dropwise. After stirring at 0° C. for 10 min, the reaction was quenched with saturated NH 4 Cl, extracted with EtOAc, the organic layer washed with water, brine, dried over sodium sulfate, filtered, concentrated and purified by normal phase chromatography. The stereochemistry at the C4 position is not identified. LCMS-ESI+ (m/z): H+ calculated for C31H29F2N3O5, theoretical: 561.21, observed: 562.149.

Step 13: (1R,11S,14S)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-14-methoxy-11-methyl-6,9-dioxo-10, 15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7-diene-5-carboxamide ( 19-1 ) of the synthesis:

(1R,11S,14S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-14-methoxy-11-methyl-6,9-dioxo in EtOH (10 mL) 20% Pd(OH) in a solution of -10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide (13.5 mg, 0.024 mmol) )2/C (50 wt % water) (3.0 mg) was added, the resulting mixture was degassed and flushed with nitrogen 3 times, then it was degassed and flushed 3 times with hydrogen, which was then hydrogenated for 4 hours at room temperature. Hydrogenation was carried out under a balloon. The reaction was degassed, flushed with nitrogen, filtered through a 0.45 um syringe filter, concentrated, redissolved in DMF, filtered and purified by reverse phase preparative HPLC. LCMS-ESI+ (m/z): H+ calculated for C24H25F2N3O5, theoretical: 473.18, observed: 474.263. 1H NMR (400 MHz, acetone-d6) δ 10.88 (s, 1H), 7.53 - 7.43 (m, 1H), 7.08 - 6.94 (m, 2H), 4.62 (pd, J = 15.2, 6.1 Hz, 3H), 3.96 - 3.82 (m, 2H), 3.63 - 3.57 (m, 1H), 3.57 - 3.51 (m, 1H), 3.45 (s, 3H), 3.43 - 3.32 (m, 2H), 2.92 - 2.88 (m, 1H) ), 2.16 (dd, J = 16.1, 3.4 Hz, 1H), 2.00 - 1.81 (m, 3H), 1.28 (d, J = 6.7 Hz, 3H), 1.24 - 1.16 (m, 1H).

Step 14: (1R,11S,14S)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-14-methoxy-11-methyl-6,9-dioxo-10, 15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide ( 19-2 ) of the synthesis:

(1R,11S,14S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-14-methoxy-11-methyl-6,9-dioxo-10,15-dia Zatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide (6 mg, 0.0107 mmol) was mixed with a 1:1 mixture of toluene/TFA (3.0 mL). The reaction was concentrated, redissolved in DMF, filtered and purified by reverse phase preparative HPLC. LCMS-ESI+ (m/z): H+ calculated for C24H23F2N3O5, theoretical: 471.16, observed: 472.203. 1H NMR (400 MHz, chloroform-d) δ 10.79 (s, 1H), 7.39 (td, J = 8.7, 6.5 Hz, 1H), 6.92 - 6.76 (m, 2H), 5.66 (dt, J = 11.6, 3.2) Hz, 1H), 5.52 (ddd, J = 11.5, 2.6, 1.6 Hz, 1H), 5.36 (dq, J = 7.2, 2.6 Hz, 2H), 4.65 (s, 2H), 4.28 (q, J = 3.0 Hz) , 1H), 4.07 - 3.92 (m, 2H), 3.63 (ddd, J = 18.7, 10.1, 8.4 Hz, 1H), 3.38 (d, J = 13.7 Hz, 1H), 3.28 (s, 3H), 2.72 ( dd, J = 12.8, 8.3 Hz, 1H), 1.78 (dt, J = 12.7, 9.7 Hz, 1H), 1.38 (d, J = 7.3 Hz, 3H).

Step 15: (1R,11S,14S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-3-hydroxy-14-methoxy-11-methyl-6,9- Synthesis of dioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide:

(1R,11S,14S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-14-methoxy-11-methyl-6,9-dioxo in THF (2 mL) A solution of -10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide (41.8 mg, 0.0744 mmol) was cooled to -78°C. and 1.0 M LHMDS in THF (0.373 mL, 0.373 mmol) was added. The resulting mixture was stirred for 25 min, then a solution of 2-(benzenesulfonyl)-3-phenyl-oxaziridine (77.8 mg, 0.298 mmol) in THF (0.8 mL) was added dropwise to the cold mixture. After stirring at −78° C. for 30 min, the reaction was warmed to −10° C. and stirred at that temperature for 90 min. The reaction was quenched with MeOH, concentrated and purified by normal phase chromatography. LCMS-ESI+ (m/z): H+ calculated for C31H29F2N3O6, theoretical: 577.20, observed: 578.211.

Step 16: (1R,11S,14S)-N-[(2,4-difluorophenyl)methyl]-3,7-dihydroxy-14-methoxy-11-methyl-6,9-dioxo -10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide ( 19-3 ) synthesis of:

The residue from the previous step was dissolved in toluene (0.3 mL), cooled to 0° C. and TFA (0.3 mL) was added. The reaction was slowly warmed to room temperature to melt the ice and stirred at room temperature overnight. The reaction was concentrated, redissolved in DMF, filtered and purified by reverse phase preparative HPLC. LCMS-ESI+ (m/z): H+ calculated for C24H23F2N3O6, theoretical: 487.16, observed: 488.255. 1H NMR (400 MHz, chloroform-d) δ 11.14 (s, 1H), 7.46 - 7.33 (m, 1H), 6.93 - 6.79 (m, 2H), 5.73 (t, J = 7.7 Hz, 1H), 5.67 ( dt, J = 11.5, 3.2 Hz, 1H), 5.53 (ddd, J = 11.5, 2.6, 1.6 Hz, 1H), 5.42 - 5.32 (m, 1H), 4.68 (d, J = 5.5 Hz, 2H), 4.13 (q, J = 3.0 Hz, 1H), 4.05 (d, J = 13.8 Hz, 1H), 3.55 (d, J = 13.8 Hz, 1H), 3.25 (s, 4H), 3.18 - 3.08 (m, 2H) , 1.90 (dd, J = 12.8, 7.9 Hz, 1H), 1.40 (d, J = 7.2 Hz, 3H).

Intermediate 20a:

Step 1: Synthesis of methyl (3S,7S)-3-amino-7-methyl-1,2,4,7-tetrahydroazepine-3-carboxylate bis TFA salt:

O1-Benzyl O3-methyl (3S,7S)-3-(benzyloxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1,3-dicarboxylate (5 g, 11.0 mmol) was heated in TFA (25 mL) at 100° C. for 4 h. The reaction was cooled to room temperature, concentrated and the resulting residue co-evaporated with EtOAc (8x20 mL) and used directly in the next step. LCMS-ESI+ (m/z): H+ calculated for C9H16N2O2, theoretical: 184.12, observed: 185.02. Methyl (3S,7S)-3-amino-7-methyl-1,2,4,7-tetrahydroazepine-3-carboxylate bis TFA salt (4.556 g, 11.1 mol) was mixed with EtOAc (84.0 mL) at room temperature was dissolved in Saturated aqueous sodium carbonate solution (13.2 mL) was added followed by di-tert-butyl dicarbonate (7.235 g, 33.2 mmol). The resulting mixture was heated to 70° C. overnight. The reaction was cooled to room temperature, diluted with EtOAc, washed with water, brine, dried over sodium sulfate, filtered, concentrated and purified by normal phase chromatography. LCMS-ESI+ (m/z): H+ calculated for C19H32N2O6, theoretical: 384.23, observed: 384.746.

Step 2: tert-Butyl (3S,7S)-3-(tert-butoxycarbonylamino)-3-(hydroxymethyl)-7-methyl-4,7-dihydro-2H-azepine-1- Synthesis of carboxylates:

O1-tert-Butyl O3-methyl (3S,7S)-3-(tert-butoxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1,3-dicarboxylate ( 3.756 g, 9,77 mmol) was dissolved in THF (97.0 mL) and cooled to 0°C. The resulting mixture was flushed with nitrogen prior to addition of 1.0 M LAH in THF (12.7 mL, 12.7 mmol). The reaction was stirred at 0° C. for 10 min, then removed from the cooling bath and stirred at room temperature for 30 min. The reaction was cooled back to 0° C. and quenched dropwise with saturated Rochelle salt. The mixture was then diluted with EtOAc and the organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated and used directly in the next step. LCMS-ESI+ (m/z): H+ calculated for C18H32N2O5, theoretical: 356.23, observed: 356.837.

Step 3: Synthesis of tert-butyl (3S,7S)-3-(tert-butoxycarbonylamino)-3-formyl-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate :

tert-Butyl (3S,7S)-3-(tert-butoxycarbonylamino)-3-(hydroxymethyl)-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate ( 3.48 g, 9.76 mmol) was dissolved in DCM (65 mL) and cooled to 0 °C. Dess-Martin periodinane (6.21 g, 14.6 mmol) was added in portions. After addition, the reaction was warmed to room temperature and stirred overnight. The reaction was cooled back to 0° C., 1 N sodium thiosulfate (80 mL) was added, and saturated sodium bicarbonate (80 mL) was added. The mixture was stirred vigorously for 30 minutes. The layers were separated and the aqueous layer was extracted with DCM (x2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting product was purified by normal phase chromatography (80 g silica gel 0-40% EtOAc/hexanes). LCMS-ESI+ (m/z): H+ calculated for C18H30N2O5, theoretical: 354.22, observed: 355.016.

Step 4: tert-Butyl (3R,7S)-3-[(E)-2-(5-benzyloxy-6-methoxycarbonyl-4-oxo-pyran-2-yl)vinyl]-3-( Synthesis of tert-butoxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate:

Methyl 3-benzyloxy-6-(dimethoxyphosphorylmethyl)-4-oxo-pyran-2-carboxylate (1.96 g, 5.12 mmol) was dissolved in THF (25 mL) and cooled to -78°C. 1.0 M LDA in THF/hexanes (5,12 mL, 5.12 mmol) was added dropwise. The resulting mixture was stirred at -78 °C for 45 min. Then tert-Butyl (3S,7S)-3-(tert-butoxycarbonylamino)-3-formyl-7-methyl-4,7-dihydro-2H-azepine-1 in THF (9 mL) A solution of -carboxylate (1.21 g, 3.4 mmol) was added to the cold mixture. The newly formed mixture was stirred at −78° C. for 10 min, then warmed to −10° C. in 1 hour and stirred at −10° C. for an additional 60 min. The reaction was slowly quenched with saturated ammonium chloride. The mixture was diluted with EtOAc, washed with saturated ammonium chloride, brine, dried over sodium sulfate, filtered, concentrated and purified by normal phase chromatography. LCMS-ESI+ (m/z): H+ calculated for C33H42N2O9, theoretical: 610.29, observed: 610.897.

Step 5: tert-Butyl (3S,7S)-3-[2-(5-benzyloxy-6-methoxycarbonyl-4-oxo-pyran-2-yl)ethyl]-3-(tert-butoxy Synthesis of carbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate:

tert-Butyl (3R,7S)-3-[(E)-2-(5-benzyloxy-6-methoxycarbonyl-4-oxo-pyran-2-yl)vinyl]- in toluene (32.5 mL) A solution of 3-(tert-butoxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate (650 mg, 1.06 mmol) was purged with nitrogen. poly(methylhydrosiloxane) (0.64 g, 10.6 mmol) followed by chloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]copper(I) (78 mg, 0.16 mmol) and 2.0M sodium tert-butoxide in THF (0.16 mL, 0.319 mmol) were added under nitrogen. The reaction was then stirred under a nitrogen balloon for 1 hour. The reaction was quenched with water and stirred vigorously for 30 min, brine (20 mL) was added, stirred for an additional 10 min, and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purified by normal phase chromatography. LCMS-ESI+ (m/z): H+ calculated for C33H44N2O9, theoretical: 612.30, observed: 612.746.

Step 6: (1S,11S)-7-benzyloxy-11-methyl-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-6,9 - Synthesis of dione:

tert-Butyl (3S,7S)-3-[2-(5-benzyloxy-6-methoxycarbonyl-4-oxo-pyran-2-yl)ethyl]-3-(tert-butoxycarbonylamino )-7-Methyl-4,7-dihydro-2H-azepine-1-carboxylate (0.41 g, 0.669 mmol) was dissolved in DCM (16 mL), cooled to 0° C. and TFA was added to the side of the flask. was added dropwise slowly. The newly formed mixture was stirred at 0° C. for 30 min, then at room temperature for 2 h. The reaction was concentrated, co-evaporated with DCM (3x5 mL) and further dried on a vacuum line for 3 h. The residue was then dissolved in EtOH (40 mL) and heated to 90° C. for 2 h. The reaction was cooled to room temperature, concentrated and purified by normal phase chromatography. LCMS-ESI+ (m/z): H+ calculated for C22H22N2O3, theoretical: 362.16, observed: 363.30.

Intermediate 20b:

Step 1: (1S,11S)-7-benzyloxy-5-iodo-11-methyl-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-tri Synthesis of ene-6,9-dione:

(1S,11S)-7-benzyloxy-11-methyl-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12- in MeOH (34 mL) at room temperature To a solution of triene-6,9-dione (640 mg, 1.77 mmol) was added MCPBA (792 mg, 3.53 mmol) and NIS (795 mg, 3.53 mmol). The resulting mixture was heated to 80° C. for 20 minutes. The reaction was cooled to room temperature, diluted with DCM, washed with 1 N sodium thiosulfate, saturated NaHCO 3 , dried over sodium sulfate, filtered, concentrated and purified by normal phase chromatography. 1H NMR (400 MHz, chloroform-d) δ 7.68 - 7.57 (m, 2H), 7.39 - 7.26 (m, 3H), 5.64 - 5.51 (m, 2H), 5.51 - 5.39 (m, 2H), 5.15 (d , J = 10.1 Hz, 1H), 3.74 (d, J = 13.6 Hz, 1H), 3.30 - 3.19 (m, 3H), 2.59 - 2.49 (m, 2H), 2.25 - 2.09 (m, 2H), 1.23 ( d, J = 5.8 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calculated for C22H21IN2O3: 489.07, observed: 489.1.

Step 2: (1S,11S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-11-methyl-6,9-dioxo-10,15-diazatetracyclo[ 6.6.1.11,10.04,15] Synthesis of hexadeca-4,7,12-triene-5-carboxamide:

(1S,11S)-7-benzyloxy-5-iodo-11-methyl-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4 in DMSO (12 mL) at room temperature, (2,4-difluorophenyl)methanamine (418 mg, 2.92 mmol) in a solution of 7,12-triene-6,9-dione (285 mg, 0.584 mmol) followed by DIPEA (377 mg, 2.92 mmol) ), tetrakis(triphenylphosphine)palladium(0) (33.7 mg, 0.0292 mmol) and PdCl2dppf (21.4 mg, 0.0292 mmol) were added. The resulting mixture was degassed and flushed with CO 3 times, then heated to 85° C. under a CO balloon for 3 hours. The reaction was cooled to room temperature, diluted with EtOAc, washed with water, saturated NH 4 Cl, brine, dried over sodium sulfate, filtered, concentrated and purified by normal phase chromatography to afford intermediate 20b . LCMS-ESI+ (m/z): [M+H]+ calculated for C30H27F2N3O4, theoretical: 531.20, observed: 532.203.

Intermediate 20c:

Intermediate 20c was prepared in a similar manner to that of Intermediate 20b . 1H NMR (400 MHz, chloroform-d) δ 10.83 (t, J = 5.7 Hz, 1H), 7.61 - 7.49 (m, 2H), 7.39 - 7.27 (m, 3H), 6.72 - 6.59 (m, 2H), 5.59 (ddd, J = 13.0, 7.3, 3.8 Hz, 1H), 5.50 - 5.40 (m, 3H), 5.19 (d, J = 10.3 Hz, 1H), 4.64 (d, J = 5.6 Hz, 2H), 4.10 (dd, J = 18.5, 8.4 Hz, 1H), 3.81 (d, J = 13.6 Hz, 1H), 3.49 (ddd, J = 19.0, 11.7, 7.9 Hz, 1H), 3.07 (d, J = 13.6 Hz, 1H), 2.52 (d, J = 7.5 Hz, 2H), 2.22 (dd, J = 12.8, 7.8 Hz, 1H), 1.93 (td, J = 12.2, 8.8 Hz, 1H), 1.28 (d, J = 7.2) Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calculated for C30H26F3N3O4: 550.19, observed: 550.2.

Example 20: (3S,6aS)-11-hydroxy-3-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,6,7,8 Preparation of ,10-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (20):

To Intermediate 20c (20 mg) was added toluene (0.75 mL) followed by TFA (0.75 mL). The reaction was stirred at 20° C. under ambient atmosphere while monitoring by LCMS until all starting material was consumed. The reaction was diluted with acetonitrile and concentrated in vacuo. Purification by silica gel flash column chromatography (0% to 20% methanol in dichloromethane) gave compound 20 . 1H NMR (400 MHz, chloroform-d) δ 10.59 (t, J = 5.8 Hz, 1H), 6.68 (dd, J = 8.7, 7.5 Hz, 2H), 5.62 (ddt, J = 8.1, 4.4, 2.0 Hz, 1H), 5.58 - 5.48 (m, 1H), 5.48 - 5.36 (m, 1H), 4.66 (d, J = 5.6 Hz, 2H), 4.17 (dd, J = 19.1, 9.2 Hz, 1H), 3.97 (d) , J = 13.6 Hz, 1H), 3.51 (ddd, J = 18.9, 11.2, 7.9 Hz, 1H), 3.34 (d, J = 13.6 Hz, 1H), 2.57 (dd, J = 16.5, 8.3 Hz, 1H) , 2.56 - 2.45 (m, 1H), 2.30 (dd, J = 12.8, 7.8 Hz, 1H), 2.10 - 1.97 (m, 1H), 1.37 (d, J = 7.3 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calculated for C23H20F3N3O4: 460.1, observed: 460.2.

Example 21: (3S,6aR,8R)-8,11-dihydroxy-3-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3, 6,7,8,10-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide and (3S,6aR,8S) -8,11-dihydroxy-3-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,6,7,8,10-hexahydro- Preparation of 2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (21-1 and 21-2):

Step 1. To 20a (25 mg) was added THF (0.7 mL). The reaction flask was cooled to −80° C., then LiHMDS (1 M in THF, 50 uL) was added dropwise. After 5 min at -80°C (rac)-3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (36 mg, 2 eq) was added as a solution in THF (1 mL). The reaction was stirred at -80°C. After 30 min more LiHMDS (1 M in THF, 30 uL) was added followed by more Davis oxaziridine (36 mg) in THF (1 mL). The reaction was allowed to warm slowly to −10° C. for 60 minutes, after which it was quenched by addition of methanol. The mixture was removed from the cooling bath and concentrated in vacuo. Purification by silica gel flash column chromatography (0% to 20% MeOH in DCM) gave the desired product as a mixture of diastereomers. LCMS-ESI+ (m/z): [M+H]+ calculated for C22H22N2O4: 379.17, observed: 379.3.

Step 2. To the product from step 1 (28 mg) was added mCPBA (66 mg, 4 equiv) followed by NIS (66 mg, 4 equiv) followed by MeOH (3 mL). The vial was sealed under ambient atmosphere and stirred in a metal heating block at 80°C. After 1 h, the reaction was allowed to cool to 20 °C. The reaction was diluted with DCM and then washed once with 1 N aqueous sodium thiosulfate followed by saturated aqueous NaHCO 3 . The combined aqueous phases were extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel flash column chromatography (0% to 20% MeOH in DCM) afforded the desired product. LCMS-ESI+ (m/z): [M+H]+ calculated for C22H21IN2O4: 505.06, observed: 505.1.

Step 3. To the product from step 2 (35 mg) under argon in DMSO (1.5 mL) was added 2,4,6-trifluorobenzylamine (56 mg, 5 equiv) followed by DIPEA (60 µL, 5 equiv) added. The flask was cycled 5 times between high vacuum and a CO atmosphere. Then Pd(PPh ₃ ) ₄ (4 mg, 0.05 equiv) was added. The flask was again cycled 5 times between high vacuum and CO atmosphere, after which the reaction was warmed to 85° C. in a metal heating block for 2 h, at which time all starting material was consumed by LCMS. The reaction was allowed to cool to 20°C. It was diluted with ethyl acetate. The organic phase was washed with 0.2 N HCl (2x) followed by water (2x) followed by brine (1x). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel flash column chromatography (25% to 100% ethyl acetate in hexanes) gave the desired product as a mixture of diastereomers. Further purification by chiral SFC (Daicel Chiralpak AD-H column, 50% iPrOH in CO2 with NH3 modifier) gave two diastereomers. Peak 1 (earlier-eluting product, empirically assigned structure): H NMR (400 MHz, chloroform-d) δ 10.78 (t, J = 5.6 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.37 - 7.29 (m, 3H), 6.68 (dd, J = 8.7, 7.5 Hz, 2H), 5.69 (d, J = 7.2 Hz, 1H), 5.66 - 5.57 (m, 1H), 5.49 (d, J = 10.3) Hz, 1H), 5.48 - 5.42 (m, 2H), 5.18 (d, J = 10.3 Hz, 1H), 4.70 (dd, J = 14.5, 5.9 Hz, 1H), 4.62 (dd, J = 14.5, 5.5 Hz) , 1H), 3.82 (d, J = 13.6 Hz, 1H), 3.05 (d, J = 13.6 Hz, 1H), 2.90 (dd, J = 16.6, 8.9 Hz, 1H), 2.69 (dq, J = 16.7, 3.5 Hz, 1H), 2.37 (d, J = 14.0 Hz, 1H), 2.10 (dd, J = 14.0, 7.4 Hz, 1H), 1.27 (d, J = 7.3 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calculated for C30H26F3N3O5: 566.19, observed: 566.2. Peak 2 (slower-eluting product, experimentally assigned structure): 1H NMR (400 MHz, chloroform-d) δ 11.42 (t, J = 5.6 Hz, 1H), 7.56 - 7.45 (m, 2H), 7.39 - 7.27 (m, 3H), 7.08 (s, 1H), 6.68 (t, J = 8.1 Hz, 2H), 5.70 (dd, J = 9.3, 7.4 Hz, 1H), 5.64 - 5.54 (m, 1H), 5.52 - 5.38 (m, 3H), 5.23 (d, J = 10.5 Hz, 1H), 4.68 (d, J = 5.6 Hz, 2H), 3.82 (d, J = 13.8 Hz, 1H), 3.14 (d, J) = 13.7 Hz, 1H), 2.71 (dd, J = 12.9, 7.3 Hz, 1H), 2.55 - 2.39 (m, 2H), 2.01 (dd, J = 12.9, 9.3 Hz, 1H), 1.29 (d, J = 7.2 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calculated for C30H26F3N3O5: 566.19, observed: 566.2.

Step 4. To peak 1 from step 3 was added toluene followed by TFA. The reaction was stirred at 20° C. while monitoring by LCMS until the starting material was consumed. The reaction was diluted with acetonitrile and concentrated in vacuo. Purification by reverse phase preparative HPLC (acetonitrile/water, 0.1% TFA modifier) gave compound 21-1. 1H NMR (400 MHz, acetonitrile-d3) δ 10.68 (s, 1H), 6.86 (t, J = 8.5 Hz, 2H), 5.62 (d, J = 5.3 Hz, 2H), 5.49 (d, J = 11.4) Hz, 1H), 5.28 (s, 1H), 4.63 (d, J = 5.2 Hz, 2H), 3.95 (d, J = 13.8 Hz, 1H), 3.35 (d, J = 13.7 Hz, 1H), 2.81 ( dd, J = 17.0, 8.7 Hz, 1H), 2.65 (d, J = 17.0 Hz, 1H), 2.28 (d, J = 1.6 Hz, 2H), 1.29 (d, J = 6.9 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calculated for C23H20F3N3O5: 476.14, observed: 476.3.

Step 4. To peak 2 from step 3 was added toluene followed by TFA. The reaction was stirred at 20° C. while monitoring by LCMS until the starting material was consumed. The reaction was diluted with acetonitrile and concentrated in vacuo. Purification by reverse phase preparative HPLC (acetonitrile/water, 0.1% TFA modifier) gave 21-2. 1H NMR (400 MHz, acetonitrile-d3) δ 11.34 (s, 1H), 6.97 (s, 1H), 6.86 (t, J = 8.6 Hz, 2H), 5.58 (dt, J = 8.1, 6.0 Hz, 2H) ), 5.48 (dt, J = 11.7, 2.3 Hz, 1H), 5.27 (s, 1H), 4.73 - 4.53 (m, 2H), 3.96 (d, J = 13.9 Hz, 1H), 3.48 (d, J = 13.8 Hz, 1H), 2.76 (dd, J = 12.7, 7.2 Hz, 1H), 2.56 (dd, J = 16.8, 8.6 Hz, 1H), 2.46 - 2.34 (m, 1H), 2.02 - 1.96 (m, 1H) ), 1.30 (d, J = 7.2 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calculated for C23H20F3N3O5: 476.14, observed: 476.2.

Intermediate 22a

To a screw-top vial under argon was added 20c (130 mg) followed by dioxane (4.8 mL) followed by selenium dioxide (210 mg, 8 equiv). The vial was sealed under argon and stirred at 100° C. for 6 h. The mixture was filtered through celite to remove insolubles, washing with ethyl acetate, and concentrated in vacuo. Purification by silica gel flash column chromatography (25% to 100% ethyl acetate in hexanes) afforded 22a . 1H NMR (400 MHz, chloroform-d) δ 10.74 (t, J = 5.7 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.41 - 7.26 (m, 3H), 6.67 (dd, J = 8.8, 7.5 Hz, 2H), 6.28 (dd, J = 11.9, 2.5 Hz, 1H), 5.99 (dd, J = 11.9, 1.7 Hz, 1H), 5.60 (qt, J = 7.5, 2.2 Hz, 1H), 5.46 (d) , J = 10.1 Hz, 1H), 5.08 (d, J = 10.2 Hz, 1H), 4.65 (d, J = 5.5 Hz, 2H), 4.11 (dd, J = 18.8, 8.8 Hz, 1H), 3.97 (d) , J = 14.3 Hz, 1H), 3.81 (ddd, J = 18.8, 10.9, 8.5 Hz, 1H), 3.45 (d, J = 14.3 Hz, 1H), 2.31 (dd, J = 13.3, 8.4 Hz, 1H) , 2.03 - 1.93 (m, 1H), 1.39 (d, J = 7.4 Hz, 3H). LCMS-ESI+ (m/z): calculated for C ₃₀ H ₂₆ F ₃ N ₃ O ₅ [M+H]+: 564.2, observed: 564.1.

Intermediate 22b

To a glass screw-top vial charged with intermediate 22a (80 mg) was added methanol (4 mL) followed by cesium chloride heptahydrate (69 mg, 1.3 equiv) followed by sodium borohydride (5.5 mg, 1 equiv). The reaction was stirred at 20° C. for 30 min, quenched with saturated aqueous sodium bicarbonate, then extracted with 95:5 dichloromethane:methanol. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give intermediate 22b , which was used in the next step without any further purification. 1H NMR (400 MHz, chloroform-d) δ 10.89 - 10.77 (m, 1H), 7.60 - 7.50 (m, 2H), 7.39 - 7.29 (m, 3H), 6.67 (dd, J = 8.7, 7.5 Hz, 2H ), 5.56 (dt, J = 11.4, 3.2 Hz, 1H), 5.47 - 5.40 (m, 1H), 5.38 (dt, J = 7.2, 2.3 Hz, 1H), 5.32 - 5.26 (m, 1H), 5.19 ( d, J = 10.4 Hz, 1H), 4.96 (s, 1H), 4.74 (dd, J = 14.5, 6.6 Hz, 1H), 4.47 (dd, J = 14.4, 4.6 Hz, 1H), 3.94 - 3.78 (m , 2H), 3.68 - 3.54 (m, 1H), 3.05 (d, J = 13.8 Hz, 1H), 2.72 (dd, J = 12.7, 8.4 Hz, 1H), 1.72 - 1.64 (m, 1H), 1.26 ( d, J = 7.3 Hz, 3H). LCMS-ESI+ (m/z): calculated for C ₃₀ H ₂₆ F ₃ N ₃ O ₅ [M+H]+: 566.2, observed: 566.2.

Example 22: (3S,6S,6aR)-11-hydroxy-6-methoxy-3-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1, Preparation of 3,6,7,8,10-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (22):

Step 1. To a glass vial filled with intermediate 22b (80 mg) under argon was added DMF (2.8 mL). The vial was cooled to 0° C., then NaH (60% in mineral oil, 7.4 mg, 1.3 eq) was added. The reaction was stirred at 0° C. for 5 min, then MeI (10 μL, 1.1 eq). The reaction was stirred at 0° C. for 1 h. The reaction was then quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic phase was washed with water, then brine. The combined aqueous phases were back extracted with more ethyl acetate. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. Silica gel flash column chromatography (25% to 100% ethyl acetate in hexanes) gave the desired product. 1H NMR (400 MHz, chloroform-d) δ 10.87 (s, 1H), 7.62 - 7.53 (m, 2H), 7.35 (dd, J = 8.0, 6.1 Hz, 3H), 6.76 - 6.63 (m, 2H), 5.62 (dt, J = 11.4, 3.1 Hz, 1H), 5.53 (d, J = 10.5 Hz, 1H), 5.50 - 5.45 (m, 1H), 5.42 (dq, J = 7.5, 2.3 Hz, 1H), 5.24 (d, J = 10.4 Hz, 1H), 4.67 (d, J = 4.2 Hz, 2H), 4.26 (d, J = 3.2 Hz, 1H), 3.95 (dd, J = 18.5, 8.9 Hz, 1H), 3.85 (d, J = 13.8 Hz, 1H), 3.62 (ddd, J = 18.8, 10.7, 8.5 Hz, 1H), 3.28 (s, 3H), 3.05 (d, J = 13.7 Hz, 1H), 2.63 (dd, J = 12.7, 8.3 Hz, 1H), 1.66 (ddd, J = 12.9, 10.8, 9.1 Hz, 1H), 1.29 (d, J = 7.3 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calculated for C31H28F3N3O5: 580.2, observed: 580.2.

Step 2. To the product from step 1 (5 mg) was added toluene (0.18 mL) followed by TFA (0.18 mL). The reaction was sealed under ambient atmosphere and stirred at 60° C. while monitoring by LCMS until all starting material was consumed. The reaction was diluted with acetonitrile and concentrated in vacuo. Purification by silica gel flash column chromatography (0% to 20% methanol in dichloromethane) gave compound 22 . 1H NMR (400 MHz, acetonitrile-d3) δ 10.61 (s, 1H), 6.85 (t, J = 8.5 Hz, 2H), 5.63 (dt, J = 11.5, 3.2 Hz, 1H), 5.49 (ddd, J) = 11.6, 2.7, 1.6 Hz, 1H), 5.22 (d, J = 7.9 Hz, 1H), 4.65 - 4.50 (m, 2H), 4.26 (q, J = 3.0 Hz, 1H), 3.97 (d, J = 13.9 Hz, 1H), 3.77 (dd, J = 18.5, 9.1 Hz, 1H), 3.43 (d, J = 9.0 Hz, 1H), 3.40 - 3.32 (m, 1H), 3.21 (s, 3H), 2.53 ( dd, J = 12.8, 8.2 Hz, 1H), 1.85 - 1.72 (m, 1H), 1.28 (d, J = 7.3 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calculated for C24H22F3N3O5: 490.2, observed: 490.2.

Example 23: (3S,6S,6aR)-6,11-dihydroxy-3-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3, 4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide and (3S, 6S,6aR)-11-hydroxy-6-methoxy-3-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6 ,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (23-1 and 23-2) of manufacturing.

Step 1 . To a glass screw-top vial filled with Intermediate 22a (50 mg) was added THF (2.5 mL). The vial was cooled to −80° C. under argon, then lithium tri-sec-butylborohydride (1 M in THF, 90 μL, 1 eq) was added. After 15 min at -80°C, the reaction was quenched with saturated aqueous ammonium chloride, then extracted with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium bicarbonate, then once with brine, then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel flash column chromatography (25% to 100% ethyl acetate in hexanes) afforded the desired product. 1H NMR (400 MHz, chloroform-d) δ 10.76 (t, J = 5.6 Hz, 1H), 7.64 - 7.49 (m, 3H), 7.39 - 7.28 (m, 4H), 6.67 (dd, J = 8.7, 7.5 Hz, 2H), 5.46 (d, J = 10.2 Hz, 1H), 5.10 (d, J = 10.2 Hz, 1H), 4.98 (td, J = 6.9, 2.8 Hz, 1H), 4.70 - 4.61 (m, 2H) ), 4.11 - 4.05 (m, 1H), 3.99 (d, J = 14.9 Hz, 1H), 3.58 (ddd, J = 18.9, 11.2, 8.4 Hz, 1H), 3.39 (d, J = 15.0 Hz, 1H) , 3.02 (td, J = 12.7, 2.6 Hz, 1H), 2.46 (ddd, J = 13.0, 7.0, 2.7 Hz, 1H), 2.37 - 2.27 (m, 1H), 2.22 (tdd, J = 12.3, 6.5, 2.7 Hz, 1H), 2.03 - 1.94 (m, 1H), 1.83 - 1.72 (m, 1H), 1.30 (d, J = 7.1 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calculated for C30H26F3N3O5: 566.2, observed: 566.2.

Step 2. To a glass screw-top vial charged with the product from step 1 (27 mg) was added methanol (1.4 mL) followed by sodium borohydride (1.8 mg, 1.0 equiv). Vigorous gas evolution was observed during sodium borohydride addition. After 10 min at 20° C., the reaction was quenched with saturated aqueous sodium bicarbonate and then extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product, which was carried forward to the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ 10.97 (t, J = 5.6 Hz, 1H), 7.67 - 7.57 (m, 2H), 7.42 - 7.30 (m, 3H), 6.67 (dd, J = 8.7, 7.5 Hz, 2H), 5.38 (d, J = 10.0 Hz, 1H), 5.24 (d, J = 10.1 Hz, 1H), 4.86 (dt, J = 10.5, 6.7 Hz, 1H), 4.68 (dd, J = 14.5) , 5.5 Hz, 1H), 4.58 (dd, J = 14.5, 4.8 Hz, 1H), 3.86 - 3.71 (m, 2H), 3.63 (dd, J = 18.3, 9.3 Hz, 1H), 3.41 (d, J = 14.7 Hz, 1H), 3.20 (d, J = 14.7 Hz, 1H), 2.35 (dd, J = 12.6, 8.0 Hz, 1H), 2.06 - 1.92 (m, 2H), 1.69 (ddd, J = 14.5, 7.3) , 3.8 Hz, 1H), 1.49 - 1.35 (m, 1H), 1.33 - 1.22 (m, 1H), 1.18 (d, J = 6.7 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calculated for C30H28F3N3O5: 568.2, observed: 568.2.

Step 3. To a glass vial filled with the product from step 2 (13 mg) under argon was added DMF (0.5 mL). The vial was cooled to 0°C. Sodium hydride (60% in mineral oil, 1.2 mg, 1.3 eq) was added. The reaction was stirred at 0° C. for 5 min, then MeI (2.6 mg, 0.8 eq) was added. The reaction was stirred at 0° C. for 45 min, then quenched with saturated aqueous NH 4 Cl and extracted with ethyl acetate. The organic phase was washed with water, then brine. The combined aqueous phases were extracted with more ethyl acetate. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. Silica gel flash column chromatography (25% to 100% ethyl acetate in hexanes) gave the desired product as a mixture with unreacted starting material. LCMS-ESI+ (m/z): [M+H]+ calculated for C31H30F3N3O5: 582.2, observed: 582.3.

Step 4. To the product mixture from step 3 (7 mg) was added toluene (0.25 mL) followed by TFA (0.25 mL). The reaction was sealed under ambient atmosphere and stirred at 60° C. for 15 minutes. The reaction was diluted with acetonitrile and concentrated in vacuo. The crude was redissolved in 1:1 DMF:water and purified by reverse phase preparative HPLC (20% to 100% acetonitrile in water, 0.1% TFA). 23-1 and 23-2 were produced.

23-2: 1H NMR (400 MHz, acetonitrile-d3) δ 10.79 (s, 1H), 6.84 (t, J = 8.5 Hz, 2H), 4.64 - 4.56 (m, 1H), 4.56 (s, 2H) , 3.68 (d, J = 3.4 Hz, 1H), 3.65 (s, 1H), 3.63 (s, 1H), 3.52 (dd, J = 10.4, 8.2 Hz, 1H), 3.42 (d, J = 4.6 Hz, 1H), 3.39 (d, J = 2.7 Hz, 1H), 3.31 (s, 3H), 2.26 (dd, J = 12.8, 7.9 Hz, 1H), 2.21 - 1.99 (m, 2H), 1.51 - 1.36 (m) , 1H), 1.19 (d, J = 6.6 Hz, 3H), 1.00 - 0.85 (m, 1H). LCMS-ESI+ (m/z): [M+H]+ calculated for C24H24F3N3O5: 492.2, observed: 492.2.

23-1 : 1H NMR (400 MHz, acetonitrile-d3) δ 10.84 (s, 1H), 6.84 (t, J = 8.5 Hz, 2H), 4.65 - 4.57 (m, 1H), 4.56 (d, J = 5.6 Hz, 2H), 3.76 (dd, J = 11.6, 4.1 Hz, 1H), 3.66 (d, J = 14.7 Hz, 1H), 3.63 - 3.47 (m, 2H), 3.44 (s, 1H), 2.28 ( dd, J = 12.7, 7.8 Hz, 1H), 2.16 - 2.07 (m, 1H), 2.01 (dd, J = 14.5, 7.3 Hz, 1H), 1.71 (ddd, J = 15.0, 7.6, 4.1 Hz, 1H) , 1.55 - 1.42 (m, 1H), 1.25 - 1.09 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calculated for C23H22F3N3O5: 478.2, observed: 478.2.

Example 24: HIV MT-4 Antiviral and Cytotoxicity Assay

Antiviral Assay in MT-4 Cells

Compounds were tested in a high-speed 384-well assay format for their ability to inhibit replication of HIV-1 (IIIB) in MT-4 cells. Compounds were serially diluted (1:3) in DMSO in 384-well polypropylene plates and into complete RPMI medium (10% FBS, 1% P/S) using a Biotek Micro Flow and Labcyte ECHO acoustic dispenser. It was further diluted 200-fold. Each plate contained up to 8 test compounds as negative control (no drug control) and 5 μM AZT positive control. MT-4 cells were pre-infected with either 10 μL of RPMI (mock infected) or a fresh 1:250 dilution of HIV-1 IIIB rich virus stock. Infected and uninfected MT-4 cells were further diluted in complete RPMI medium and added to each plate using a Micro Flow dispenser. After 5 days of incubation in a wet and temperature controlled incubator (37° C.), Cell Titer Glo (Promega) was added to the assay plates and chemiluminescence was read using an Envision plate-reader. EC ₅₀ values were defined as the compound concentration that resulted in a 50% reduction in the luminescent signal and were calculated using a sigmoidal dose-response model to generate a curve fit.

Cytotoxicity assay in MT-4 cells

Assays were performed as described above, except that uninfected MT-4 cells were added to each well containing the test compound. In addition, 10 μM puromycin was added to the last column of each assay plate to assess baseline levels of cytotoxicity.

Example 25: HIV MT-4 Serum Shift Antiviral Reporter Assay

To quantify the amount of protein binding to human serum, compounds were serially diluted (1:3) in DMSO and transferred acoustically to 384 well assay plates via a Labcyte ECHO robot. Each plate contained up to 8 test compounds, including negative and positive controls (DMSO, 5 μM AZT each). Assay plates were prepared in duplicate and tested in either CCM (cell culture medium) or HS/CCM (human serum/cell culture medium). MT-4 cells were initially pre-infected with pLai RLuc reporter virus at 37°C for 2 h, then CCM (RPMI medium, 10% FBS, 1% P/S) or HS/CCM (RPMI medium, 10% FBS, 50% HS, 1% P/S) and subsequently added to each plate using a Biotek Micro Flow dispenser. After 72 hours incubation in a wet and temperature controlled incubator (37° C.), Renilla Glo (Promega) was added to all assay plates and chemiluminescence was read using an Envision plate-reader. EC ₅₀ values were defined as the compound concentration that resulted in a 50% reduction in the luminescent signal and were calculated using a sigmoidal dose-response model to generate a curve fit. To determine the amount of protein binding, the EC ₅₀ fold shift (or EC ₅₀ shift) was calculated by dividing EC ₅₀ (HS/CCM) / EC ₅₀ (CCM).

Compounds of the present disclosure demonstrate antiviral activity in this assay as shown in Table 1 below. Accordingly, the compounds of the embodiments disclosed herein may be useful for treating the proliferation of the HIV virus, for treating AIDS, or for delaying the development of symptoms of AIDS or ARC.

[Table 1]

The data in Table 1 represent the mean over time of each assay for each compound. For a particular compound, a number of assays were performed.

US patents, US patent application publications, US patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned herein are incorporated herein by reference in their entirety to the extent not inconsistent with this description.

From the foregoing, it will be understood that, although specific embodiments have been described herein for purposes of limitation, various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, the present disclosure is not limited as by the appended claims.

Claims (195)

A compound of formula (I) or a pharmaceutically acceptable salt thereof:
[Formula I]

In the above formula,
R ¹ is H, C _6-10 aryl or C _6-10 heteroaryl, C _6-10 aryl or C _6-10 heteroaryl optionally substituted by 1 to 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl;
Y is -C(O)NH-,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

is selected from the group consisting of;
L is -CR ^3a R ^3b- , -C(O)-, -SO _2- , -CR ^3a R ^3b -CR ^3c R ^3d- or -N(R ^a )-;
W ¹ is a bond or -CR ^4a R ^4b- ;
W ² is -CR ^5a R ^5b- , -CR ^5a R ^5b CR ^5c R ^5d- , -CR ^6a =CR ^6b- , -N(R ⁷ )-, -O-, -S(O) _n- , - C(O)NR ^e -, -CR ^5a R ^5b- N(R ⁷ )-, -CR ^5a R ^5b- O-, -CR ^5a R ^5b- S(O) _n- , -CR ^5a R ^5b- C (O)NR ^e- , -CR ^5a R ^5b- NR ^e- C(O)-, -S(O) _n N(R ^e ) -CR ^5a R ^5b- or -N(R ^e ) -S(O ) _n- CR ^5a R ^5b- ;
X is a bond or -CR ^8a R ^8b- ;
Z is -CR ^9a R ^9b- , -CR ^9a R ^9b CR ^9c R ^9d- or -CR ^10a =CR ^10b- ;
T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d ; U is -NR ^{11- ,} -CR ^12a R ^12b- , -S(O) _n- , -C(O) - or -O-; T and U together

ego;
R ^2a , R ^2b , R ^2c , R ^2d , R ^12a and R ^12b are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, Halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a _, -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , - C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ;
(i) R ^2a and R ^2b , (ii) R ^2c and R ^2d or (iii) R ^12a and R ^12b together with the carbon atom to which they are attached are (i) 3-7 membered carbocyclic ring or (ii) a 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, a 3-7 membered carbocyclic ring or a 4-7 membered heteroatom the cyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;
R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or —OC _1-4 alkyl;
(i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, represent (i) a 3- to 7-membered carbocyclic ring or (ii) N, O and form a 3-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, the 3-7 membered carbocyclic ring or the 3-7 membered heterocyclic ring having 1 to 3 members optionally substituted with R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;
R ^4a , R ^4b , R ^5a , R ^5b , R ^5c , R ^5d , R ^8a , R ^8b , R ^9a , R ^9b , R ^9c and R ^9d are independently H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, hydroxyl, cyano, —OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl;
(i) R ^4a and R ^4b , (ii) R ^5a and R ^5b , (iii) R ^5c and R ^5d , (iv) R ^5a and R ^5c , (v) R ^5b and R ^5d , (vi) R ^8a and any one of R ^8b , (vii) R ^9a and R ^9b , (viii) R ^9c and R ^9d , (ix) R ^9a and R ^9c , (x) R ^9b and R ^9d , (xi) R ^8b and R one of ^5a , R ^5b , R ^5c , R ^5d and R ⁷ , or (xii) one of R ^9a , R ^9b , R ^9c and R ^9d and one of R ^4a , R ^4b , R ^5a , R ^5b and R ⁷ . are, together with the carbon atoms to which they are attached, (i) a 3-7 membered carbocyclic ring or (ii) a 4-7 membered heterocyclic containing 1 or 2 heteroatoms selected from N, O and S forming a ring, the 3- to 7-membered carbocyclic ring or 4- to 7-membered heterocyclic ring is optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo, halo, cya no, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;
each R ^6a , R ^6b , R ^10a and R ^10b is independently H, halo, C _1-4 haloalkyl or C _1-6 alkyl;
(i) R ^6a and R ^6b or (ii) R ^10a and R ^10b , together with the carbon atom to which each is attached, is (i) a 5- to 10-membered carbocyclic ring, (ii) N, O and a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, (iii) a 6-10 membered aromatic ring, or (iv) 1 to 3 members selected from N, O and S form a 5-10 membered heteroaromatic ring containing heteroatoms, a 5-10 membered carbocyclic ring, a 5-10 membered heterocyclic ring, a 6-10 membered aromatic ring, or a 5-10 membered ring the heteroaromatic ring is optionally substituted with 1 to 4 R ^A4 , each R ^A4 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;
R ⁷ is H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, C(O)R ^c or SO ₂ R ^c ;
R ¹¹ is H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, -C(O)-R ^a , -S(O) _n- R ^a , -CH ₂ - R ^a ;
each R ^a is independently (i) H, (ii) C _1-6 alkyl, (iii) C _3-6 cycloalkyl, (iv) 5-10 membered carbocyclic ring, (v) N, O and 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, (vi) 6-10 membered aromatic ring, or (iv) 1 to 3 members selected from N, O and S a 5- to 10-membered heteroaromatic ring containing heteroatoms;
C _1-6 alkyl, C _3-6 cycloalkyl, 5-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring is (i) oxo (ii) halo, (iii) cyano, (iv) -OC _1-4 alkyl, (v) C _1-6 alkyl, (vi) -OR ^e (vii) 3- to 10-membered carbocy a click ring, (viii) a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, (ix) a 6-10 membered aromatic ring, or (x) N, O and 0-4 substituents independently selected from the group consisting of a 5- to 10-membered heteroaromatic ring containing 1-3 heteroatoms selected from S; the 3-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A5 ; , each R ^A5 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;
R ^b is H, C _1-4 alkyl, C _1-4 haloalkyl or C _3-6 cycloalkyl;
R ^f is H, halo, C _1-4 alkyl or C _1-4 haloalkyl;
each R ^c is independently H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl; C(O)R ^d or —SO ₂ R ^d ;
each R ^d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, —NR ^e ₂ or —OR ^e ;
each R ^e is independently H, C _1-4 alkyl or C _3-6 cycloalkyl, each C _1-4 alkyl or C _3-6 cycloalkyl optionally substituted with halo or cyano;
each n is 0, 1 or 2. According to claim 1,
R ¹ is H, C _6-10 aryl or C _6-10 heteroaryl, C _6-10 aryl or C _6-10 heteroaryl optionally substituted by 1 to 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl;
Y is -C(O)NH-,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

is selected from the group consisting of;
L is -CR ^3a R ^3b- , -C(O)-, -SO _2- , -CR ^3a R ^3b -CR ^3c R ^3d- or -N(R ^a )-;
W ¹ is a bond or -CR ^4a R ^4b- ;
W ² is -CR ^5a R ^5b- , -CR ^5a R ^5b CR ^5c R ^5d- , -CR ^6a =CR ^6b- , -N(R ⁷ )-, -O-, -S(O) _n- , - C(O)NR ^e -, -CR ^5a R ^5b- N(R ⁷ )-, -CR ^5a R ^5b- O-, -CR ^5a R ^5b- S(O) _n- , -CR ^5a R ^5b- C (O)NR ^e- , -CR ^5a R ^5b- NR ^e- C(O)-, -S(O) _n N(R ^e ) -CR ^5a R ^5b- or -N(R ^e ) -S(O ) _n- CR ^5a R ^5b- ;
X is a bond or -CR ^8a R ^8b- ;
Z is -CR ^9a R ^9b- , -CR ^9a R ^9b CR ^9c R ^9d- or -CR ^10a =CR ^10b- ;
T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d ; U is -NR ^{11- ,} -CR ^12a R ^12b- , -S(O) _n- , -C(O) - or -O-; T and U together

ego;
R ^2a , R ^2b , R ^2c , R ^2d , R ^12a and R ^12b are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, Halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a _, -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , - C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ;
(i) R ^2a and R ^2b , (ii) R ^2c and R ^2d or (iii) R ^12a and R ^12b together with the carbon atom to which they are attached are (i) 3-7 membered carbocyclic ring or (ii) a 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, a 3-7 membered carbocyclic ring or a 4-7 membered heteroatom the cyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;
R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or —OC _1-4 alkyl;
R ^4a , R ^4b , R ^5a , R ^5b , R ^5c , R ^5d , R ^8a , R ^8b , R ^9a , R ^9b , R ^9c and R ^9d are independently H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, hydroxyl, cyano, —OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl;
each R ^6a , R ^6b , R ^10a and R ^10b is independently H, halo, C _1-4 haloalkyl or C _1-6 alkyl;
R ⁷ is H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, C(O)R ^c or SO ₂ R ^c ;
R ¹¹ is H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, -C(O)-R ^a , -S(O) _n- R ^a , —CH ₂ -R ^a ;
each R ^a is independently (i) H, (ii) C _1-6 alkyl, (iii) C _3-6 cycloalkyl, (iv) 5-10 membered carbocyclic ring, (v) N, O and 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, (vi) 6-10 membered aromatic ring, or (iv) 1 to 3 membered selected from N, O and S a 5- to 10-membered heteroaromatic ring containing heteroatoms;
C _1-6 alkyl, C _3-6 cycloalkyl, 5-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring is (i) oxo (ii) halo, (iii) cyano, (iv) -OC _1-4 alkyl, (v) C _1-6 alkyl, (vi) -OR ^e (vii) 3- to 10-membered carbocy a click ring, (viii) a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, (ix) a 6-10 membered aromatic ring, or (x) N, O and 0-4 substituents independently selected from the group consisting of a 5- to 10-membered heteroaromatic ring containing 1-3 heteroatoms selected from S; the 3-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A5 ; , each R ^A5 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;
R ^b is H, C _1-4 alkyl, C _1-4 haloalkyl or C _3-6 cycloalkyl;
R ^f is H, halo, C _1-4 alkyl or C _1-4 haloalkyl;
each R ^c is independently H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl; C(O)R ^d or —SO ₂ R ^d ;
each R ^d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, —NR ^e ₂ or —OR ^e ;
each R ^e is independently H, C _1-4 alkyl or C _3-6 cycloalkyl, each C _1-4 alkyl or C _3-6 cycloalkyl optionally substituted with halo or cyano;
and each n is 0, 1 or 2. The compound or a pharmaceutically acceptable salt thereof. According to claim 1,
R ¹ is H, C _6-10 aryl or C _6-10 heteroaryl, C _6-10 aryl or C _6-10 heteroaryl optionally substituted by 1 to 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl;
Y is -C(O)NH-,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

is selected from the group consisting of;
L is -CR ^3a R ^3b- , -C(O)-, -SO _2- , -CR ^3a R ^3b -CR ^3c R ^3d- or -N(R ^a )-;
W ¹ is a bond or -CR ^4a R ^4b- ;
W ² is -CR ^5a R ^5b- , -CR ^5a R ^5b CR ^5c R ^5d- , -CR ^6a =CR ^6b- , -N(R ⁷ )-, -O-, -S(O) _n- , - C(O)NR ^e -, -CR ^5a R ^5b- N(R ⁷ )-, -CR ^5a R ^5b- O-, -CR ^5a R ^5b- S(O) _n- , -CR ^5a R ^5b- C (O)NR ^e- , -CR ^5a R ^5b- NR ^e- C(O)-, -S(O) _n N(R ^e ) -CR ^5a R ^5b- or -N(R ^e ) -S(O ) _n- CR ^5a R ^5b- ;
X is a bond or -CR ^8a R ^8b- ;
Z is -CR ^9a R ^9b- , -CR ^9a R ^9b CR ^9c R ^9d- or -CR ^10a =CR ^10b- ;
T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d ; U is -NR ^{11- ,} -CR ^12a R ^12b- , -S(O) _n- , -C(O) - or -O-; T and U together

ego;
R ^2a , R ^2b , R ^2c , R ^2d , R ^12a and R ^12b are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, Halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a _, -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , - C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ;
R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or —OC _1-4 alkyl;
(i) R ^3a and R ^3b or (ii) R ^3c and R ^3d , together with the carbon atom to which they are attached, represent (i) a 3- to 7-membered carbocyclic ring or (ii) N, O and form a 3-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, the 3-7 membered carbocyclic ring or the 3-7 membered heterocyclic ring having 1 to 3 members optionally substituted with R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;
R ^4a , R ^4b , R ^5a , R ^5b , R ^5c , R ^5d , R ^8a , R ^8b , R ^9a , R ^9b , R ^9c and R ^9d are independently H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, hydroxyl, cyano, —OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl;
each R ^6a , R ^6b , R ^10a and R ^10b is independently H, halo, C _1-4 haloalkyl or C _1-6 alkyl;
R ⁷ is H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, C(O)R ^c or SO ₂ R ^c ;
R ¹¹ is H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, -C(O)-R ^a , -S(O) _n- R ^a , —CH ₂ -R ^a ;
each R ^a is independently (i) H, (ii) C _1-6 alkyl, (iii) C _3-6 cycloalkyl, (iv) 5-10 membered carbocyclic ring, (v) N, O and 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, (vi) 6-10 membered aromatic ring, or (iv) 1 to 3 membered selected from N, O and S a 5- to 10-membered heteroaromatic ring containing heteroatoms;
C _1-6 alkyl, C _3-6 cycloalkyl, 5-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring is (i) oxo (ii) halo, (iii) cyano, (iv) -OC _1-4 alkyl, (v) C _1-6 alkyl, (vi) -OR ^e (vii) 3- to 10-membered carbocy a click ring, (viii) a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, (ix) a 6-10 membered aromatic ring, or (x) N, O and 0-4 substituents independently selected from the group consisting of a 5- to 10-membered heteroaromatic ring containing 1-3 heteroatoms selected from S; the 3-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A5 ; , each R ^A5 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;
R ^b is H, C _1-4 alkyl, C _1-4 haloalkyl or C _3-6 cycloalkyl;
R ^f is H, halo, C _1-4 alkyl or C _1-4 haloalkyl;
each R ^c is independently H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl; C(O)R ^d or —SO ₂ R ^d ;
each R ^d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, —NR ^e ₂ or —OR ^e ;
each R ^e is independently H, C _1-4 alkyl or C _3-6 cycloalkyl, each C _1-4 alkyl or C _3-6 cycloalkyl optionally substituted with halo or cyano;
and each n is 0, 1 or 2. The compound or a pharmaceutically acceptable salt thereof. According to claim 1,
R ¹ is H, C _6-10 aryl or C _6-10 heteroaryl, C _6-10 aryl or C _6-10 heteroaryl optionally substituted by 1 to 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl;
Y is -C(O)NH-,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

is selected from the group consisting of;
L is -CR ^3a R ^3b- , -C(O)-, -SO _2- , -CR ^3a R ^3b -CR ^3c R ^3d- or -N(R ^a )-;
W ¹ is a bond or -CR ^4a R ^4b- ;
W ² is -CR ^5a R ^5b- , -CR ^5a R ^5b CR ^5c R ^5d- , -CR ^6a =CR ^6b- , -N(R ⁷ )-, -O-, -S(O) _n- , - C(O)NR ^e -, -CR ^5a R ^5b- N(R ⁷ )-, -CR ^5a R ^5b- O-, -CR ^5a R ^5b- S(O) _n- , -CR ^5a R ^5b- C (O)NR ^e- , -CR ^5a R ^5b- NR ^e- C(O)-, -S(O) _n N(R ^e ) -CR ^5a R ^5b- or -N(R ^e ) -S(O ) _n- CR ^5a R ^5b- ;
X is a bond or -CR ^8a R ^8b- ;
Z is -CR ^9a R ^9b- , -CR ^9a R ^9b CR ^9c R ^9d- or -CR ^10a =CR ^10b- ;
T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d ; U is -NR ^{11- ,} -CR ^12a R ^12b- , -S(O) _n- , -C(O) - or -O-; T and U together

ego;
R ^2a , R ^2b , R ^2c , R ^2d , R ^12a and R ^12b are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, Halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a _, -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , - C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ;
R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or —OC _1-4 alkyl;
R ^4a , R ^4b , R ^5a , R ^5b , R ^5c , R ^5d , R ^8a , R ^8b , R ^9a , R ^9b , R ^9c and R ^9d are independently H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, hydroxyl, cyano, —OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl;
(i) R ^4a and R ^4b , (ii) R ^5a and R ^5b , (iii) R ^5c and R ^5d , (iv) R ^5a and R ^5c , (v) R ^5b and R ^5d , (vi) R ^8a and any one of R ^8b , (vii) R ^9a and R ^9b , (viii) R ^9c and R ^9d , (ix) R ^9a and R ^9c , (x) R ^9b and R ^9d , (xi) R ^8b and R one of ^5a , R ^5b , R ^5c , R ^5d and R ⁷ , or (x) one of R ^9a , R ^9b , R ^9c and R ^9d and one of R ^4a , R ^4b , R ^5a , R ^5b and R ⁷ . are, together with the carbon atoms to which they are attached, (i) a 3-7 membered carbocyclic ring or (ii) a 4-7 membered heterocyclic containing 1 or 2 heteroatoms selected from N, O and S forming a ring, the 3- to 7-membered carbocyclic ring or 4- to 7-membered heterocyclic ring is optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo, halo, cya no, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;
each R ^6a , R ^6b , R ^10a and R ^10b is independently H, halo, C _1-4 haloalkyl or C _1-6 alkyl;
R ⁷ is H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, C(O)R ^c or SO ₂ R ^c ;
R ¹¹ is H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, -C(O)-R ^a , -S(O) _n- R ^a , —CH ₂ -R ^a ;
each R ^a is independently (i) H, (ii) C _1-6 alkyl, (iii) C _3-6 cycloalkyl, (iv) 5-10 membered carbocyclic ring, (v) N, O and 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, (vi) 6-10 membered aromatic ring, or (iv) 1 to 3 membered selected from N, O and S a 5- to 10-membered heteroaromatic ring containing heteroatoms;
C _1-6 alkyl, C _3-6 cycloalkyl, 5-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring is (i) oxo (ii) halo, (iii) cyano, (iv) -OC _1-4 alkyl, (v) C _1-6 alkyl, (vi) -OR ^e (vii) 3- to 10-membered carbocy a click ring, (viii) a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, (ix) a 6-10 membered aromatic ring, or (x) N, O and 0-4 substituents independently selected from the group consisting of a 5- to 10-membered heteroaromatic ring containing 1-3 heteroatoms selected from S; the 3-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A5 ; , each R ^A5 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;
R ^b is H, C _1-4 alkyl, C _1-4 haloalkyl or C _3-6 cycloalkyl;
R ^f is H, halo, C _1-4 alkyl or C _1-4 haloalkyl;
each R ^c is independently H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl; C(O)R ^d or —SO ₂ R ^d ;
each R ^d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, —NR ^e ₂ or —OR ^e ;
each R ^e is independently H, C _1-4 alkyl or C _3-6 cycloalkyl, each C _1-4 alkyl or C _3-6 cycloalkyl optionally substituted with halo or cyano;
and each n is 0, 1 or 2. The compound or a pharmaceutically acceptable salt thereof. According to claim 1,
R ¹ is H, C _6-10 aryl or C _6-10 heteroaryl, C _6-10 aryl or C _6-10 heteroaryl optionally substituted by 1 to 4 R ^A1 , each R ^A1 is independently halo, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, -OC _1-4 alkyl, -OC _3-6 cycloalkyl or C _1-4 alkyl-OC _1-4 alkyl;
Y is -C(O)NH-,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

is selected from the group consisting of;
L is -CR ^3a R ^3b- , -C(O)-, -SO _2- , -CR ^3a R ^3b -CR ^3c R ^3d- or -N(R ^a )-;
W ¹ is a bond or -CR ^4a R ^4b- ;
W ² is -CR ^5a R ^5b- , -CR ^5a R ^5b CR ^5c R ^5d- , -CR ^6a =CR ^6b- , -N(R ⁷ )-, -O-, -S(O) _n- , - C(O)NR ^e -, -CR ^5a R ^5b- N(R ⁷ )-, -CR ^5a R ^5b- O-, -CR ^5a R ^5b- S(O) _n- , -CR ^5a R ^5b- C (O)NR ^e- , -CR ^5a R ^5b- NR ^e- C(O)-, -S(O) _n N(R ^e ) -CR ^5a R ^5b- or -N(R ^e ) -S(O ) _n- CR ^5a R ^5b- ;
X is a bond or -CR ^8a R ^8b- ;
Z is -CR ^9a R ^9b- , -CR ^9a R ^9b CR ^9c R ^9d- or -CR ^10a =CR ^10b- ;
T is -CR ^2a R ^2b- or --CR ^2a R ^2b- CR ^2c R ^2d ; U is -NR ^{11- ,} -CR ^12a R ^12b- , -S(O) _n- , -C(O) - or -O-; T and U together

ego;
R ^2a , R ^2b , R ^2c , R ^2d , R ^12a and R ^12b are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, Halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a _, -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , - C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ;
R ^3a , R ^3b , R ^3c and R ^3d are independently H, C _1-6 alkyl, C _1-4 haloalkyl or —OC _1-4 alkyl;
R ^4a , R ^4b , R ^5a , R ^5b , R ^5c , R ^5d , R ^8a , R ^8b , R ^9a , R ^9b , R ^9c and R ^9d are independently H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, halo, hydroxyl, cyano, —OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl;
each R ^6a , R ^6b , R ^10a and R ^10b is independently H, halo, C _1-4 haloalkyl or C _1-6 alkyl;
(i) R ^6a and R ^6b or (ii) R ^10a and R ^10b , together with the carbon atom to which each is attached, is (i) a 5- to 10-membered carbocyclic ring, (ii) N, O and a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, (iii) a 6-10 membered aromatic ring, or (iv) 1 to 3 members selected from N, O and S form a 5-10 membered heteroaromatic ring containing heteroatoms, a 5-10 membered carbocyclic ring, a 5-10 membered heterocyclic ring, a 6-10 membered aromatic ring, or a 5-10 membered ring the heteroaromatic ring is optionally substituted with 1 to 4 R ^A4 , each R ^A4 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;
R ⁷ is H, C _1-6 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, C(O)R ^c or SO ₂ R ^c ;
R ¹¹ is H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, -C(O)-R ^a , -S(O) _n- R ^a , —CH ₂ -R ^a ;
each R ^a is independently (i) H, (ii) C _1-6 alkyl, (iii) C _3-6 cycloalkyl, (iv) 5-10 membered carbocyclic ring, (v) N, O and 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, (vi) 6-10 membered aromatic ring, or (iv) 1 to 3 membered selected from N, O and S a 5- to 10-membered heteroaromatic ring containing heteroatoms;
C _1-6 alkyl, C _3-6 cycloalkyl, 5-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring is (i) oxo (ii) halo, (iii) cyano, (iv) -OC _1-4 alkyl, (v) C _1-6 alkyl, (vi) -OR ^e (vii) 3- to 10-membered carbocy a click ring, (viii) a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, (ix) a 6-10 membered aromatic ring, or (x) N, O and 0-4 substituents independently selected from the group consisting of a 5- to 10-membered heteroaromatic ring containing 1-3 heteroatoms selected from S; the 3-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A5 ; , each R ^A5 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e ;
R ^b is H, C _1-4 alkyl, C _1-4 haloalkyl or C _3-6 cycloalkyl;
R ^f is H, halo, C _1-4 alkyl or C _1-4 haloalkyl;
each R ^c is independently H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl; C(O)R ^d or —SO ₂ R ^d ;
each R ^d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, —NR ^e ₂ or —OR ^e ;
each R ^e is independently H, C _1-4 alkyl or C _3-6 cycloalkyl, each C _1-4 alkyl or C _3-6 cycloalkyl optionally substituted with halo or cyano;
and each n is 0, 1 or 2. The compound or a pharmaceutically acceptable salt thereof. 6. A compound according to any one of claims 1 to 5, having the formula Ia, or a pharmaceutically acceptable salt thereof:
[Formula Ia]

. 6. A compound according to any one of claims 1 to 5, having the formula Ib, or a pharmaceutically acceptable salt thereof:
[Formula Ib]

. 8. The method of any one of claims 1 to 7, wherein Y is -C(O)NH-;

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of. 9. The method of any one of claims 1 to 8, wherein Y is -C(O)NH- or

A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of. 10. The method of any one of claims 1 to 9, wherein Y is

Phosphorus, a compound, or a pharmaceutically acceptable salt thereof. 10. The compound according to any one of claims 1 to 9, having the formula II: or a pharmaceutically acceptable salt thereof:
[Formula II]

. 12. A compound according to any one of claims 1 to 11, having the formula IIa, or a pharmaceutically acceptable salt thereof:
[Formula IIa]

. 12. A compound according to any one of claims 1 to 11, having the formula IIb, or a pharmaceutically acceptable salt thereof:
[Formula IIb]

. 14. The method of any one of claims 1-13, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl; C _3-6 Halocycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH _2- S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NHR ^a- , -NR ^e- C(O)R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NHR ^a- or -S(O) _n- R ^a- ; 15. The method of any one of claims 1 to 14, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl; C _3-6 halocycloalkyl, halo, cyano, —CH ₂ R ^a- , —CH ₂ OR ^a _, —OR ^a , or —NHR ^a , or a pharmaceutically acceptable salt thereof. 16. The method of any one of claims 1-15, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl; C _3-6 halocycloalkyl, halo, cyano, —CH ₂ R ^a- , —CH ₂ OR ^a or —OR ^a , or a pharmaceutically acceptable salt thereof. 17. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H, halo or —OR ^a . 18. The method of any one of claims 1-17, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H, halo or —OR ^a ; each R ^a is independently H, or R ^a is independently H or C _1-6 alkyl. 19. The method of any one of claims 1 to 18, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H, halo or —OR ^a ; R ^a is H, or R ^a is independently H or C _1-3 alkyl, or a pharmaceutically acceptable salt thereof. 19. The method of any one of claims 1 to 18, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H, halo or —OR ^a ; R ^a is H, or R ^a is independently H or methyl. 17. The method of any one of claims 1 to 16, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl; C _3-6 halocycloalkyl or haloin, a compound or a pharmaceutically acceptable salt thereof. 17. The compound or medicament according to any one of claims 1 to 16, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H, C _1-6 alkyl, C _3-6 cycloalkyl or halo. Scientifically acceptable salts. 23. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-22, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H or halo. 15. The method of any one of claims 1-14, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H, -C(O)-NH(R ^a )-, -NR ^e- C(O). )R ^a- , -NR ^e- S(O) _n R ^a- , -S(O) _n- NH(R ^a )-, -S(O) _n- R ^a- or -OC(O)-NHR ^a phosphorus, a compound, or a pharmaceutically acceptable salt thereof. 15. The method of any one of claims 1-14, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H, -OR ^a , -NHR ^a , -C(O)-NH(R ^a ), -NR ^e- C(O)R ^a or -NR ^e- S(O) _n R ^a , or a pharmaceutically acceptable salt thereof. 15. The compound or pharmaceutically thereof according to any one of claims 1 to 14, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H, -OR ^a or -OC(O)-NHR ^a acceptable salts. 15. The method of any one of claims 1-14, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H, -S(O) _n- NH(R ^a ) or -S(O) _n- R ^a- , a compound or a pharmaceutically acceptable salt thereof. 15. The compound or pharmaceutically thereof according to any one of claims 1 to 14, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H, halo, cyano, -NHR ^a- or -OR ^a as acceptable salts. 29. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 and 28, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H or -NHR ^a . 17. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H, halo, cyano or —OR ^a . 31. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 and 30, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H or cyano. 31. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 and 30, wherein R ^2a , R ^2b , R ^2c and R ^2d are independently H or —OR ^a . 14. The compound of any one of claims 1-13, wherein either (i) R ^2a and R ^2b or (ii) R ^2c and R ^2d , together with the carbon to which they are attached, is (i) 3-7 form a membered carbocyclic ring or (ii) a 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, a 3-7 membered carbocyclic ring or a 4 membered to 7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or -OR ^e , a compound. 34. The method of any one of claims 1-33, wherein R ^a is independently H, C _1-6 alkyl or C _3-6 cycloalkyl, and each C _1-6 alkyl or C _3-6 cycloalkyl is Halo, cyano, -OC _1-4 alkyl, 5-10 membered carbocyclic ring, 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, 6 membered optionally substituted with 0 to 4 substituents independently selected from the group consisting of a to 10 membered aromatic ring, or a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S; the 5-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring, or 5-10 membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A5 ; , each R ^A5 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e , or a pharmaceutically acceptable salt thereof. 35. The method of any one of claims 1-34, wherein each R ^a is independently H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl which is halo, cyano, -OC ₁ -C ₄ 1 to 2 independently selected from the group consisting of alkyl, a 5 to 10 membered carbocyclic ring, and a 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S A compound or a pharmaceutically acceptable salt thereof, optionally substituted with a substituent. 36. The group of any one of claims 1-35, wherein R ^a is H, C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl, which is from the group consisting of halo, cyano and —OC ₁ -C ₄ alkyl. Optionally substituted with 1 to 2 substituents independently selected from, a compound or a pharmaceutically acceptable salt thereof. 37. The method of any one of claims 1-36, wherein R ^a is C ₃ - optionally substituted with 1-2 substituents independently selected from the group consisting of halo, cyano and -OC ₁ -C ₄ alkyl. C ₆ cycloalkyl, the compound or a pharmaceutically acceptable salt thereof. 37. The method of any one of claims 1-36, wherein R ^a is C ₁ - optionally substituted with 1-2 substituents independently selected from the group consisting of halo, cyano, -OC ₁ -C ₄ alkyl. C ₆ alkyl, the compound or a pharmaceutically acceptable salt thereof. 37. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 36, wherein R ^a is -OC _1-4 alkyl or C _1-6 alkyl optionally substituted with halo. 40. A compound according to any one of claims 1 to 39, having formula III: or a pharmaceutically acceptable salt thereof:
[Formula III]

. 41. A compound according to any one of claims 1 to 40, having the formula IIIa, or a pharmaceutically acceptable salt thereof:
[Formula IIIa]

. 41. A compound according to any one of claims 1 to 40, having the formula IIIb, or a pharmaceutically acceptable salt thereof:
[Formula IIIb]

. 43. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 42, wherein U is -NR ¹¹ , -CR ^12a R ^12b , -C(O) ^- or -O-. 44. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 43, wherein U is -NR ^{11 ,} -CR ^12a R ^12b or -O-. 45. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-44, wherein U is -NR ¹¹ or -CR ^12a R ^12b . 46. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 45, wherein U is -NR ¹¹ . 47. The method of any one of claims 1-46, wherein R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ halocycloalkyl. Phosphorus, a compound, or a pharmaceutically acceptable salt thereof. 48. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 47, wherein R ¹¹ is H, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ halocycloalkyl. 47. The compound according to any one of claims 1 to 46, wherein R ¹¹ is -C(O)-R ^a , -S(O) _n- R ^a , -CH ₂ -R ^a , or a pharmaceutically thereof. acceptable salts. 43. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 42, wherein U is -S-, -S(O)- or -S(O) _2- . 51. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 42 and 50, wherein U is -S-. 51. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 42 and 50, wherein U is -S(O)-. 51. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 42 and 50, wherein U is -S(O) _2- . 44. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 43, wherein U is -C(O)-. 45. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-44, wherein U is -O-. 46. A compound according to any one of claims 1 to 45, having formula IV, or a pharmaceutically acceptable salt thereof:
[Formula IV]

. 57. A compound according to any one of claims 1 to 45 and 56, having formula IVa, or a pharmaceutically acceptable salt thereof:
[Formula IVa]

. 57. The compound of any one of claims 1-45 and 56, having the formula IVb, or a pharmaceutically acceptable salt thereof:
[Formula IVb]

. 59. The method according to any one of claims 56 to 58,
X is -CR ^8a R ^8b- ;
W ¹ is a bond or -CR ^4a R ^4b- ;
W ² is -CR ^5a R ^5b- or -CR ^6a =CR ^6b- ;
Z is -CR ^9a R ^9b- ;
L is -CH ₂ -;
R ^2a , R ^2b , R ^12a and R ^12b are independently H, C _1-6 alkyl, halo, —OR ^a— or —CH ₂ OR ^a ;
R ^a is H or C _1-6 alkyl;
R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a , R ^9b are independently H, hydroxyl, C _1-6 alkyl or —OC _1-4 alkyl;
both R ^6a and R ^6b are H;
R ¹ is C _6-10 aryl optionally substituted with 1 to 4 R ^A1 , and each R ^A1 is independently fluoro or chloro. 59. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 58, wherein R ^12a and R ^12b are independently H, -OR ^a or -OC(O)-NHR ^a . 59. The method of any one of claims 1-58, wherein R ^12a and R ^12b are independently H, -NHR ^a , -C(O)-NH(R ^a ), -NR ^e- C(O)R ^a , -NR ^e- S(O) _n R ^a , or a pharmaceutically acceptable salt thereof. 59. The compound of any one of claims 1-58, wherein R ^12a and R ^12b are independently H, -S(O) _n- NH(R ^a ) or -S(O) _n- R ^a- . or a pharmaceutically acceptable salt thereof. 59. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 58, wherein R ^12a and R ^12b are independently H, halo, cyano, -NHR ^a- or -OR ^a . 61. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 60, wherein R ^12a and R ^12b are independently H or -NHR ^a . 59. The compound of any one of claims 1-58, wherein R ^12a and R ^12b are independently H, halo, cyano or —OR ^a . 66. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 58 and 65, wherein R ^12a and R ^12b are independently H or cyano. 66. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 58 and 65, wherein R ^12a and R ^12b are independently H or -OR ^a . 68. The compound of any one of claims 1-58, 65 and 67, wherein R ^12a and R ^12b are independently H or -OR ^a ; each R ^a is H or C _1-6 alkyl; or a pharmaceutically acceptable salt thereof. 69. The compound of any one of claims 1-58, 65, 67 and 68, wherein R ^12a and R ^12b are independently H or -OR ^a ; each R ^a is H or C _1-3 alkyl; or a pharmaceutically acceptable salt thereof. 70. The compound of any one of claims 1-58, 65 and 67-69, wherein R ^12a and R ^12b are independently H or —OR ^a ; each R ^a is H or methyl; or a pharmaceutically acceptable salt thereof. 68. The compound of any one of claims 1-58, 65 and 67, wherein R ^12a and R ^12b are independently H or -OR ^a , and R ^a is C _3-6 cycloalkyl; or A pharmaceutically acceptable salt thereof. 68. The compound of any one of claims 1-58, 65 and 67, wherein R ^12a and R ^12b are independently H or -OR ^a , and R ^a is C _1-4 haloalkyl; or A pharmaceutically acceptable salt thereof. 68. The method of any one of claims 1-58, 65 and 67, wherein R ^12a and R ^12b are independently H or -OR ^a , wherein R ^a is optionally substituted with -OC _1-4 alkyl. C _1-4 alkyl, the compound or a pharmaceutically acceptable salt thereof. 59. The compound of any one of claims 1 to 58, wherein R ^12a and R ^12b together with the carbon atom to which they are attached are (i) a 3 to 7 membered carbocyclic ring or (ii) N, O and S to form a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from, a 3 to 7 membered carbocyclic ring or a 4 to 7 membered heterocyclic ring containing 1 to 3 R optionally substituted with ^A2 , and each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _1-6 cycloalkyl or —OR ^e . 76. The compound of any one of claims 1-58 or 74, wherein R ^12a and R ^12b , together with the carbon atom to which they are attached, form (i) a 3- to 7-membered carbocyclic ring; the to 7 membered carbocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _1-6 cycloalkyl or — OR ^e , compound. 58. The method of any one of claims 1-58 and 74, wherein R ^12a and R ^12b , together with the carbon atom to which they are attached, contain 1 or 2 heteroatoms selected from N, O and S. form a 7 to 7 membered heterocyclic ring, wherein the 4 to 7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A2 , each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _1-6 cycloalkyl or —OR ^e . 14. The compound according to any one of claims 1 to 13, having the formula (V), or a pharmaceutically acceptable salt thereof:
[Formula V]

. 78. The compound according to any one of claims 1 to 13 and 77, having the formula Va, or a pharmaceutically acceptable salt thereof:
[Formula Va]

. 79. The compound according to any one of claims 1 to 13 and 78, having the formula Vb: or a pharmaceutically acceptable salt thereof:
[Formula Vb]

. 80. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 79, wherein W ¹ is a bond. 80. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 79, wherein W ¹ is -CR ^4a R ^4b- . 82. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 81, wherein W ² is -CR ^5a R ^5b- or -CR ^6a =CR ^6b- . 83. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 82, wherein W ² is -CR ^5a R ^5b- . 83. The method of any one of claims 1-82, wherein W ² is -CR ^6a =CR ^6b- ; R ^6a and R ^6b are independently H, halo, C _1-4 haloalkyl or C _1-6 alkyl, or a pharmaceutically acceptable salt thereof. 83. The method of any one of claims 1-82, wherein W ² is -CR ^6a =CR ^6b- and each of R ^6a and R ^6b , together with the carbon atom to which each is attached, is (i) from 5 members to 10 membered carbocyclic ring, (ii) 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, (iii) 6-10 membered aromatic ring, or (iv) ) form a 5-10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S, a 5-10 membered carbocyclic ring, a 5-10 membered heterocyclic ring, 6 a compound or an agent thereof, wherein the 1 to 10 membered aromatic ring, or 5 to 10 membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A4 , each R ^A4 is independently halo or C _1-4 alkyl Scientifically acceptable salts. 83. The method of any one of claims 1-82, wherein W2 is -CR ^6a =CR ^6b - and each of R ^6a and R ^6b , together with the carbon atom to which each is attached, is (i) 6-10 members. form a membered aromatic ring, or (ii) a 5-10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S, a 6-10 membered aromatic ring or a 5-10 membered heteroatom The aromatic ring is optionally substituted with 1 to 4 R ^A4 , and each R ^A4 is independently halo or C _1-4 alkyl. 84. The method of any one of claims 1-82 and 85, wherein W ² is -CR ^6a =CR ^6b -, and each of R ^6a and R ^6b , together with the carbon atom to which it is attached, is (i ) 5-10 membered carbocyclic ring or (ii) 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, 5-10 membered carbocyclic ring the click ring or 5-10 membered heterocyclic ring is optionally substituted with 1 to 4 R ^A4 , each R ^A4 is independently halo or C _1-4 alkyl, or a pharmaceutically acceptable compound thereof salt. 88. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 87, wherein X is a bond. 88. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 87, wherein X is -CR ^8a R ^8b- . 91. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 89, wherein Z is -CR ^9a R ^9b . 91. The method of any one of claims 1-90, wherein Z is -CR ^10a =CR ^10b - and each of R ^10a and R ^10b is independently H, halo, C _1-4 haloalkyl or C _1-6 Alkyl, a compound, or a pharmaceutically acceptable salt thereof. 91. The method of any one of claims 1-90, wherein Z is -CR ^10a =CR ^10b -, and each of R ^10a and R ^10b , together with the carbon atom to which each is attached, is (i) 5 to 10 members. a membered carbocyclic ring, (ii) a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, (iii) a 6-10 membered aromatic ring, or (iv) 5-10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S, 5-10 membered carbocyclic ring, 5-10 membered heterocyclic ring, 6 membered to 10 membered aromatic ring, or 5 to 10 membered heteroaromatic ring is optionally substituted with 1 to 4 R ^A4 , each R ^A4 is independently halo, oxo, cyano or C _1-4 alkyl; A compound or a pharmaceutically acceptable salt thereof. 93. The method of any one of claims 1-92, wherein Z is -CR ^10a =CR ^10b -, and each of R ^10a and R ^10b , together with the carbon atom to which each is attached, is (i) 6 to 10 members. form a membered aromatic ring, or (ii) a 5-10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S, a 6-10 membered aromatic ring or a 5-10 membered heteroatom The aromatic ring is optionally substituted with 1 to 4 R ^A4 , and each R ^A4 is independently halo or C _1-4 alkyl. 91. The method of any one of claims 1-90, wherein Z is -CR ^10a =CR ^10b -, and each of R ^10a and R ^10b , together with the carbon atom to which each is attached, is (i) 5 to 10 members. form a membered carbocyclic ring or (ii) a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, a 5-10 membered carbocyclic ring or 5 membered The compound or a pharmaceutically acceptable salt thereof, wherein the to 10-membered heterocyclic ring is optionally substituted with 1 to 4 R ^A4 , and each R ^A4 is independently halo or C _1-4 alkyl. 95. The compound of any one of claims 1 to 94, having Formula VI: or a pharmaceutically acceptable salt thereof:
[Formula VI]

;
wherein m is 0, 1, 2, 3 or 4;
each R ² is independently C _1-6 alkyl or C _3-6 cycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH ₂ -S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S( O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ; two R ² at the same carbon atom, together with the carbon atom to which they are both attached, are (i) a 3- to 7-membered carbocyclic ring or (ii) one or two selected from N, O and S forming a 4 to 7 membered heterocyclic ring containing heteroatoms, the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring optionally substituted with 1 to 3 R ^A2 ; each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e . 96. The compound of any one of claims 1-95, having formula VIa: or a pharmaceutically acceptable salt thereof:
[Formula VIa]

;
wherein m is 0, 1, 2, 3 or 4;
each R ² is independently C _1-6 alkyl or C _3-6 cycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH ₂ -S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S( O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ; two R ² at the same carbon atom, together with the carbon atom to which they are both attached, are (i) a 3- to 7-membered carbocyclic ring or (ii) one or two selected from N, O and S forming a 4 to 7 membered heterocyclic ring containing heteroatoms, the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring optionally substituted with 1 to 3 R ^A2 ; each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e . 96. The compound of any one of claims 1-95, having the formula VIb: or a pharmaceutically acceptable salt thereof:
[Formula VIb]

;
wherein m is 0, 1, 2, 3 or 4;
each R ² is independently C _1-6 alkyl or C _3-6 cycloalkyl, halo, cyano, -CH ₂ R ^a- , -CH ₂ OR ^a , -CH ₂ -S(O) _n R ^a- , -OR ^a , -OC(O)-NHR ^a , -NHR ^a- , -C(O)-NH(R ^a )-, -NR ^e- C(O)R ^a- , -NR ^e- S( O) _n R ^a- , -S(O) _n- NH(R ^a )- or -S(O) _n- R ^a- ; two R ² at the same carbon atom, together with the carbon atom to which they are both attached, are (i) a 3- to 7-membered carbocyclic ring or (ii) one or two selected from N, O and S forming a 4 to 7 membered heterocyclic ring containing heteroatoms, the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring optionally substituted with 1 to 3 R ^A2 ; each R ^A2 is independently oxo, halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e . 98. The compound of any one of claims 1-97, wherein L is -C(O)-. 98. The compound of any one of claims 1-97, wherein L is -SO ₂ -. 98. The compound of any one of claims 1-97, wherein L is -CH ₂ -CH ₂ -. 98. The compound of any one of claims 1-97, wherein L is -N(R ^a )-. 98. The compound of any one of claims 1-97, wherein L is -CR ^3a R ^3b- . 103. The compound of any one of claims 1-102, having formula VII, or a pharmaceutically acceptable salt thereof:
[Formula VII]

. 103. The compound of any one of claims 1 to 102, wherein the compound of formula VIIa or a pharmaceutically acceptable salt thereof:
[Formula VIIa]

. 103. The compound of any one of claims 1-102, having the formula (VIIb), or a pharmaceutically acceptable salt thereof:
[Formula VIIb]

. 106. The method of any one of claims 1 to 105, wherein R ¹ is phenyl, pyridyl, pyridazine, pyrazine or pyrimidine, and wherein said phenyl, pyridyl, pyridazine, pyrazine or pyrimidine is 1 or 2 , 3 or 4 R ^A1 , each R ^A1 is independently halo, C _1-4 alkyl, C _1-4 haloalkyl or -OC _1-4 alkyl, or a pharmaceutically thereof acceptable salts. 107. The method of any one of claims 1-106, wherein R ¹ is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted with 1, 2, 3 or 4 R ^A1 , each R ^A1 is independently halo, C _1-4 alkyl, C _1-4 haloalkyl or —OC _1-4 alkyl. The compound or a pharmaceutically acceptable salt thereof. 108. The compound or pharmaceutically thereof according to any one of claims 1 to 107, wherein R ¹ is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1, 2, 3 or 4 halogens. as acceptable salts. 109. The compound of any one of claims 1 to 108, wherein R ¹ is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 2 or 3 halogens selected from chloro and fluoro. as acceptable salts. 108. The method of any one of claims 1 to 107, wherein R ¹ is pyridyl, said pyridyl is optionally substituted with 1, 2, 3 or 4 R ^A1 , and each R ^A1 is independently halo, C _1-4 alkyl, C _1-4 haloalkyl, or -OC _1-4 alkyl. The compound or a pharmaceutically acceptable salt thereof. 112. The compound or pharmaceutically thereof according to any one of claims 1 to 107 and 110, wherein R ¹ is pyridyl, wherein the pyridyl is substituted with 1, 2, 3 or 4 halogens. as acceptable salts. 112. The compound or pharmaceutical thereof according to any one of claims 1 to 107 and 111, wherein R ¹ is pyridyl, wherein the pyridyl is substituted with 2 or 3 halogens selected from chloro and fluoro. as acceptable salts. 108. The method of any one of claims 1-107, wherein R ¹ is phenyl optionally substituted with 1, 2, 3 or 4 R ^A1 , each R ^A1 is independently halo, C _{1 - 4} alkyl, C _1-4 haloalkyl or —OC _1-4 alkyl, or a pharmaceutically acceptable salt thereof. 114. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 98 and 113, wherein R ¹ is phenyl substituted with 1, 2, 3 or 4 halogens. 115. The compound of any one of claims 1-98, 113 and 114, wherein R ¹ is phenyl substituted with 2 or 3 halogens selected from chloro and fluoro, or a pharmaceutically acceptable compound thereof. possible salts. 116. The method of any one of claims 1 to 115, wherein R ¹ is

,

,

,

,

,

and

A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of. 116. The method of any one of claims 1 to 115, wherein R ¹ is

,

and

A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of. 116. The method of any one of claims 1 to 115, wherein R ¹ is

,

,

and

A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of. 114. A compound according to any one of claims 1 to 113, having formula VIII, or a pharmaceutically acceptable salt thereof:
[Formula VIII]

;
In the above formula, p is 2 or 3. 120. The compound of any one of claims 1 to 119, wherein the compound has formula VIIIa: or a pharmaceutically acceptable salt thereof:
[Formula VIIIa]

;
In the above formula, p is 2 or 3. 120. A compound according to any one of claims 1 to 119, having the formula VIIIb, or a pharmaceutically acceptable salt thereof:
[Formula VIIIb]

;
In the above formula, p is 2 or 3. 122. The compound of any one of the preceding claims, wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a and R ^9b are each independently H, C _1-6 alkyl, C _1-4 haloalkyl, halo, hydroxyl, cyano, -OC _1-4 alkyl or C _1-4 alkylene-OC _1-4 alkyl, or a pharmaceutically acceptable salt thereof. 123. The compound of any one of the preceding claims, wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a and R ^9b are each independently H, C ₁ -C ₆ alkyl; halo or -OC _1-4 alkyl, or a pharmaceutically acceptable salt thereof. 122. The compound of any one of the preceding claims, wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a and R ^9b are each independently H, C ₁ -C ₆ alkyl; Halo or cyanoin, a compound or a pharmaceutically acceptable salt thereof. 122. The method of any one of the preceding claims, wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a and R ^9b are each independently H, halo or C ₁ -C ₄ Alkyl, a compound, or a pharmaceutically acceptable salt thereof. 122. The method of any one of the preceding claims, wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a and R ^9b are each independently H, fluoro, chloro or C ₁ -C ₄ alkyl, a compound or a pharmaceutically acceptable salt thereof. 125. The compound of any one of claims 1-124, wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a and R ^9b are each independently H or cyano. Scientifically acceptable salts. 123. The method of any one of claims 1-122, wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a and R ^9b are each independently H or C ₁ -C _1-4 . Haloalkyl, a compound, or a pharmaceutically acceptable salt thereof. 129. The compound of any one of claims 1-122 and 128, wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a and R ^9b are each independently H, —CH ₃ . , -CHF ₂ or -CH ₂ F, a compound or a pharmaceutically acceptable salt thereof. 123. The method of any one of claims 1-122, wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^8a , R ^8b , R ^9a and R ^9b are each independently H, —CH ₃ or —OCH _{3 .} Phosphorus, a compound, or a pharmaceutically acceptable salt thereof. 130. The compound of claim 129, wherein R ^8a , R ^8b , R ^9a or R ^9b is H, -CH ₃ , -CHF ₂ or -CH ₂ F. 122. The method of any one of the preceding claims, wherein (i) R ^4a and R ^4b , (ii) R ^5a and R ^5b , (iii) R ^8a and R ^8b , or (iv) R ^9a and R ^9b . any one of, together with the carbon atom to which they are attached, is (i) a 3-7 membered carbocyclic ring or (ii) a 4-7 membered heteroatom selected from N, O and S forming a heterocyclic ring, wherein the 3-7 membered carbocyclic ring or 4-7 membered heterocyclic ring is optionally substituted with 1 to 3 R ^A3 , each R ^A3 is independently oxo; halo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or —OR ^e . 122. The method of any one of the preceding claims, wherein (i) R ^4a and R ^4b , (ii) R ^5a and R ^5b , (iii) R ^8a and R ^8b , or (iv) R ^9a and R ^9b . any one of, together with the carbon atom to which they are attached, forms (i) a 3- to 7-membered carbocyclic ring. 122. The method of any one of the preceding claims, wherein (i) R ^4a and R ^4b , (ii) R ^5a and R ^5b , (iii) R ^8a and R ^8b , or (iv) R ^9a and R ^9b . are taken together with the carbon atom to which they are attached to form a 3-membered carbocyclic ring. 127. The compound of any one of claims 95-126, wherein m is 0, 1 or 2. 135. The compound of any one of claims 95-134, wherein m is 0. 135. The compound of any one of claims 95-134, wherein m is 1. 135. The compound of any one of claims 95-134, wherein m is 2. 139. The compound of any one of claims 95-138, wherein each R ² is independently -OR ^a or -OC(O)-NHR ^a . 139. The method of any one of claims 95-138, wherein each R ² is independently -NHR ^a , -C(O)-NH(R ^a ), -NR ^e -C(O)R ^a , -NR ^e- S(O) _n R ^a , a compound or a pharmaceutically acceptable salt thereof. 139. The compound of any one of claims 95-138, wherein each R ² is independently -S(O) _n- NH(R ^a ) or -S(O) _n- R ^a- . Scientifically acceptable salts. 139. The compound of any one of claims 95-138, wherein each R ² is independently halo, cyano, -NHR ^a- or -OR ^a . 139. The compound of any one of claims 95-138, wherein each R ² is independently -NHR ^a . 139. The compound of any one of claims 95-138, wherein each R ² is independently halo, cyano or -OR ^a . 145. The compound of any one of claims 1-138 and 144, wherein each R ² is independently halo or cyano. 139. The compound of any one of claims 95-138, wherein R ² is haloin, or a pharmaceutically acceptable salt thereof. 139. The compound of any one of claims 95-138, wherein R ² is cyano, or a pharmaceutically acceptable salt thereof. 136. The compound of any one of claims 1-135, wherein each R ² is independently halo or -OR ^a . 145. The compound of any one of claims 1-135 and 148, wherein each R ² is independently halo or —OR ^a , and each R ^a is independently H or C ₁ -C ₆ alkyl. or a pharmaceutically acceptable salt thereof. _135. ^{The _ _} _{_} Alkyl, a compound, or a pharmaceutically acceptable salt thereof. 151. The compound of any one of claims 1-135 and 148-150, wherein each R ² is independently halo or -OR ^a , and each R ^a is independently H or methyl; or A pharmaceutically acceptable salt thereof. 136. The compound of any one of claims 1-135, wherein each R ² is independently —OR ^a . 136. The method of any one of claims 95-135, wherein R ² is -OR ^a and R ^a is 1 to 2 substituents independently selected from the group consisting of halo, cyano and -OC ₁ -C ₄ alkyl. C ₃ -C ₆ cycloalkyl optionally substituted with a compound, or a pharmaceutically acceptable salt thereof. 136. The method of any one of claims 95-135, wherein R ² is -OR ^a ; R ^a is C ₁ -C ₆ alkyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, -OC ₁ -C ₄ alkyl, a compound or a pharmaceutically acceptable salt thereof . 136. The method of any one of claims 95-135, wherein R ² is -OR ^a ; R ^a is -OC _1-4 alkyl or C ₁ -C ₆ alkyl optionally substituted with halo, or a pharmaceutically acceptable salt thereof. 156. The method of any one of claims 95-135 and 155, wherein R ² is -OR ^a ; R ^a is C ₁ -C ₆ alkyl optionally substituted with —OC _1-4 alkyl, or a pharmaceutically acceptable salt thereof. 156. The compound of any one of claims 119-155, wherein p is 3 and each R ^A1 is independently halo. 156. The compound of any one of claims 119-155, wherein p is 2 and each R ^A1 is independently halo. 159. The compound of any one of claims 1-158, wherein each R ^A1 is independently fluoro or chloro. A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:

and

. A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:

,

,

,

,

,

' and

. A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:

,

,

,

,

,

,

,

,

,

,

,

,

,

and

. 163. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 162, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 164. The pharmaceutical composition of claim 163, further comprising one, two, three or four additional therapeutic agents. 165. The pharmaceutical composition of claim 164, wherein the additional therapeutic agent or therapeutic agents is an anti-HIV agent. 166. The method of claim 164 or 165, wherein the additional therapeutic agent or therapeutic agents is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversing agent, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof; pharmaceutical composition. 166. The pharmaceutical composition of any one of claims 164 to 166, wherein the additional therapeutic agent or therapeutic agents comprises an HIV capsid inhibitor. 167. The pharmaceutical composition of any one of claims 164-167, wherein the additional therapeutic agent or therapeutic agents comprises lenacapavir. 166. The pharmaceutical composition of any one of claims 164-166, wherein the additional therapeutic agent or therapeutic agents comprises a nucleoside reverse transcriptase translocation inhibitor. 169. The pharmaceutical composition of any one of claims 164-166 and 169, wherein the additional therapeutic agent or therapeutic agents comprises islatravir. 166. The pharmaceutical composition of any one of claims 164 to 166, wherein the additional therapeutic agent or therapeutic agents comprises an HIV capsid inhibitor and a nucleoside reverse transcriptase translocation inhibitor. 172. The pharmaceutical composition of any one of claims 164-166 and 171, wherein the additional therapeutic agent or therapeutic agents comprises lenacapavir and islatravir. 167. The method of any one of claims 164 to 166, wherein the additional therapeutic agent or therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil, N-(( S )-1-(3-(4) -Chloro-3-(methylsulfonamido)-l-(2,2,2-trifluoroethyl) -lH -indazol-7-yl)-6-(3-methyl-3-(methylsulf phonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b S ,4a R )-5,5-di Fluoro-3-(trifluoromethyl)-3b, 4,4a ,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2- c ]pyrazol-l-yl) Acetamide, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition. 174. The pharmaceutical composition according to any one of claims 163 to 173, wherein the pharmaceutical composition is for oral or parenteral administration. 163. A kit comprising the compound of any one of claims 1 to 162, or a pharmaceutically acceptable salt thereof, and instructions for use. 175. The kit of claim 175, further comprising one, two, three or four additional therapeutic agents or therapeutic agents. 178. The kit of claim 176, wherein the additional therapeutic agent or therapeutic agents is an anti-HIV agent. 178. The method of claim 176 or 177, wherein the additional therapeutic agent or therapeutic agents is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, CXCR4 An inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latent reversing agent, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof. 178. The method of any one of claims 176-178, wherein the additional therapeutic agent or therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil, N-(( S )-l-(3-(4) -Chloro-3-(methylsulfonamido)-l-(2,2,2-trifluoroethyl) -lH -indazol-7-yl)-6-(3-methyl-3-(methylsulf phonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b S ,4a R )-5,5-di Fluoro-3-(trifluoromethyl)-3b, 4,4a ,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2- c ]pyrazol-l-yl) Acetamide, or a pharmaceutically acceptable salt thereof, the kit. 174. A method of treating HIV infection in a human having or at risk of having an infection, comprising: a therapeutically effective amount of a compound of any one of claims 1-162, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof; A method comprising administering to a human the pharmaceutical composition of any one of the preceding claims. 190. The method of claim 180, further comprising administering to the human a therapeutically effective amount of one, two, three or four additional therapeutic agents. 182. The method of claim 181, wherein the additional therapeutic agent or therapeutic agents is an anti-HIV agent. 183. The method of claim 181 or 182, wherein the additional therapeutic agent or therapeutic agents is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, CXCR4 An inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latent reversing agent, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof. 184. The method of any one of claims 181-183, wherein the additional therapeutic agent or therapeutic agents comprises an HIV capsid inhibitor or a nucleoside reverse transcriptase translocation inhibitor. 185. The method of any one of claims 181-184, wherein the additional therapeutic agent or therapeutic agents comprises lenacapavir and islatravir. 185. The method of any one of claims 181-184, wherein the additional therapeutic agent or therapeutic agents comprises an HIV capsid inhibitor. 189. The method of any one of claims 181-184 and 186, wherein the additional therapeutic agent or therapeutic agents comprises lenacapavir. 185. The method of any one of claims 181-184, wherein the additional therapeutic agent or therapeutic agents comprises a nucleoside reverse transcriptase translocation inhibitor. 189. The method of any one of claims 181-184 and 188, wherein the additional therapeutic agent or therapeutic agents comprises islatravir. 184. The method of any one of claims 181-183, wherein the additional therapeutic agent or therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil, N-(( S )-1-(3-(4) -Chloro-3-(methylsulfonamido)-l-(2,2,2-trifluoroethyl) -lH -indazol-7-yl)-6-(3-methyl-3-(methylsulf phonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b S ,4a R )-5,5-di Fluoro-3-(trifluoromethyl)-3b, 4,4a ,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2- c ]pyrazol-l-yl) acetamide, or a pharmaceutically acceptable salt thereof. 190. The method of any one of claims 180-190, wherein administration is oral, intravenous, subcutaneous or intramuscular. 163. The compound of any one of claims 1-162, or a pharmaceutically acceptable salt thereof, or the medicament of any one of claims 163-174, for the treatment of HIV infection in a human having or at risk of having an infection. use of the pharmaceutical composition. 172. A compound of any one of claims 1-162, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 163-174, for use in medical treatment. 163. A compound of any one of claims 1-162, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 163-174, for use in the treatment of HIV infection. 172. A compound of any one of claims 1-162, or a pharmaceutically acceptable salt thereof, or 163-174, in the manufacture of a medicament for the treatment of an HIV infection in a human having or at risk of having an infection. Use of a pharmaceutical composition according to any one of the preceding claims.