EA041590B1 - GLUCOCORTICOID RECEPTOR INHIBITORS - Google Patents

Description

Cross-references to related applications

This application claims priority from U.S. Application Ser. 62/405801, filed Oct. 7, 2016, and U.S. Patent Application Ser. in all its fullness.

Background of the Invention

There is a need in the art for effective treatment of cancer, neoplastic disease, and hypercortisolism.

Brief summary of the present invention

This document provides substituted steroid derivatives of the compounds and pharmaceutical compositions containing these compounds. The claimed compounds and compositions are useful as glucocorticoid receptor (GR) inhibitors. In addition, the subject compounds and compositions are useful in the treatment of cancer or chemotherapy-resistant cancer in a subject, said cancer expressing the glucocorticoid receptor (GR), such as triple-negative breast cancer, high-grade serous ovarian cancer, castration-resistant prostate cancer. cancer, double-resistant prostate cancer, or non-small cell lung cancer.

Certain embodiments provided herein describe compounds having the structure of formula (III) or a pharmaceutically acceptable salt thereof.

^R1

Formula (III) where ring A is a 6 - or 10-membered aryl;

R ¹ is -NR ^4a R ^5a ;

each R ² is independently halogen, C _1-6 αkyl, or C _1-6 haloalkyl;

or R ¹ and R ² on adjacent atoms are taken together with the atoms to which they are connected to form a heterocycle;

R ³ is C _2-8 alkyl, C _1-6 haloalkyl or 3-6 membered carbocyclyl;

R ^4a is C _2-8 alkyl or 3-6 membered carbocyclyl;

R ^5a is hydrogen or C _1-6 alkyl; or

R ^4a and R ^5a are taken together with the N atom to which they are attached to form a heterocycle optionally substituted with oxo, C1-6 alkyl, -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a or - R ^b -S(O)tR ^a , where R ^a is C1-6 alkyl, R ^b is a direct bond and t is 2;

each R ⁸ and R ⁹ is independently hydrogen, C _1-6 alkyl, or C _1-6 haloalkyl;

each R ¹⁰ and R ¹¹ independently represents hydrogen, C _1-6 αkyl or C _1-6 haloalkyl;

R ¹² is hydrogen, C _1-6 alkyl or C _1-6 haloalkyl; and n is 0, 1, or 2.

In some embodiments of a compound of formula (III) or a pharmaceutically acceptable salt thereof, R ¹² is C 1-6 alkyl or hydrogen. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt thereof, ring A is phenyl. In some embodiments of a compound of formula (III) or a pharmaceutically acceptable salt thereof, R ^4a is C2-4 alkyl. In some embodiments of a compound of formula (III) or a pharmaceutically acceptable salt thereof, R ^5a is hydrogen or C1-6αkyl. In some embodiments of a compound of formula (III) or a pharmaceutically acceptable salt thereof, n is 0. In some embodiments of a compound of formula (III) or a pharmaceutically acceptable salt thereof, the R ³ ring is C4-8 alkyl, C _1-6 haloalkyl, or 3 -membered carbocyclyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt thereof, R ³ is C _4-8 alkyl. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt thereof, R ⁸ and R ⁹ are hydrogen.

In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt thereof, R ¹⁰ and R ¹¹ are each hydrogen.

In some embodiments of a compound of formula (III) or a pharmaceutically acceptable salt thereof, the compound has the structure of formula (IIIa)

- 1 041590

In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt thereof, the compound is selected from

- 2 041590

or a pharmaceutically acceptable salt thereof.

In some embodiments, the connection is

or a pharmaceutically acceptable salt thereof.

In some embodiments provided herein, a pharmaceutical composition is described comprising a pharmaceutically acceptable excipient and a compound described herein, or a pharmaceutically acceptable salt thereof.

Also provided herein are methods of treating or preventing cancer or chemotherapy-resistant cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, said cancer expressing a glucocorticoid receptor (GR).

In some embodiments, the cancer is a triple negative cancer

- 3 041590 breast cancer, high-grade serous ovarian cancer, castration-resistant prostate cancer or double-resistant prostate cancer. In some embodiments, the cancer is non-small cell lung cancer.

In some embodiments, the methods further comprise administering to the subject a second therapeutic agent, which is nab-paclitaxel or enzalutamide.

Other embodiments provided herein describe the use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the treatment of cancer or chemotherapy-resistant cancer in a subject, said cancer expressing a glucocorticoid receptor (GR).

According to some embodiments of the invention, the use of the compound /

\ 11 I ^OH ^G and T ⁿ Τ' /

G That or a pharmaceutically acceptable salt thereof in combination with nab-paclitaxel or enzalutamide for the treatment of cancer or chemotherapy-resistant cancer in a subject, said cancer expressing the glucocorticoid receptor (GR).

Inclusion by reference

All publications, patents and patent applications mentioned in the present description, are incorporated herein by reference for the specific purposes specified in this document.

Detailed disclosure of the present invention

This document provides substituted steroid derivatives of the compounds and pharmaceutical compositions containing these compounds. The claimed compounds and compositions are useful as glucocorticoid receptor (GR) inhibitors. In addition, the claimed compounds and compositions are useful in the treatment of cancer such as prostate cancer, breast cancer, lung cancer and ovarian cancer, and hypercortisolism.

Certain embodiments provided herein describe compounds having the structure of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

R ¹ /X ^he ^ ^r3 (R ² ) _n Г ^А ) MeJ

R ¹² H X

^R9

I | n I n

RlO R ¹¹

Formula (III) wherein ring A is heteroaryl, aryl, cycloalkyl or heterocyclyl;

R ¹ is -NR ^4a R ^5a ;

each R ² is independently -NR ⁴ R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halogen, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted hydroxyalkyl, -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁴ R ⁵ , -OC(O)OR ⁶ , -OC(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -S(O)R ⁷ , -SR ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -CN, - CO2H or -NO ₂ ; or

R ¹ and R ² on adjacent atoms are taken together with the atoms to which they are connected to form an optionally substituted heterocycle;

R ³ is optionally substituted C2-8 alkyl, halogen, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, -Si(R ⁶ )3, -OR ⁶ or -S(O) ₂ R ⁷ ;

R ^4a is C _2-8 alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -S(O)2R ⁷ , -C(O)N(R ¹³ )2, -C(O )R ⁶ or -C(O)OR ⁶ ;

R ^5a is -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -S(O)2R ⁷ , -C(O)N(R ¹³ )2, - C(O)R ⁶ or -C(O)OR ⁶ ; or

R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R ⁴ and R ⁵ is independently -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -S(O)2R ⁷ , -C(O)N(R ¹³ )2, -C(O)R ⁶ or

-C(O)OR ⁶ ; or

R ⁴ and R ⁵ are taken together with the N atom to which they are attached to form a substituted or unsubstituted heterocycle;

each R ⁶ is independently optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

R ⁷ is optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

each R ⁸ and R ⁹ is independently -H, optionally substituted alkyl, haloalkyl, halogen, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, -OH, -S(O)2R ⁷ , -C(O)2H, -C(O)R ⁶ or -C(O)OR ⁶ ; or

R ⁸ and R ⁹ are taken together with the atom to which they are attached to form a substituted or unsubstituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -NR ⁶ -, -S- and -S(O)2-;

each R ¹⁰ and R ¹¹ is independently -H, optionally substituted alkyl, halogen, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, -OH, -S(O)2R ⁷ , -C(O)2H, -C(O)R ⁶ or -C(O)OR ⁶ ; or

R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form a substituted or unsubstituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -NR ⁶ -, -S and - S(O)2-;

R ¹² is hydrogen, optionally substituted alkyl, haloalkyl, hydroxy, halogen, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroalkyl;

each R ¹³ is independently H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and n is 0, 1, 2, 3, or 4.

In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹² is hydrogen, alkyl, haloalkyl, hydroxy, halogen, carbocyclyl, or heteroalkyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate or prodrug thereof, R ¹² is C 1-6 alkyl or hydrogen. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹² is methyl. In some embodiments of a compound of formula (III) or a pharmaceutically acceptable salt, solvate or prodrug thereof, R ¹² is H. In some embodiments of a compound of formula (III) or a pharmaceutically acceptable salt, solvate or prodrug thereof, ring A is monocyclic heteroaryl or monocyclic aryl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring A is phenyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ^4a is _{C2_8} alkyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ^4a is C3_6alkyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ^4a is _{C2_4} alkyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ^4a is ethyl, isopropyl, or t-butyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate or prodrug thereof, R ^5a is -H, optionally substituted alkyl or haloalkyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ^5a is

- 5 041590 is -H or alkyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ^5a is C ₁ . ₆ alkyl. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted heterocycle. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted pyrrolidinyl, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted piperidinyl or optionally substituted piperazinyl. In some embodiments of a compound of formula (III) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, n is 0, 1, or 2. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, n is 0. In some embodiments, in embodiments of a compound of formula (III) or a pharmaceutically acceptable salt, solvate or prodrug thereof, n is 1.

In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ² is independently -NR4R ⁵ , halogen, -OR ⁶ , alkyl, fluoroalkyl, carbocyclyl, heteroalkyl, heterocyclyl, -S(O)2NR ⁴ R ⁵ or -S(O)2R ⁷ . In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is an optionally substituted C2_8 alkyl, haloalkyl, or an optionally substituted carbocyclyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is C4-8 alkyl, haloalkyl, or optionally substituted carbocyclyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is CF3, t-butyl, or cyclopropyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is _{C4_8} alkyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is t-butyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is haloalkyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is CF3. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is an optionally substituted carbocyclyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ³ is cyclopropyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ⁸ and R ⁹ is independently —H, alkyl, or carbocyclyl. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ⁸ and R ⁹ are -H. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ¹⁰ and R ¹¹ is independently -H, C1. ₆ αkyl, halogen, C ₁ . ₆ alkoxy or -OH. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ¹⁰ and R ¹¹ is -H. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form a 3-, 4-, 5-, or 6-membered ring. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each R ⁴ and R ⁵ is independently —H, C1.6αkyl, or S(O)2R ⁷ . In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ⁴ and R ⁵ attached to the same N atom, are taken together with the N atom to which they are attached to form a substituted or unsubstituted 4 -, 5 - or 6-membered heterocyclic ring, additionally containing 0-3 heteroatoms selected from the group consisting of -O-, -NH-, -NR ⁶ -, -S- and -S(O) 2-. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ⁶ is alkyl, carbocyclyl, or fluoroalkyl. In some embodiments of a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R ⁷ is alkyl, carbocyclyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heterocyclyl.

In some embodiments of a compound of formula (III) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, the compound has the structure of formula (IIIa)

- 6 041590

Formula (Sha)

In some embodiments provided herein, a pharmaceutical composition is described comprising a pharmaceutically acceptable excipient and a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Also provided herein are methods of treating or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound having the structure of formula (III) or (IIIa) or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Also provided herein are methods of reducing the incidence of cancer recurrence, the method comprising administering to a subject in cancer remission a therapeutically effective amount of a compound having the structure of formula (III) or (IIIa) or a pharmaceutically acceptable salt, solvate or prodrug thereof. Certain embodiments provided herein describe methods of treating chemotherapy-resistant cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound having the structure of formula (III) or (IIIa), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments, the cancer is triple-negative breast cancer, high-grade serous ovarian cancer, castration-resistant prostate cancer, or double-resistant prostate cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the methods further comprise administering a second therapeutic agent to the subject. In some embodiments, the methods further comprise administering one or more additional therapeutic agents. In some embodiments, the second or additional therapeutic agent is an inhibitor of androgen receptor signaling. In specific embodiments, the androgen receptor signaling inhibitor is 3,3'-diindolylmethane (DIM), abiraterone acetate, ARN-509, bexlosteride, bicalutamide, dutasteride, epristeride, enzalutamide, finasteride, flutamide, isonsteride, ketoconazole, N-butylbenzenesulfonamide, nilutamide, megestrol, steroidal antiandrogens, turosteride, or any combination thereof. In some embodiments, the second or additional therapeutic agent is a chemotherapeutic agent. In other embodiments, the second or additional therapeutic agent is cisplatin, carboplatin, paclitaxel, gemcitabine, doxorubicin, camptothecin, topotecan, or any combination thereof. In some embodiments, the second or additional therapeutic agent is an immunotherapeutic agent (eg, an anti-PD-L1 antibody agent or an anti-PD1 antibody agent). In certain embodiments, the second or additional therapeutic agent is an anti-PD-L1 antibody agent. In certain embodiments, the second or additional therapeutic agent is an anti-PD1 antibody agent.

In other embodiments provided herein, methods of treating a disease or disorder associated with elevated cortisol levels in a subject are described, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure of formula (III) or (IIIa) or a pharmaceutically acceptable thereof. salt, solvate or prodrug. In certain embodiments, the disease or disorder associated with elevated cortisol is Cushing's syndrome. In certain embodiments, the disease or disorder associated with elevated cortisol is refractory Cushing's syndrome.

As used herein and in the appended claims, singular forms include plural denominators unless the context clearly indicates otherwise. Thus, for example, a reference to an agent includes a plurality of such agents, and a reference to a cell includes a reference to one or more cells (or a plurality of cells) and their equivalents known to those skilled in the art, and so on. When ranges are used herein for physical properties such as molecular weight or chemical properties such as chemical formulas, all combinations and subcombinations of ranges and their specific embodiments are intended to be included. The term approximately, when referring to a number or range of numbers, means that a number or range of numbers refers to an approximate value within the

- 7 041590 lax variability of values from experiment to experiment (or within the statistical error of the experiment), and thus the number or numerical range, in some cases, will vary from 1 to 15% of the specified number or numerical range. The term containing (and related terms such as contain, or contains, or having or including) is not intended to exclude that in certain other embodiments, such as an embodiment of any claimed composition, a composition, method, or process described herein, and etc. consist of or consist mainly of the features described.

Definitions.

In the context of the present description and the appended claims, unless otherwise indicated, the following terms have the meanings given below.

Amino refers to the -NH2 radical. Cyano refers to the -CN radical. Nitro refers to the -NO2 radical. Oxa refers to the -O- radical. Oxo refers to the =O radical. Thiooxo refers to the =S radical. Imino refers to the =N-H radical. Oxymo refers to the radical =N-OH. Hydrazino refers to the =N-NH2 radical.

Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturated bonds, having from one to fifteen carbon atoms (eg, C1- _C15 alkyl). In certain embodiments, alkyl contains from one to thirteen carbon atoms (eg, C1-C ₁₃ alkyl). In certain embodiments, alkyl contains from one to eight carbon atoms (eg, C1- _C8 alkyl). In other embodiments, the alkyl contains from one to five carbon atoms (eg, C1- _C8 alkyl). In other embodiments, alkyl contains from one to four carbon atoms (eg, C1- _C4 alkyl). In other embodiments, alkyl contains one to three carbon atoms (eg, C ₁ -C ₃ αkyl). In other embodiments, alkyl contains one to two carbon atoms (eg, C1- _C2 alkyl). In other embodiments, the alkyl contains one carbon atom (eg, C1 alkyl). In other embodiments, alkyl contains five to fifteen carbon atoms (eg, C ₅ -C ₁₅ alkyl). In other embodiments, alkyl contains five to eight carbon atoms (eg, C ₅ -C ₈ alkyl). In other embodiments, alkyl contains two to five carbon atoms (eg, C ₂ -C ₅ alkyl). In other embodiments, alkyl contains three to five carbon atoms (eg, C ₃ -C ₅ alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl ( isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is connected to the rest of the molecule by a single bond. Unless otherwise specifically stated herein, the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thiooxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(O)- R ^a , -N(R ^a )2, -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a )2, -N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a )2, -N(R ^a )C(O)R ^a , -N(R ^a )S(O)tR ^a (where t is 1 or 2), - S(O)tOR ^a (where t is 1 or 2), -S(O)tR ^a (where t is 1 or 2) and -S(O) _t N(R ^a )2 (where t is 1 or 2 ), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl ), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl ).

Alkoxy refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, the alkenyl contains two to eight carbon atoms. In other embodiments, the alkenyl contains two to four carbon atoms. Alkenyl is linked to the rest of the molecule by a single bond, such as ethenyl (i.e. vinyl), prop-1-enyl (i.e. allyl), but1-enyl, penta-1-enyl, penta-1,4-dienyl and etc. Unless otherwise specifically noted herein, the alkenyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thiooxo, imino, oximo, trimethylsilanyl, -OR ^a , SR ^a , -OC(O)-R ^a , -N(R ^a )2, -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a )2, -N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a )2, -N(R ^a )C(O)R ^a , -N(R ^a )S(O)tR ^a (where t is 1 or 2), -S (O)tOR ^a (where t is 1 or 2), -S(O)tR ^a (where t is 1 or 2) and -S(O)tN(R ^a )2 (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally

- 8 041590 substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl ), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond having from two to twelve carbon atoms. In certain embodiments, the alkynyl contains two to eight carbon atoms. In other embodiments, the alkynyl contains two to six carbon atoms. In other embodiments, the alkynyl contains two to four carbon atoms. The alkynyl is linked to the rest of the molecule by a single bond, eg ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise specifically noted herein, the alkynyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thiooxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(O)- R ^a , -N(R ^a )2, -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a )2, -N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a )2, -N(R ^a )C(O)R ^a , -N(R ^a )S(O)tR ^a (where t is 1 or 2), - S(O)tOR ^a (where t is 1 or 2), -S(O)tR ^a (where t is 1 or 2) and -S(O) _t N(R ^a )2 (where t is 1 or 2 ), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl ), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl ), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

Alkylene or alkylene chain refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group consisting entirely of carbon and hydrogen, containing no unsaturated bonds and having from one to twelve carbon atoms, e.g. methylene, ethylene, propylene, n -butylene, etc. The alkylene chain is connected to the rest of the molecule through a single bond and to the radical group through a single bond. The connection points of the alkylene chain to the rest of the molecule and to the radical group are provided by one carbon atom in the alkylene chain or by any two carbon atoms within the chain. In certain embodiments, the alkylene contains from one to eight carbon atoms (eg, C1- _C8 alkylene). In other embodiments, the alkylene contains from one to five carbon atoms (eg, C1- _C8 alkylene). In other embodiments, the alkylene contains from one to four carbon atoms (eg, C1- _C4 alkylene). In other embodiments, the alkylene contains from one to three carbon atoms (eg, C ₁ -C ₃ alkylene). In other embodiments, the alkylene contains one to two carbon atoms (eg, C ₁ -C ₂ alkylene). In other embodiments, the alkylene contains one carbon atom (eg, C1 alkylene). In other embodiments, the alkylene contains five to eight carbon atoms (eg, C ₅ -C ₈ alkylene). In other embodiments, the alkylene contains two to five carbon atoms (eg, C ₂ -C ₅ alkylene). In other embodiments, the alkylene contains three to five carbon atoms (eg, C ₃ -C ₅ alkylene). Unless otherwise specifically noted herein, the alkylene chain is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thiooxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(O)- R ^a , -N(R ^a )2, -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a )2, -N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a )2, -N(R ^a )C(O)R ^a , -N(R ^a )S(O)tR ^a (where t is 1 or 2), - S(O)tOR ^a (where t is 1 or 2), -S(O)tR ^a (where t is 1 or 2) and -S(O)tN(R ^a )2 (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), g heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl ).

Alkynylene or alkynylene chain refers to a straight or branched divalent carbon

- 9 041590 lhydrogen chain linking the rest of the molecule with a radical group consisting exclusively of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is connected to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, the alkynylene contains two to eight carbon atoms (eg, C2- _C8 alkynylene). In other embodiments, the alkynylene contains two to five carbon atoms (eg, C2- _C5 alkynylene). In other embodiments, the alkynylene contains two to four carbon atoms (eg, C2- _C4 alkynylene). In other embodiments, the alkynylene contains two to three carbon atoms (eg, C2- _C3 alkynylene).

In other embodiments, the alkynylene contains two carbon atoms (eg, C2 alkylene). In other embodiments, the alkynylene contains five to eight carbon atoms (eg, C ₅ -C ₈ alkynylene). In other embodiments, the alkynylene contains three to five carbon atoms (eg, C ₃ -C ₅ alkynylene). Unless otherwise specifically stated herein, the alkynylene chain is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thiooxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(O)R ^a , -N(R ^a )2, -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a )2, -N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a )2, -N(R ^a )C(O)R ^a , -N(R ^a )S(O)tR ^a (where t is 1 or 2), -S (O)tOR ^a (where t is 1 or 2), -S(O)tR ^a (where t is 1 or 2) and S(O) _t N(R ^a )2 (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl ).

Aryl refers to a radical formed from an aromatic monocyclic or polycyclic hydrocarbon ring system by removal of a hydrogen atom from a carbon atom of the ring. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon, from five to eighteen carbon atoms, where at least one of the rings in the ring system is completely unsaturated, i. it contains a cyclic, delocalized (4n+2) π-electron system in accordance with Huckel's theory. The ring system from which the aryl groups are derived includes, without limitation, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless specifically stated otherwise in this specification, the term aryl or the prefix ar- (as, for example, in the term aralkyl) is intended to include aryl radicals optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, halogen, fluoroalkyl -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a )2, -R ^b -N(R ^a )2, -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a )2, -R ^b -OR ^c -C(O )N(R ^a )2, -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S (O)tR ^a (where t is 1 or 2), -R ^b -S(O)tR ^a (where t is 1 or 2), -R ^b -S(O)tOR ^a (where t is 1 or 2) and -R ^b -S(O)tN(R ^a )2 (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl ( optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently is a straight bond or a straight or branched alkylene or alkenylene chain; and R ^c is a straight or branched alkylene or alkenylene chain, where each of the above substituents is unsubstituted unless otherwise indicated.

Aralkyl refers to a radical of the formula -Rc-aryl, where ^Rc is an alkylene chain as defined above, eg methylene, ethylene, etc. The alkylene chain portion of the aralkyl radical is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl radical is optionally substituted as described above for the aryl group.

- 10 041590

Aralkenyl refers to a radical of the formula -R ^d -aryl, where R ^d is the alkenylene chain as defined above. The aryl portion of the aralkenyl radical is optionally substituted as described above for the aryl group. The alkenylene chain portion of the aralkenyl radical is optionally substituted as defined above for the alkenylene group.

Aralkynil refers to a radical of the formula -R ^e -aryl, where R ^e represents the alkynylene chain as defined above. The aryl portion of the aralkynyl radical is optionally substituted as described above for the aryl group. The alkynylene chain portion of the aralkynyl radical is optionally substituted as defined above for the alkynylene chain.

Aralkoxy refers to an oxygen-linked radical of the formula -OR ^c -aryl, where R ^c is an alkylene chain as defined above, eg methylene, ethylene, etc. The alkylene chain portion of the aralkyl radical is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl radical is optionally substituted as described above for the aryl group.

Carbocyclyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems having three to fifteen carbon atoms. In certain embodiments, the carbocyclyl contains three to ten carbon atoms. In other embodiments, the carbocyclyl contains five to seven carbon atoms. Carbocyclyl is connected to the rest of the molecule by a single bond. Carbocyclyl is saturated (ie, containing only C-C single bonds) or unsaturated (ie, containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also called a cycloalkyl. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Unsaturated carbocyclyl is also called cycloalkenyl. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, etc. Unless otherwise specifically stated herein, the term carbocyclyl is intended to include carbocyclyl radicals optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, halogen, fluoroalkyl, oxo, thiooxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a , -R ^b -OC(O )-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a )2, -R ^b -N(R ^a )2, -R ^b -C( O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a )2, -R ^b -OR ^c -C(O)N(R ^a )2, - R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O)tR ^a (where t equals 1 or 2), -R ^b -S(O)tR ^a (where t is 1 or 2), - R ^b -S(O)tOR ^a (where t is 1 or 2) and -R ^b -S(O)tN(R ^a )2 (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy , methoxy, or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain; and R ^c is a straight or branched alkylene or alkenylene chain, where each of the above substituents is unsubstituted unless otherwise indicated.

Carbocyclylalkyl refers to a radical of formula -R ^c -carbocyclyl, where R ^c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

Carbocyclylalkynyl refers to a radical of the formula -R ^c -carbocyclyl, where R ^c is the alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical are optionally substituted as defined above.

Carbocyclylalkoxy refers to a radical bonded via an oxygen atom of the formula -OR ^c -carbocyclyl, where R ^c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

As used herein, a carboxylic acid bioisostere refers to a functional group or moiety that exhibits physical, biological and/or chemical properties similar to those of a carboxylic acid molecule. Examples of carboxylic acid bioisosteres include

- 11 041590 no limit

he he about etc.

Deuteroalkyl refers to an alkyl group where 1 or more hydrogen atoms of the alkyl are replaced by deuterium.

Halogen or halogen refers to substituents that are bromine, chlorine, fluorine or iodine.

Haloalkyl refers to an alkyl radical as defined above substituted with one or more halo radicals as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, trichloromethyl, dichloromethyl, chloromethyl , 2,2,2-trichloroethyl, 1-chloromethyl-2-chloroethyl, tribromomethyl, dibromomethyl, bromomethyl, 2,2,2-tribromoethyl, 1-bromomethyl-2-bromoethyl, etc. In some embodiments, the alkyl portion of the haloalkyl radical is optionally substituted as defined above for an alkyl group.

Fluoroalkyl refers to an alkyl radical as defined above substituted with one or more fluoro radicals as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl moiety of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

Heteroalkyl refers to an alkyl group in which one or more alkyl backbone atoms are selected from an atom other than carbon, eg oxygen, nitrogen (eg -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl is connected to the rest of the molecule at the carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is C ₁ -C ₆ heteroalkyl. Unless otherwise specifically stated herein, the heteroalkyl chain is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thiooxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(O)- R ^a , -N(R ^a )2, -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a )2, -N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a )2, -N(R ^a )C(O)R ^a , -N(R ^a )S(O)tR ^a (where t is 1 or 2), - S(O)tOR ^a (where t is 1 or 2), -S(O)tR ^a (where t is 1 or 2) and -S(O)tN(R ^a )2 (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl ), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

Heterocyclyl refers to a stable radical in the form of a 3-18 membered non-aromatic ring that contains two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specifically stated herein, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally in oxidized form. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is connected to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, without limitation, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperazolidinyl, piperazolidinyl, , 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxothiomorpholinyl. Unless otherwise specifically stated herein, the term heterocyclyl is meant to include heterocyclyl radicals as defined above optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halogen, fluoroalkyl, oxo, thiooxo, cyano, nitro, optionally substituted aryl, optionally substituted aral

- 12 041590 kila, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a , -R ^b -OC( O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a )2, -R ^b -N(R ^a )2, -R ^b -C (O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a )2, -R ^b -OR ^c -C(O)N(R ^a )2, -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O)tR ^a (where t is 1 or 2), -R ^b -S(O)tR ^a (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2) and -R ^b -S (O)tN(R ^a )2 (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (neo optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a direct or a branched alkylene or alkenylene chain; and R ^c is a straight or branched alkylene or alkenylene chain, where each of the above substituents is unsubstituted unless otherwise indicated.

N-heterocyclyl or N-linked heterocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen atom, where the point of connection of the heterocyclyl radical with the rest of the molecule is provided through the nitrogen atom in the heterocyclyl radical. The N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, without limitation, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

C-heterocyclyl or C-linked heterocyclyl refers to a heterocyclyl radical as defined above containing at least one heteroatom, where the point of connection of the heterocyclyl radical with the rest of the molecule is provided through a carbon atom in the heterocyclyl radical. The C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, without limitation, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, etc.

Heterocyclylalkyl refers to a radical of the formula -R ^c -heterocyclyl, where R ^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, then the heterocyclyl is optionally bonded to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for the alkylene chain. The heterocyclyl moiety of the heterocyclylalkyl radical is optionally substituted as defined above for the heterocyclyl group.

Heterocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula -OR ^c heterocyclyl, where R ^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, then the heterocyclyl is optionally bonded to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for the alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy radical is optionally substituted as defined above for the heterocyclyl group.

Heteroaryl refers to a radical derived from a 3-18 membered aromatic ring radical that contains two to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i. it contains a cyclic, delocalized (4n+2) π-electron system in accordance with Hückel's theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical are optionally in oxidized form. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is connected to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, without limitation, azepinyl, acridinyl, benzimidazolyl, benzdolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4 ]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxynyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[ 1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5Hcyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[b]quinazolinyl, 5,6-dihydrobenzo[I]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c] pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10

- 13 041590 hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5 ,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranil, 5,6,6a,7,8,9,10,10a-octahydrobenzo [I]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl , pyrido[3,4d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5 ]thieno[2,3d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8tetrahydropyrido[4,5-с ]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thiene o[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl and thiophenyl (i.e. thienyl). Unless otherwise specifically stated herein, the term heteroaryl is intended to include heteroaryl radicals as defined above optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halogen, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thiooxo, cyano -R ^b -OR ^a -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b OC(O)-N(R ^a )2, -R ^b -N(R ^a )2, -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a )2, -R ^b -OR ^c -C(O)N( R ^a )2, -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) tR ^a (where t is 1 or 2), -R ^b -S(O)tR ^a (where t is 1 or 2), -R ^b S(O)tOR ^a (where t is 1 or 2) and -R ^b -S(O)tN(R ^a )2 ( where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen , hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is not independently represents a direct bond or a straight or branched alkylene or alkenylene chain; and R ^c represents a straight or branched alkylene or alkenylene chain, where each of the above substituents is unsubstituted, unless otherwise indicated.

N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen atom, where the point of connection of the heteroaryl radical with the rest of the molecule is provided through the nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

C-heteroaryl refers to a heteroaryl radical as defined above, where the connection point of the heteroaryl radical to the rest of the molecule is provided through a carbon atom in the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

Heteroarylalkyl refers to a radical of the formula -R ^c -heteroaryl, where R ^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, then the heteroaryl is optionally bonded to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkyl radical is optionally substituted as defined above for the heteroaryl group.

Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula -OR ^c heteroaryl, where R ^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, then the heteroaryl is optionally bonded to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkoxy radical is optionally substituted as defined above for the heteroaryl group.

The compounds disclosed herein according to some embodiments contain one or more centers of asymmetry, and thus contribute to the formation of enantiomers, diastereoisomers and other stereoisomeric forms, which are defined, in terms of absolute stereochemistry, as (R)- or (S)- . Unless otherwise indicated, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by this disclosure. When the compounds described herein contain double bonds in alkenes, and unless otherwise indicated, the present disclosure is intended to include geometric isomers of both E and Z (eg, cis or trans). Similarly, it is understood that all possible isomers, as well as

- 14 041590 their racemic and optically pure forms, and all tautomeric forms, are also included. The term geometric isomer refers to E or Z geometric isomers (eg, cis or trans) at the position of the substituents relative to the double bond of the alkene. The term positional isomer refers to structural isomers in terms of the arrangement of substituents around the central ring, such as ortho-, meta- and para-isomers in terms of the arrangement of substituents around the benzene ring.

The compounds described herein may be characterized by their natural isotopic composition, or one or more of the atoms may be artificially enriched in relation to a particular isotope with the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variants of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention. For example, hydrogen has three naturally occurring isotopes, designated 1H (protium), ^2H (deuterium), and ^3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enrichment with deuterium may provide certain therapeutic benefits, such as increased half-life and/or exposure in vivo, or may provide a compound useful for studying drug elimination and metabolism pathways in vivo. Isotopically enriched compounds can be prepared using conventional techniques well known to those skilled in the art, or by methods analogous to those described in the Schemes and Examples herein using appropriate isotopically enriched reagents and/or intermediates. In some embodiments, the compounds described herein contain one or more isotopic variants (e.g., deuterium, tritium, ¹³ C and/or ¹⁴ C).

A tautomer refers to a molecule in which a proton shift is possible from one atom of the molecule to another atom of the same molecule. Compounds provided herein, in certain embodiments, exist as tautomers. Under conditions where tautomerization is possible, there will be a chemical equilibrium of the tautomers. The exact ratio of tautomers depends on several factors including phase state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include

The pharmaceutically acceptable salt includes both acid and base addition salts. A pharmaceutically acceptable salt of any of the substituted steroid derivatives described herein is intended to encompass any and all possible pharmaceutically acceptable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

A pharmaceutically acceptable acid addition salt refers to those salts which retain the biological efficacy and free base properties, which are not biologically or otherwise unacceptable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid. , hydroiodic acid, hydrofluoric acid, phosphoric acid, etc. Also included are salts that form with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy-alkanoic acids, carboxylic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and include, e.g. acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid , ethanesulfonic acid, p-toluenesulfonic

- 15 041590 acid, salicylic acid, etc. Illustrative salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates. , suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Amino acid salts such as arginates, gluconates, and galacturonates are also contemplated (see, for example, Berge S. M. et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of base compounds, in some embodiments, are prepared by converting the base forms with sufficient amount of the desired acid to form the salt according to methods and techniques with which one of skill in the art is familiar.

A pharmaceutically acceptable base addition salt refers to those salts that retain the biological effectiveness and free acid properties that are not biologically or otherwise unacceptable. Such salts are obtained by adding an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts in some embodiments are formed with metals or amines such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, without limitation, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, e.g., isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine , 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chlorprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines , piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

In the context of this document, treatment, or the implementation of treatment, or weakening, or relief are used interchangeably. These terms refer to an approach to obtain beneficial or desired results, including, without limitation, therapeutic benefit and/or prophylactic benefit. By therapeutic benefit is meant the elimination or alleviation of the primary disorder being treated. Also, a therapeutic benefit is achieved by eliminating or alleviating one or more of the physiological symptoms associated with the primary disorder such that the patient is improved despite the patient still suffering from the primary disorder. For prophylactic benefit, the compositions of some embodiments are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though the disease has not been diagnosed.

A prodrug means a compound that, in some embodiments, is converted under physiological conditions or by solvolysis to a biologically active compound as described herein. Thus, the term prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable. The prodrug is usually inactive when administered to a subject, however it is converted in vivo to the active compound, for example by hydrolysis. A compound in prodrug form often provides solubility, tissue compatibility, or delayed release advantages in the mammalian body (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam ).

Abbreviations used in this document have their usual meaning in the field of chemistry and biology. The following abbreviations have the indicated meaning throughout the text

Na ₂ HPO ₄ - sodium hydrogen phosphate,

AcOH - acetic acid, aq. - aqueous, NH ₄ Cl - ammonium chloride, DCM - dichloromethane, DMPU - 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, ESI - electrospray ionization, EtOAc - ethyl acetate, g - grams, h - hour,

LCMS - liquid chromatography with mass spectrometry,

LDA - lithium diisopropylamide,

MgSO ₄ - magnesium sulfate,

- 16 041590 m / s - the ratio of mass and charge, mg - milligram, MeOH - methanol, min - minute, NMR - nuclear magnetic resonance, RT or rt - room temperature, sat. - saturated, NaHCO3 - sodium bicarbonate, NaBH4 - sodium borohydride, Na2CO3 - sodium carbonate, NaCl - sodium chloride, Na2SO4 - sodium sulfate, Na2S2O3 - sodium thiosulfate, TFA - trifluoroacetic acid; and THF - tetrahydrofuran.

Substituted steroid derivatives.

The present document describes substituted steroid derivatives of the compound which are GR inhibitors. Such compounds and compositions containing such compounds are useful in the treatment of cancer, neoplastic disease, and diseases and disorders associated with elevated cortisol levels.

Certain embodiments provided herein describe a compound having the structure of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

^R1

Formula (I) wherein Ring A is heteroaryl, aryl, cycloalkyl, or heterocyclyl;

R ¹ is -H, -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halogen, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl , optionally substituted heterocyclylalkyl, optionally substituted hydroxyalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(O)OR ⁶ , -C(O)NR ⁴ R ⁵ , -OC(O)OR ⁶ , -OC(O)NR4R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -S(O)R ⁷ , -SR ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -P(O)(OR ⁶ )2, -P(O)(R ⁶ )2, -CN, -CO2H or -NO2;

each R ² is independently -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halogen, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted hydroxyalkyl, -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁴ R ⁵ , -OC(O)OR ⁶ , -OC(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -S(O)R ⁷ , -SR ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -CN, -CO2H or -NO2;

R ³ is optionally substituted alkyl, halogen, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, -Si(R ⁶ )3, -OR ⁶ or -S(O)2R ⁷ ;

each R ⁴ and R ⁵ is independently -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -S(O)2R ⁷ , -C(O)N(R ¹³ )2, -C(O)R ⁶ or -C(O)OR ⁶ ; or

R ⁴ and R ⁵ connected to the same N atom are taken together with the N atom to which they are connected to form a substituted or unsubstituted heterocycle;

each R ⁶ is independently optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

R ⁷ is optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

- 17 041590 each R ⁸ and R ⁹ independently represents -H, optionally substituted alkyl, haloalkyl, halogen, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, -OH, -OR ⁶ , -NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , -CN, -S(O)2R ⁷ , -C(O)2H, -C(O)R ⁶ or C(O)OR ⁶ ; or

R ⁸ and R ⁹ are taken together with the atom to which they are attached to form a substituted or unsubstituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -NR ⁶ -, -S- and -S(O)2-;

each R ¹⁰ and R ¹¹ is independently -H, optionally substituted alkyl, halogen, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, -OH, -S(O)2R ⁷ , -C(O)2H, -C(O)R ⁶ or -C(O)OR ⁶ ; or

R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form a substituted or unsubstituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -NR ⁶ -, -S- and -S(O)2-;

R ¹² is hydrogen, optionally substituted alkyl, haloalkyl, deuteroalkyl, hydroxy, halogen, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroalkyl;

each R ¹³ is independently H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and n is 0, 1, 2, 3, or 4.

In some embodiments, Ring A is monocyclic or bicyclic heteroaryl, monocyclic or bicyclic aryl, monocyclic cycloalkyl, or monocyclic heterocyclyl;

R ¹ is -H, -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halogen, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted hydroxyalkyl , -C(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(OhR ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -P(O)(OR ⁶ )2, -CN or -CO2H;

each R ² is independently -NR ⁴ R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halo, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted hydroxyalkyl, -C(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -CN or -CO2H;

R ³ is optionally substituted alkyl, halogen, haloalkyl, deuteroalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, -Si(R ⁶ ) ₃ , -OR ⁶ or -S(O)2R ⁷ ;

each R ⁴ and R ⁵ is independently -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -S(O)2R ⁷ , -C(O)N(R ¹³ )2, -C(O)R ⁶ or -C(O)OR ⁶ ; or

R ⁴ and R ⁵ connected to the same N atom are taken together with the N atom to which they are connected to form a substituted or unsubstituted 4-, 5- or 6-membered heterocycle;

R ⁶ is optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

R ⁷ is optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

each R ⁸ and R ⁹ is independently -H, optionally substituted alkyl, haloalkyl, halogen, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, -OH, -S(O)2R ⁷ , -C(O)2H, -C(O)R ⁶ or -C(O)OR ⁶ ;

or R ⁸ and R ⁹ are taken together with the atom to which they are attached to form a substituted or unsubstituted 3-, 4-, 5- or 6-membered ring containing 0 or 1 heteroatom selected from the group consisting of -O- , -NH-, -NR ⁶ -, -S- and -S(O)2-;

each R ¹⁰ and R ¹¹ independently represents -H, optionally substituted alkyl, halogen, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, or -OH; or

R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form a substituted or unsubstituted 3-, 4-, 5-, or 6-membered ring containing 0 or 1 heteroatom selected from the group consisting of -O-, -NH-, -NR ⁶ -, -S- and -S(O) ₂ -;

R ¹² is hydrogen, optionally substituted alkyl, haloalkyl, hydroxy, halogen, optionally substituted carbocyclyl, or optionally substituted heteroalkyl;

each R ¹³ is independently H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and n is 0, 1, 2, 3, or 4.

In some embodiments, Ring A is aryl or bicyclic heteroaryl;

R ¹ is -NR4R ⁵ , halogen, -OR ⁶ , C1.6 alkyl, C1.6 fluoroalkyl, C3-6 carbocyclyl, C3-6 heterocyclyl, aryl, heteroaryl, -C(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -P(O)(R ⁶ )2, -P(O)(OR ⁶ )2 or -CN;

each R ² is independently -NR4R ⁵ , halogen, -OR ⁶ , C ₁ . ₆ alkyl, C ₁ . ₆ fluoroalkyl, C ₃ _ ₆ carbocyclyl, C ₁ . ₆ heteroalkyl, C ₃ _ ₆ heterocyclyl or -CN;

R ³ is C ₁ . ₆ alkyl, C ₁ . ₆ fluoroalkyl, carbocyclyl or heterocyclylalkyl;

each R ⁴ and R ⁵ is independently -H, C ₁ . ₆ alkyl, C ₁ . ₆ fluoroalkyl, C ₃ _ ₆ -carbocyclyl, C ₁ . ₆ carbocyclylalkyl, C ₂ _ ₆ -heterocyclyl, C ₁ . ₆ αkyl, C ₃ _ ₆ heterocyclyl, -S(O) ₂ R ⁷ or -C(O)N(R ¹³ ); or

R ⁴ and R ⁵ connected to the same N atom are taken together with the N atom to which they are connected to form a substituted or unsubstituted 4-, 5- or 6-membered heterocycle;

R ⁶ is alkyl;

R ⁷ is C ₁ . ₆ alkyl, C ₃ - ₆ carbocyclyl or phenyl optionally substituted with halogen or alkyl;

each R ⁸ and R ⁹ independently represents -H, C ₁ . ₆ alkyl, C ₁ . ₆ fluoroalkyl, halogen or C ₃ _ ₆ carbocyclyl;

each R ¹⁰ and R ¹¹ is independently —H or C ₁ .6alkyl;

R ¹² is hydrogen or C ₁ . ₆ alkyl;

each R ¹³ is independently hydrogen or C ₁ . ₆ alkyl; and n is 0, 1, 2, 3, or 4.

In some embodiments, Ring A is phenyl, 3-benzodioxyl, or 1,4-benzodioxanyl;

R ¹ is -NR ⁴ R ⁵ , halogen, -OR ⁶ , alkyl or fluoroalkyl;

each R ² is independently —NR ⁴ R ⁵ , halogen, alkyl, carbocyclyl, alkoxy, or —CN;

R ³ is C ₁ . ₆ alkyl, C ₁ . ₆ fluoroalkyl, carbocyclyl, deuteroalkyl or heteroalkyl;

each R ⁴ and R ⁵ independently represents -H, C ₁ . ₆ alkyl, heteroalkyl or -S(O) ₂ R ⁷ ; or

R ⁴ and R ⁵ connected to the same N atom are taken together with the N atom to which they are connected to form a substituted or unsubstituted 4-, 5- or 6-membered heterocycle;

R ⁶ is alkyl;

R ⁷ is C ₁ . ₆ alkyl, C ₃ _ ₆ carbocyclyl or phenyl optionally substituted with halogen or alkyl;

each R ⁸ and R ⁹ is independently -H or C ₁ . ₆ alkyl;

each R ¹⁰ and R ¹¹ independently represents -H;

R ¹² is hydrogen;

each R ¹³ is independently hydrogen or C ₁ . ₆ alkyl; and n is 0, 1, or 2.

In some embodiments, ring A is phenyl;

R ¹ is -NR ⁴ R ⁵ , -OR ⁶ , alkyl or fluoroalkyl;

each R ² is independently —NR ⁴ R ⁵ , halogen, alkyl;

R ³ is C ₁ . ₆ alkyl, C ₁ . ₆ fluoroalkyl, carbocyclyl, deuteroalkyl or heteroalkyl;

each R ⁴ and R ⁵ is independently —H, C ₁ .6 alkyl or heteroalkyl; or

R ⁴ and R ⁵ connected to the same N atom are taken together with the N atom to which they are connected to form a substituted or unsubstituted 4-, 5- or 6-membered heterocycle;

R ⁶ is alkyl;

R ⁷ is C ₁ . ₆ alkyl, C ₃ - ₆ carbocyclyl or phenyl optionally substituted with halogen or alkyl;

each R ⁸ and R ⁹ is independently -H or C ₁ . ₆ alkyl;

each R ¹⁰ and R ¹¹ independently represents -H;

R ¹² is hydrogen;

each R ¹³ is independently hydrogen or C ₁ . ₆ alkyl; and n is 0, 1, or 2.

- 19 041590

In some embodiments, ring A is 3-benzodioxylyl or

1,4-benzodioxanyl;

R ¹ is -H;

R ³ is C ₁ . ₆ alkyl;

each R ⁸ and R ⁹ is independently —H or O^alkyl;

each R ¹⁰ and R ¹¹ independently represents -H;

R ¹² is hydrogen;

each R ¹³ is independently hydrogen or C ₁ . ₆ alkyl; and n is 0.

For any possible embodiments of formula (I), the substituents are selected from a subset of the listed alternatives.

In some embodiments, Ring A is monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, or bicyclic heteroaryl. In some embodiments, Ring A is monocyclic heteroaryl or monocyclic aryl. In some embodiments, ring A is bicyclic heteroaryl or bicyclic aryl. In some embodiments, ring A is an N-linked heteroaryl. In some embodiments, ring A is a C-linked heteroaryl. In some embodiments, Ring A is aryl.

In certain embodiments, ring A is phenyl, naphthyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzisoxazolyl, benzothienyl, benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl. In some embodiments, R ¹ is furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. In some embodiments, Ring A is pyrimidinyl, pyridinyl, pyrazinyl, triazinyl, or thiazolyl. In certain embodiments, ring A is a C-linked imidazolyl. In certain embodiments, ring A is an N-linked imidazolyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyrimidinyl optionally substituted with alkyl or alkoxy. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is triazinyl. In some embodiments, ring A is thiazolyl.

In some embodiments, Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ring A is phenyl.

In some embodiments, ring A is a bicyclic heteroaryl. In certain embodiments, Ring A is an optionally substituted 3-benzodioxyl or 1,4-benzodioxanyl. In some embodiments, Ring A is an unsubstituted 3-benzodioxyl or 1,4-benzodioxanyl. In some embodiments, Ring A is phenyl, 3-benzodioxyl, or 1,4-benzodioxanyl.

In some embodiments, R ¹ is -H, -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halogen, optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted hydroxyalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(O)NR4R ⁵ , -OC(O)OR ⁶ , -OC(O)NR4R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -S(O)R ⁷ , -SR ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -P(O)(OR ⁶ )2, -P(O)(R ⁶ )2, -CN or -NO2. In some embodiments, R ¹ is -H, -NR4R ⁵ , halogen, -OR ⁶ , optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -C(O)NR4R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -P(O)(R ⁶ )2, -P(O)(OR ⁶ )2 or -CN. In some embodiments, R ¹ is -H, -NR4R ⁵ , optionally substituted alkylNR4R ⁵ , halogen, -OR ⁶ , optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, -C(O)R ⁶ , -C(O)NR4R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O) ₂ R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -CN or -СО2Н. In some embodiments, R ¹ is -NR4R ⁵ , halogen, -OR ⁶ , alkyl, fluoroalkyl, carbocyclyl, heteroalkyl, heterocyclyl, -S(O) ₂ NR ⁴ R ⁵ , -S(O) 2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ or -CN. In some embodiments, R ¹ is -NR4R ⁵ , halo, -OR ⁶ , C ₁ . ₆ alkyl, C ₁ . ₆ fluoroalkyl, C ₃ _ ₆ carbocyclyl,

- 20 041590

C ₃ - ₆ heterocyclyl, aryl, heteroaryl, -C(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -P(O)(R ⁶ )2, -P(O)(OR ⁶ )2 or -CN. In some embodiments, R ¹ is -NR ⁴ R ⁵ , halo, -OR ⁶ , -S(O)2NR ⁴ R ⁵ , -P(O)(R ⁶ )2 or -P(O)(OR ⁶ ) 2. In certain embodiments, R ¹ is -NR4R ⁵ , halogen, -OR ⁶ , alkyl, or fluoroalkyl. In certain embodiments, R ¹ is halo, -OR ⁶ , or alkyl. In other embodiments, R ¹ is -NMe2, -NHMe, -NH2, -NEt2, -NHEt, -NPr2, -NHPr, -N(i-Pr2), -NH(i-Pr), -NBu2, -NHBu , -NEt2, -NHEt, -N(i-Bu2), -NH(i-Bu), -NMeEt, -NMePr, -N(Me)(i-Pr), -NMePr, -N(Me)(Bu ), -NMeBu, -NEtPr, -N(Et)(i-Pr), -N(Et)(Bu), -NEtBu, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl , methoxy, ethoxy, propoxy, isopropoxy, morpholino or pyrrolidino. In certain embodiments, R ¹ is C 1-6 alkyl, fluoroalkyl, C _3-6 carbocyclyl, or C _3-6 heterocyclyl. In some embodiments, R ¹ is -H. In some embodiments, R ¹ is -NR4R ⁵ . In some embodiments, R ¹ is -NMe2. In some embodiments, R ¹ is -NHMe. In some embodiments, R ¹ is -NH2. In some embodiments, R ¹ is -NMeEt. In some embodiments, R ¹ is -NEt2. In some embodiments, R ¹ is halogen. In some embodiments, R ¹ is fluoro. In some embodiments, R ¹ is chlorine. In some embodiments, R ¹ is bromine. In some embodiments, R ¹ is C1. ₆ alkyl. In some embodiments, R ¹ is methyl. In some embodiments, R ¹ is ethyl. In some embodiments, R ¹ is propyl. In some embodiments, R ¹ is isopropyl. In some embodiments, R ¹ is carbocyclyl. In some embodiments, R ¹ is cyclopropyl. In some embodiments, R ¹ is cyclobutyl. In some embodiments, R ¹ is cyclopentyl. In some embodiments, R ¹ is cyclohexyl. In some embodiments, R ¹ is -OR ⁶ . In some embodiments, R ¹ is methoxy. In some embodiments, R ¹ is ethoxy. In some embodiments, R ¹ is propoxy. In some embodiments, R ¹ is isopropoxy. In some embodiments, R ¹ is heterocyclyl. In some embodiments, R ¹ is azetadino, morpholino, thiomorpholino, piperidino, piperazino, or pyrrolidino. In some embodiments, R ¹ is morpholino. In some embodiments, R ¹ is pyrrolidino. In some embodiments, R ¹ is azetadino.

In other embodiments, R ¹ is an optionally substituted monocyclic aryl, an optionally substituted bicyclic aryl, an optionally substituted monocyclic heteroaryl, or an optionally substituted bicyclic heteroaryl. In certain embodiments, R ¹ is phenyl, naphthyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl. In some embodiments, R ¹ is furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. In some embodiments, R ¹ is pyrimidinyl, pyridinyl, pyrazinyl, triazinyl, or thiazolyl. In certain embodiments, R ¹ is C-linked imidazolyl. In certain embodiments, R ¹ is an N-linked imidazolyl. In some embodiments, R ¹ is pyrimidinyl. In some embodiments, R ¹ is pyrimidinyl optionally substituted with alkyl or alkoxy. In some embodiments, R ¹ is pyrazinyl. In some embodiments, R ¹ is triazinyl. In some embodiments, R ¹ is thiazolyl.

In certain embodiments, R ¹ is optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In certain embodiments, R ¹ is optionally substituted with halogen, alkyl, or alkoxy. In some embodiments, R ¹ is optionally substituted with fluorine or C _1-6 alkyl. In some embodiments, R ¹ is optionally substituted with fluorine or methyl. In some embodiments, R ¹ is optionally substituted with methyl or methoxy.

- 21 041590

In some embodiments, each R ² is independently -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halo, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted hydroxyalkyl, -C(O)R ⁶ , -C(O)NR ⁴ R ⁵ , -S(O) ₂ NR ⁴ R ⁵ , -S(O)2R ⁷ , - NR ⁴ S(O)2NR ⁴ R ⁵ or -CN. In some embodiments, each R ² is independently -NR4R ⁵ , alkyl-NR ⁴ R ⁵ , halo, -OR ⁶ , -OH, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, -C(O )R ⁶ , -C(O)NR ⁴ R ⁵ , -S(O) ₂ NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ or -CN. In some embodiments, each R ² is independently -NR4R ⁵ , halogen, -OR ⁶ , optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, -C(O)NR ⁴ R ⁵ , -S (O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -CN or -CO2H. In certain embodiments, each R ² is independently -NR4R ⁵ , halogen, -OR ⁶ , -OH, optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted hydroxyalkyl, -S(O) _2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ or -CN. In some embodiments, each R ² is independently -NR4R ⁵ , halogen, -OR ⁶ , alkyl, fluoroalkyl, carbocyclyl, heteroalkyl, heterocyclyl, -S(O) ₂ NR ⁴ R ⁵ , -NR ⁴ S(O)2NR ⁴ R ⁵ or -S(O)2R ⁷ . In some embodiments, each R ² is independently -NR4R ⁵ , C1.6-alkyl-NR ⁴ R ⁵ , halo, -OR ⁶ , -OH, C1. ₆ αkyl, C ₁ . ₆ fluoroalkyl, C ₃ . ₆ carbocyclyl, C ₁ . ₆ alkyl-C ₃ . ₆ carbocyclyl, C ₁ . ₆ heteroalkyl, C _3-6 heterocyclyl, C ₁ . ₆ alkyl-C ₃ . ₆ heterocyclyl, C ₁ . ₆ hydroxyalkyl or -CN. In some embodiments, each R ² is independently -C(O)R ⁶ , -C(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ^{7 ,} or -CN. In some embodiments, each R ² is independently —NR ⁴ R ⁵ , halo, —OR ⁶ , C1. ₆ αkyl, C ₁ . ₆ fluoroalkyl, C ₃ _ ₆ carbocyclyl, C ₁ . ₆ heteroalkyl, C ₃ _ ₆ -heterocyclyl or -CN. In some embodiments, each R ² is independently —NR ⁴ R ⁵ , halo, alkyl, carbocyclyl, alkoxy, or —CN. In some embodiments, each R ² is independently —NR4R ⁵ , halogen, alkyl, or alkoxy. In some embodiments, each R ² is independently methyl, methoxy, ethyl, propyl, isopropyl, cyclopropyl, fluorine, chlorine, or -NMe2. In some embodiments, each R ² is -NMe2, -NHMe, -NH ₂ , -NEt ₂ , -NHEt, -NPr ₂ , -NHPr, -N(i-Pr ₂ ), -NH(i-Pr), -NBu ₂ , -NHBu, -NEt2, -NHEt, -N(i-Bu2), -NH(i-Bu), -NMeEt, -NMePr, -N(Me)(i-Pr), -NMePr, - N(Me)(Bu), -NMeBu, -NEtPr, -N(Et)(i-Pr), -N(Et)(Bu), -NEtBu, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, morpholino or pyrrolidino. In some embodiments, each R ² is independently methyl, methoxy, isopropyl, cyclopropyl, fluorine, chlorine, or -NMe2. In some embodiments, R ² is methoxy. In some embodiments, R ² is methyl. In some embodiments, R ² is ethyl. In some embodiments, R ² is isopropyl. In some embodiments, R ² is propyl. In some embodiments, R ² is cyclopropyl. In some embodiments, R ² is cyclobutyl. In some embodiments, R ² is fluoro. In some embodiments, R ² is chlorine. In some embodiments, R ² is -NMe ₂ . In some embodiments, R ² is -Nth. In some embodiments, R ² is -NHMe. In some embodiments, R ² is -NMeEt.

In certain embodiments, each R ² is independently optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, each R ² is independently optionally substituted with fluorine or Cl. ₆ alkyl. In some embodiments, each R ² is independently optionally substituted with fluorine or methyl.

In some embodiments, R ³ is alkyl, halogen, haloalkyl, deuteroalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, Si(R ⁶ )3, -OR ⁶ or -S(O)2R ⁷ . In some embodiments, R ³ is alkyl, halogen, haloalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, or heteroalkyl. In some embodiments, R ³ is an optionally substituted C1. 10alkyl, halogen, haloalkyl, deuteroalkyl, carbocyclyl, optionally substituted aryl or optionally substituted heteroaryl, where R ³ is optionally substituted with halogen, alkyl, alkoxy, hydroxy, NR4R ⁵ or -S(O)2R ⁷ . In some embodiments, R ³ is C1.6 alkyl, C1-6 haloalkyl, C1.6 deuteroalkyl, C3-6 carbocyclyl, C3_6 carbocyclyl-C1_6 alkyl, C3-6 heterocyclyl, C3_6 heterocyclyl-C1_6 alkyl. In some embodiments, R ³ is alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, or heteroalkyl. In some embodiments, R ³ is C1. ₆ alkyl, C ₁ . ₆ fluoroalkyl, carbocyclyl or heterocyclylalkyl. In certain embodiments, R ³ is C _{3 -8} alkyl or C 1 -bfluoroalkyl. In some embodiments, R ³ is

C1 is alkyl. In some embodiments, R ³ is C _1-8 alkyl.

In some embodiments, R ³ is C2-8 alkyl. In some embodiments, R ³ is C3-6 alkyl. In some embodiments, R ³ is methyl. In some embodiments, R ³ is ethyl. In some embodiments, R ³ is propyl. In some embodiments, R ³ is isopropyl. In some embodiments, R ³ is tert-butyl. In some embodiments, R ³ is butyl. In some embodiments, R ³ is isobutyl. In some embodiments, R ³ is sec-butyl. In some embodiments, R ³ is carbocyclyl. In some embodiments, R ³ is cyclopropyl. In some embodiments, R ³ is cyclobutyl. In some embodiments, R ³ is cyclopentyl. In some embodiments, R ³ is cyclohexyl. In some embodiments, R ³ is halogen. In some embodiments, R ³ is fluorine. In some embodiments, R ³ is chlorine. In some embodiments, R ³ is bromine. In some embodiments, R ³ is trifluoromethyl. In some embodiments, R ³ is hydroxyalkyl. In some embodiments, R ³ is deuteromethyl. In some embodiments, R ³ is -Si(R ⁶ )3. In some embodiments, R ³ is -Si(Me)3. In some embodiments, R ³ is -Si(Ph) ₃ . In some embodiments, R ³ is -OR ⁶ . In some embodiments, R ³ is -S(O)2R ⁷ .

In other embodiments, R ³ is optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, R ³ is phenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. In some embodiments, R ³ is phenyl optionally substituted with halogen, alkyl, alkoxy, hydroxy, -NR ⁴ R ⁵ or -S(O) 2 R ⁷ . In some embodiments, R ³ is pyridinyl optionally substituted with halogen, alkyl, alkoxy, hydroxy, -NR4R ⁵ or -S(O)2R ⁷ . In some embodiments, R ³ is phenyl. In some embodiments, R ³ is pyridinyl.

In certain embodiments, R ³ is optionally substituted with halogen, alkyl, hydroxy, alkoxy, —NR ⁴ R ⁵ ; -S(O)2R ⁷ or fluoroalkyl. In some embodiments, R ³ is optionally substituted with chlorine, fluorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, dimethylamino, diethylamino, methylamino, amino, -S(O)2Me or trifluoromethyl. In certain embodiments, R ³ is optionally substituted with chlorine, fluorine, methyl, hydroxy, methoxy, dimethylamino, —S(O)2Me, or trifluoromethyl.

In some embodiments, each R ⁴ and R ⁵ is independently -H, optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, -S(O)2R ⁷ or -C(O )N(R ¹³ )2. In some embodiments, each R ⁴ and R ⁵ is independently -H, C1.6alkyl, C1.6fluoroalkyl, C3-6carbocyclyl, C1.6carbocyclylalkyl, C2-6heterocyclyl, C1.6alkyl-C3.6heterocyclyl, -S(O)2R ⁷ or -C(O)N(R ¹³ )2. In some embodiments, each R ⁴ and R ⁵ is independently -H, C1. ₆ alkyl, C ₁ . ₆ fluoroalkyl, C _3-6 carbocyclyl, C _3-5 heterocyclyl, or —S(O) ₂ R ⁷ . In some embodiments, each R ⁴ and R ⁵ is independently -H, C1_6alkyl, or -S(O)2R ⁷ . In some embodiments, each R ⁴ and R ⁵ is independently -H or alkyl. In some embodiments, each R ⁴ and R ⁵ is independently -H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl, or -S(O)2R ⁷ . In some embodiments, each R ⁴ and R ⁵ is independently —H, methyl, ethyl, propyl, or isopropyl. In some embodiments, R ⁴ and R ⁵ are -H. In some embodiments, R ⁴ and R ⁵ are methyl. In some embodiments, R ⁴ is methyl and R ⁵ is ethyl. In some embodiments, R ⁴ is methyl and R ⁵ is propyl. In some embodiments, R ⁴ is methyl and R ⁵ is isopropyl. In some embodiments, R ⁴ is H and R ⁵ is isopropyl. In some embodiments, each R ⁴ and R ⁵ is independently -H or -C(O)N(R ¹³ ) ₂ .

In other embodiments, R ⁴ and R ⁵ attached to the same N atom are

- 23 041590 together with the N atom to which they are connected to form a substituted or unsubstituted 4-, 5- or 6-membered heterocyclic ring, additionally containing 0-3 heteroatoms selected from -O-, -NH-, -NR ⁶ -, -S- and -S(O)2-. In some embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form a 4-, 5-, or 6-membered heterocycle further containing 0 or 1 oxygen in as a heteroatom. In other embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form a substituted or unsubstituted 4-, 5-, or 6-membered heterocyclic ring further containing 1 a heteroatom selected from -O-, -NH-, -NR ⁶ -, -S- and -S(O)2-. In other embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form a 4-, 5-, or 6-membered heterocyclic ring further containing 1 oxygen as heteroatom. In other embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form a 4-, 5-, or 6-membered ring. In some embodiments, the 4-, 5-, or 6-membered ring is

In certain embodiments, each R ⁴ and R ⁵ is independently optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, each R ⁴ and R ⁵ is independently optionally substituted with fluorine or C _1-6 alkyl. In some embodiments, each R ⁴ and R ⁵ is independently optionally substituted with fluorine or methyl.

In some embodiments, R ⁶ is optionally substituted alkyl, fluoroalkyl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl. In some embodiments, R ⁶ is optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl. In some embodiments, R ⁶ is alkyl, aryl, carbocyclyl, or heterocyclyl. In some embodiments, R ⁶ is alkyl, carbocyclyl, or heterocyclyl. In some embodiments, R ⁶ is alkyl, carbocyclyl, or fluoroalkyl. In some embodiments, R ⁶ is C 1-6 alkyl, C 1-6 fluoroalkyl, C 3-6 carbocyclyl, or C 3-6 heterocyclyl. In certain embodiments, R ⁶ is C 1-6 alkyl. In certain embodiments, R ⁶ is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl. In some embodiments, R ⁶ is an optionally substituted phenyl.

In some embodiments, R ⁷ is alkyl, carbocyclyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heterocyclyl. In some embodiments, R ⁷ is C1-6 alkyl, C3-6 carbocyclyl, or aryl optionally substituted with halo or alkyl. In some embodiments, R ⁷ is C 1-6 alkyl, C _3-6 carbocyclyl, or phenyl optionally substituted with halogen or alkyl. In some embodiments, R ⁷ is an optionally substituted benzyl. In some embodiments, R ⁷ is C3-6 carbocyclyl. In some embodiments, R ⁷ is phenyl. In some embodiments, R ⁷ is phenyl substituted with 1-4 €1-6alkyl or fluorine substituents. In some embodiments, R ⁷ is phenyl substituted with a C _1-6 alkyl or fluorine substituent. In some embodiments, R ⁷ is alkyl, carbocyclyl, aralkyl, or heterocyclyl.

In certain embodiments, R ⁷ is optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R ⁷ is optionally substituted with fluoro or C _1-6 alkyl. In some embodiments, R ⁷ is optionally substituted with fluorine or methyl.

In some embodiments, each R ⁸ and R ⁹ is independently -H, C1-6 alkyl, C1-6 haloalkyl, halo, C3-6 carbocyclyl, C1-6 alkyl-C3-6 carbocyclyl, C1-6 heteroalkyl, C3-6 heterocyclyl, C1-6 alkyl- C3-6heterocyclyl, -OH, -OR ⁶ , -NR4R ⁵ , -C(O)NR ⁴ R ⁵ , -CN, -S(O)2R ⁷ , -C(O)2H, -C(O)R ⁶ or -C(O)OR ⁶ or R ⁸ and R ⁹ are taken together with the atom to which they are attached to form a ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -NR ⁶ -, -S- and -S(O) ₂ -.

- 24 041590

In some embodiments, each R ⁸ and R ⁹ is independently -H, C1.6αkyl, halo, C3-6carbocylyl, methoxy, ethoxy, propoxy, isopropoxy, -NH2, -NMe2, -NHMe, -NEt2, -C(O )NH2, -C(O)NMe2, -C(O)NHMe or -CN. In some embodiments, each R ⁸ and R ⁹ is independently —H, C1-6 alkyl, C _1-6 fluoroalkyl, halogen, or C _3-6 carbocyclyl. In some embodiments, each R ⁸ and R ⁹ is independently -H, C1-6αkyl, or C3-6carbocyclyl. In some embodiments, each R ⁸ and R ⁹ is independently -H or C1-6 alkyl. In some embodiments, R ⁸ is -H and R ⁹ is C1-6 alkyl, C1-6 fluoroalkyl, or C3-6 carbocyclyl. In some embodiments, R ⁸ is -H and R ⁹ is alkyl. In some embodiments, R ⁸ is C1-6 alkyl, C _1-6 fluoroalkyl, or C _3-6 carbocyclyl, and R ⁹ is -H. In some embodiments, R ⁸ is methyl and R ⁹ is -H. In some embodiments, R ⁸ and R ⁹ are -H. In some embodiments, R ⁸ and R ⁹ are C _1-6 αkil. In some embodiments, R ⁸ and R ⁹ are methyl.

In other embodiments, R ⁸ and R ⁹ are taken together with the atom to which they are attached to form a 3-, 4-, 5-, or 6-membered ring containing 0-2 heteroatoms selected from the group consisting of -O- , -NH-, -NR ⁶ -, -S- and -S(O) ₂ -. In some embodiments, R ⁸ and R ⁹ are taken together with the atom to which they are attached to form a 3-, 4-, 5-, or 6-membered carbocyclic ring.

In some embodiments, each R ¹⁰ and R ¹¹ is independently -H, alkyl, halogen, haloalkyl, carbocyclyl, heteroalkyl, or -OH. In other embodiments, each R ¹⁰ and R ¹¹ is independently —H, C1.6alkyl, halogen, C1.6alkoxy, or —OH. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or C1. ₆ alkyl. In certain embodiments, each R ¹⁰ and R ¹¹ is independently —H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In certain embodiments, each R ¹⁰ and R ¹¹ is independently —H, fluoro, or methyl. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or methyl. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or fluorine. In certain embodiments, both R ¹⁰ and R ¹¹ are -H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or methoxy. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or -OH. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or fluoro. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or chlorine.

In some embodiments, each R ¹⁰ and R ¹¹ is independently -H, alkyl, halo, haloalkyl, carbocyclyl, heteroalkyl, or -OH, where at least one of R ¹⁰ or R ¹¹ is not H. In other embodiments, each R ¹⁰ and R ¹¹ is independently -H, C1_6alkyl, halogen, C1.6αlkoxy, or -OH, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently - H or C1. ₆ alkyl, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H, fluoro, or methyl, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or methyl, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or fluoro, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or methoxy, where at least one of R ¹⁰ or R ¹¹ is not H. According to certain In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or -OH, wherein at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or fluoro where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or chlorine, where at least one of R ¹⁰ or R ¹¹ is not H.

In some embodiments, R ¹⁰ and R ¹¹ are methyl. In some embodiments, R ¹⁰ and R ¹¹ are ethyl. In some embodiments, R ¹⁰ and R ¹¹ are propyl. In some embodiments, R ¹⁰ and R ¹¹ are fluorine. In some embodiments, R ¹⁰ and R ¹¹ are chlorine. In some embodiments, R ¹⁰ and R ¹¹ are bromine.

In some embodiments, R ¹⁰ and R ¹¹ are methoxy. In some embodiments, R ¹⁰ and R ¹¹ are ethoxy. In some embodiments, R ¹⁰ and R ¹¹ are —OH.

- 25 041590

In some embodiments, R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form a 3-, 4-, 5-, or 6-membered ring. In some embodiments, R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form cyclopropyl.

In certain embodiments, R ¹⁰ and R ¹¹ are optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R ¹⁰ and R ¹¹ are optionally substituted with fluorine or C ₁ . ₆ alkyl. In some embodiments, R ¹⁰ and R ¹¹ are optionally substituted with fluorine or methyl.

In some embodiments, R ¹² is hydrogen, C1.6 alkyl, C1.6 haloalkyl, C1.6 deuteroalkyl, C3-6 carbocyclyl, C3.6 carbocyclyl-C1.6 alkyl, C3-6 heterocyclyl, C3.6 heterocyclyl-C1.6 alkyl. In some embodiments, R ¹² is hydrogen, alkyl, haloalkyl, hydroxy, halogen, carbocyclyl, or heteroalkyl. In some embodiments, R ¹² is hydrogen, C1. ₆ alkyl, C ₁ . ₆ fluoroalkyl, carbocyclyl or heterocyclylalkyl. In certain embodiments, R ¹² is C1.6αkyl or C1.6fluoroalkyl. In some embodiments, R ¹² is C1. ₆ αkyl, C ₁ . ₆ haloalkyl, C ₁ . ₆ deuteroalkyl, C ₃ _ ₆ carbocyclyl, C ₃ . ₆ carbocyclyl-C ₁ . ₆ alkyl, C ₃ _ ₆ heterocyclyl, C ₃ . ₆ heterocyclyl-C ₁ . ₆ alkyl. In some embodiments, R ¹² is alkyl, haloalkyl, hydroxy, halogen, carbocyclyl, or heteroalkyl. In some embodiments, R ¹² is C1.6 alkyl, C1.6 fluoroalkyl, carbocyclyl, or heterocyclylalkyl. In certain embodiments, R ¹² is C1. ₆ alkyl or C ₁ . ₆ fluoroalkyl. In certain embodiments, R ¹² is hydrogen. In some embodiments, R ¹² is C1.6αkyl. In some embodiments, R ¹² is C1-3 alkyl. In some embodiments, R ¹² is C2-8 alkyl. In some embodiments, R ¹² is _C3-6 alkyl. In some embodiments, R ¹² is methyl. In some embodiments, R ¹² is ethyl. In some embodiments, R ¹² is propyl. In some embodiments, R ¹² is isopropyl. In some embodiments, R ¹² is tert-butyl. In some embodiments, R ¹² is butyl. In some embodiments, R ¹² is isobutyl. In some embodiments, R ¹² is sec-butyl. In some embodiments, R ¹² is carbocyclyl. In some embodiments, R ¹² is cyclopropyl. In some embodiments, R ¹² is cyclobutyl. In some embodiments, R ¹² is cyclopentyl. In some embodiments, R ¹² is cyclohexyl. In some embodiments, R ¹² is trifluoromethyl. In some embodiments, R ¹² is hydroxyalkyl. In some embodiments, R ¹² is deuteromethyl.

In certain embodiments, R ¹² is optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R ¹² is optionally substituted with fluorine or C ₁ . ₆ alkyl. In some embodiments, R ¹² is optionally substituted with fluorine or methyl.

In some embodiments, each R ¹³ is independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, each R ¹³ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, or optionally substituted aryl. In some embodiments, each R ¹³ is independently optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, or heteroaryl. In some embodiments, each R ¹³ is independently alkyl or aryl. In some embodiments, each R ¹³ is independently hydrogen or C ₁ . ₆ alkyl. In some embodiments, each R ¹³ is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl. In some embodiments, each R ¹³ is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, or t-butyl. In some embodiments, each R ¹³ is independently hydrogen or methyl. In some embodiments, R ¹³ is H. In other embodiments, R ¹³ is alkyl. In other embodiments, R ¹³ is aryl.

In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1

- 26 041590 or 2. In some embodiments, n is 3 or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

Any combination of the groups described above for various variables is provided herein. In the present description, the groups and their substituents are selected by a person skilled in the art to obtain stable fragments and compounds.

According to some embodiments, rasterized by the following structure of formula (Ia):

R The compounds described herein are ha-

^R3

Formula (la)

In some embodiments, those described are characterized by the following structure of formula (Ib):

R ¹ of the present document compounds ha-

^R3

Rio ^R11

Formula (IB)

According to some embodiments, rasterized by the following structure of formula (Ic):

the compounds described in this document have

^R3

RlO R ¹¹

Formula (1s)

According to some embodiments, the formula (Id) is characterized by the following structure:

^R2

R The compounds described herein are ha-

^R3

Rio ^R11

Formula (Id)

According to some embodiments, rasterized by the following structure of formula (Ie):

R The compounds described herein are ha-

^R3

Formula (1e)

In some embodiments, those described are characterized by the following structure of formula (If):

this document, the connections ha- 27 041590

In some embodiments, the compounds described herein are characterized by the following structure of formula (Ig):

Formula (If)

Formula (Ig)

According to some embodiments, those described in are rasterized by the following structure of formula (Ih):

y^-R ² he .R ³

I JI Mel ^R1 ^i?tz ^R8 j I η J η

R10 R^

Formula (Ih)

According to some embodiments, those described in are rasterized by the following structure of formula (Ii):

^R2

RV^^R ² OH ^.R ³

G |l Mel r ⁹

I I η I h

Rio ^R11

Formula (Ii) herein of compounds xa In some embodiments, the compounds described herein are characterized by the following structure of formula (Ij):

^R2

Formula (Ij)

In some embodiments, the compounds described herein are characterized by the following structure of formula (Ik):

Formula (Ik)

In some embodiments, the compounds described herein are characterized by the following structure of formula (Im):

Formula (Im)

In some embodiments, the compounds described herein are characterized by the following structure of formula (In):

^R2

Formula (In)

In some embodiments, those described in are characterized by the following structure of formula (Io):

this document connections ha-

Formula (1o)

In some embodiments, those described in are characterized by the following structure of formula (Ip):

R ² of the present document compounds ha-

Formula (1r)

In some embodiments, the compounds described herein are characterized by the following structure of formula (Iq):

Formula (Iq)

In some embodiments, the compounds described herein are characterized by the following structure of formula (Ir) or formula (Is):

- 29 041590

Formula (Ir) Formula (Is) wherein Ring B is an optionally substituted fused carbocyclyl, an optionally substituted fused heterocyclyl, an optionally substituted fused aryl, or an optionally substituted fused heteroaryl; and n is 0, 1, 2, or 3.

Some embodiments provided herein describe a compound having the structure of formula (II), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

^R1

Formula (II) wherein Ring A is heteroaryl, aryl, cycloalkyl or heterocyclyl;

R ¹ is -H, -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halogen, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl , optionally substituted heterocyclylalkyl, optionally substituted hydroxyalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(O)OR ⁶ , -C(O)NR4R ⁵ , -OC(O)OR ⁶ , -OC(O)NR ⁴ R ⁵ , -S(ObNR ⁴ R ⁵ , -S(ObR ⁷ , -S(O)R ⁷ , -SR ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -P(O)(OR ⁶ )2, -P(O)(R ⁶ )2, -CN, -CO ₂ H or -NO2;

each R ² is independently -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halogen, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted hydroxyalkyl, -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁴ R ⁵ , -OC(O)OR ⁶ , -OC(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -S(O)R ⁷ , -SR ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -CN, -CO2H or -NO2;

R ³ is optionally substituted alkyl, halogen, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, -Si(R ⁶ )3, -OR ⁶ or -S(O)2R ⁷ ;

each R ⁴ and R ⁵ is independently -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -S(O)2R ⁷ , -C(O)N(R ¹³ )2, -C(O)R ⁶ or -C(O)OR ⁶ ; or

R ⁴ and R ⁵ connected to the same N atom are taken together with the N atom to which they are connected to form a substituted or unsubstituted heterocycle;

each R ⁶ is independently optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

R ⁷ is optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

each R ¹³ is independently H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

R ¹⁴ is hydrogen or methyl; and n is 0, 1, 2, 3, or 4.

According to some embodiments

- 30 041590 ring A is aryl or bicyclic heteroaryl;

R ¹ is -NR4R ⁵ , halogen, -OR ⁶ , C^alkyl, C _1-6 fluoroalkyl, C _3-6 carbocyclyl,

C _3-6 heterocyclyl, aryl, heteroaryl, -C(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -P(O)(R ⁶ )2,

-P(O)(OR ⁶ )2 or -CN;

each R2 is independently -NR ⁴ R ⁵ , halogen, -OR ⁶ , C _1-6 alkyl, C _{1 -6} fluoroalkyl, C ₃ _ ₆ carbocyclyl, C 1_ ₆ heteroalkyl, C ₃ _ ₆ heterocyclyl, or -CN;

R ³ is _{C1_6} alkyl, _{C1_6} fluoroalkyl, carbocyclyl or heterocyclylalkyl;

each _R ⁴ and R ⁵ is independently -H, _{C1_6} alkyl, _{C1_6} fluoroalkyl _{, C3_6} carbocyclyl, _C1-6 carbocyclylalkyl, _{C2_6} heterocyclyl, _C1-6 alkyl, _{C3_6} heterocyclyl, -S (O)2R ⁷ or -C(O)N(R ¹³ ); or

R ⁴ and R ⁵ connected to the same N atom are taken together with the N atom to which they are connected to form a substituted or unsubstituted 4-, 5- or 6-membered heterocycle;

R ⁶ is alkyl;

R ⁷ is C _1-6 alkyl, C ₃ _ ₆ carbocyclyl or phenyl optionally substituted with halogen or alkyl;

each R ¹³ is independently hydrogen or C1_ ₆ alkyl;

R ¹⁴ is hydrogen or methyl; and n is 0, 1, 2, 3, or 4.

In some embodiments, Ring A is phenyl, 3-benzodioxyl, or 1,4-benzodioxanyl;

R ¹ is -NR4R ⁵ , halogen, -OR ⁶ , alkyl or fluoroalkyl;

each R ² is independently -NR4R ⁵ , halogen, alkyl, carbocyclyl, alkoxy, or -CN;

R ³ is C _1-6 alkyl, C _1-6 fluoroalkyl, carbocyclyl, deuteroalkyl or heteroalkyl;

each R ⁴ and R ⁵ is independently -H, C _1-6 alkyl, heteroalkyl or -S(O) ₂ R ⁷ ; or

R ⁴ and R ⁵ connected to the same N atom are taken together with the N atom to which they are connected to form a substituted or unsubstituted 4-, 5- or 6-membered heterocycle;

R ⁶ is alkyl;

R ⁷ is _{C1_6} alkyl, _{C3_6 carbocyclyl} or phenyl optionally substituted with halogen or alkyl;

each R ¹³ is independently hydrogen or C1_ ₆ alkyl;

R ¹⁴ is hydrogen; and n is 0, 1, or 2.

In some embodiments, ring A is phenyl;

R ¹ is -NR ⁴ R ⁵ , -OR ⁶ , alkyl or fluoroalkyl;

each R ² is independently —NR ⁴ R ⁵ , halogen, alkyl;

R ³ is C _1-6 alkyl, C _1-6 fluoroalkyl, carbocyclyl, deuteroalkyl or heteroalkyl;

each R ⁴ and R ⁵ is independently —H, C _1-6 alkyl or heteroalkyl; or

R ⁴ and R ⁵ connected to the same N atom are taken together with the N atom to which they are connected to form a substituted or unsubstituted 4-, 5- or 6-membered heterocycle;

R ⁶ is alkyl;

R ⁷ is _{C1_6} alkyl, _{C3_6 carbocyclyl} or phenyl optionally substituted with halogen or alkyl;

each R ¹³ is independently hydrogen or C _1-6 alkyl;

R ¹⁴ is hydrogen; and n is 0, 1, or 2.

In some embodiments, ring A is 3-benzodioxyl or 1,4-benzodioxanyl;

R ¹ is -H;

R ³ is C1_ ₆ alkyl;

each R ¹³ is independently hydrogen or C1_ ₆ alkyl;

R ¹⁴ is hydrogen; and n is 0.

For any possible embodiments of formula (II), the substituents are selected from a subset of the listed alternatives.

In some embodiments, Ring A is monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, or bicyclic heteroaryl. In some embodiments, Ring A is monocyclic heteroaryl or monocyclic aryl. In some embodiments, ring A is bicyclic heteroaryl or bicyclic aryl. In some embodiments, ring A is an N-linked heteroaryl. In some embodiments, ring A is a C-linked heteroaryl. In some embodiments, Ring A is aryl.

- 31 041590

In certain embodiments, ring A is phenyl, naphthyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzisoxazolyl, benzothienyl, benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl. In some embodiments, R ¹ is furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. In some embodiments, Ring A is pyrimidinyl, pyridinyl, pyrazinyl, triazinyl, or thiazolyl. In certain embodiments, ring A is a C-linked imidazolyl. In certain embodiments, ring A is an N-linked imidazolyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyrimidinyl optionally substituted with alkyl or alkoxy. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is triazinyl. In some embodiments, ring A is thiazolyl.

In some embodiments, Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ring A is phenyl.

In some embodiments, ring A is a bicyclic heteroaryl. In certain embodiments, Ring A is an optionally substituted 3-benzodioxyl or 1,4-benzodioxanyl. In some embodiments, Ring A is an unsubstituted 3-benzodioxyl or 1,4-benzodioxanyl.

In some embodiments, R ¹ is -H, -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halogen, optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted hydroxyalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(O)NR4R ⁵ , -OC(O)OR ⁶ , -OC(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O )2R ⁷ , -S(O)R ⁷ , -SR ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -P(O)(OR ⁶ )2, -P(O)(R ⁶ )2, -CN or -NO2. In some embodiments, R ¹ is -H, -NR4R ⁵ , halogen, -OR ⁶ , optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -C(O)NR4R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -P(O)(R ⁶ )2, -P(O)(OR ⁶ )2 or -CN. In some embodiments, R ¹ is -H, -NR4R ⁵ , optionally substituted alkylNR4R ⁵ , halogen, -OR ⁶ , optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, -C(O)R ⁶ , -C(O)NR4R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -CN or -CO2H. In some embodiments, R ¹ is -NR4R ⁵ , halogen, -OR ⁶ , alkyl, fluoroalkyl, carbocyclyl, heteroalkyl, heterocyclyl, -S(O) ₂ NR ⁴ R ⁵ , -S(O) 2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ or -CN. In some embodiments, R ¹ is -NR4R ⁵ , halo, -OR ⁶ , C ₁ . ₆ alkyl, C ₁ . ₆ fluoroalkyl, C ₃ _ ₆ carbocyclyl, C ₃ _ ₆ heterocyclyl, aryl, heteroaryl, -C (O) NR4R ⁵ , -S (O) ₂ NR ⁴ R ⁵ , -S (O) 2R ⁷ , -NR ⁴ S (O)2NR ⁴ R ⁵ , -P(O)(R ⁶ )2, -P(O)(OR ⁶ )2 or -CN. In some embodiments, R ¹ is -NR4R ⁵ , halo, -OR ⁶ , -S(O) ₂ NR ⁴ R ⁵ , -P(O)(R ⁶ )2 or -P(O)(OR ⁶ )2 . In certain embodiments, R ¹ is -NR4R ⁵ , halogen, -OR ⁶ , alkyl, or fluoroalkyl. In certain embodiments, R ¹ is halo, -OR ⁶ , or alkyl. In other embodiments, R ¹ is -NMe2, -NHMe, -NH2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, morpholino, or pyrrolidino. In certain embodiments, R ¹ is C1. ₆ alkyl, fluoroalkyl, C ₃ _ ₆ carbocyclyl or C ₃ _ ₆ heterocyclyl. In some embodiments, R ¹ is -H. In some embodiments, R ¹ is -NR4R ⁵ . In some embodiments, R ¹ is -NMe2. In some embodiments, R ¹ is -NHMe. In some embodiments, R ¹ is -NH2. In some embodiments, R ¹ is -NMeEt. In some embodiments, R ¹ is -NEt2. In some embodiments, R ¹ is halogen. In some embodiments, R ¹ is fluorine. In some embodiments, R ¹ is chlorine. In some embodiments, R ¹ is bromine. In some embodiments, R ¹ is C ₁ . ₆ alkyl. In some embodiments, R ¹ is methyl. In some embodiments, R ¹ is ethyl. In some embodiments, R ¹ is propyl. In some embodiments, R ¹ is isopropyl. In some embodiments, R ¹ is

- 32 041590 carbocyclyl. In some embodiments, R ¹ is cyclopropyl. In some embodiments, R ¹ is cyclobutyl. In some embodiments, R ¹ is cyclopentyl. In some embodiments, R ¹ is cyclohexyl. In some embodiments, R ¹ is -OR ⁶ . In some embodiments, R ¹ is methoxy. In some embodiments, R ¹ is ethoxy. In some embodiments, R ¹ is propoxy. In some embodiments, R ¹ is isopropoxy. In some embodiments, R ¹ is heterocyclyl. In some embodiments, R ¹ is azetadino, morpholino, thiomorpholino, piperidino, piperazino, or pyrrolidino. In some embodiments, R ¹ is morpholino. In some embodiments, R ¹ is pyrrolidino. In some embodiments, R ¹ is azetadino.

In other embodiments, R ¹ is an optionally substituted monocyclic aryl, an optionally substituted bicyclic aryl, an optionally substituted monocyclic heteroaryl, or an optionally substituted bicyclic heteroaryl. In certain embodiments, R ¹ is phenyl, naphthyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzisoxazolyl, benzothienyl, benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl. In some embodiments, R ¹ is furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. In some embodiments, R ¹ is pyrimidinyl, pyridinyl, pyrazinyl, triazinyl, or thiazolyl. In certain embodiments, R ¹ is C-linked imidazolyl. In certain embodiments, R ¹ is an N-linked imidazolyl. In some embodiments, R ¹ is pyrimidinyl. In some embodiments, R ¹ is pyrimidinyl optionally substituted with alkyl or alkoxy. In some embodiments, R ¹ is pyrazinyl. In some embodiments, R ¹ is triazinyl. In some embodiments, R ¹ is thiazolyl.

In certain embodiments, R ¹ is optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In certain embodiments, R ¹ is optionally substituted with halogen, alkyl, or alkoxy. In some embodiments, R ¹ is optionally substituted with fluoro or C _1-6 alkyl. In some embodiments, R ¹ is optionally substituted with fluorine or methyl. In some embodiments, R ¹ is optionally substituted with methyl or methoxy.

In some embodiments, each R ² is independently -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halo, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted hydroxyalkyl, -C(O)R ⁶ , -C(O)NR ⁴ R ⁵ , -S(O) ₂ NR ⁴ R ⁵ , -S(O)2R ⁷ , - NR ⁴ S(O)2NR ⁴ R ⁵ or -CN. In some embodiments, each R ² is independently -NR4R ⁵ , alkyl-NR ⁴ R ⁵ , halo, -OR ⁶ , -OH, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, -C(O )R ⁶ , -C(O)NR ⁴ R ⁵ , -S(O) ₂ NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ or -CN. In some embodiments, each R ² is independently -NR4R ⁵ , halogen, -OR ⁶ , optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, -C(O)NR ⁴ R ⁵ , -S (O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -CN or -CO2H. In certain embodiments, each R ² is independently -NR4R ⁵ , halogen, -OR ⁶ , -OH, optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted hydroxyalkyl, -S(O) _2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ or -CN. In some embodiments, each R ² is independently -NR4R ⁵ , halogen, -OR ⁶ , alkyl, fluoroalkyl, carbocyclyl, heteroalkyl, heterocyclyl, -S(O) ₂ NR ⁴ R ⁵ , -NR ⁴ S(O)2NR ⁴ R ⁵ or -S(O)2R ⁷ . In some embodiments, each R ² is independently -NR ⁴ R ⁵ , C1.6alkyl-NR ⁴ R ⁵ , halo, -OR ⁶ , -OH, C1. ₆ alkyl, C ₁ . ₆ fluoroalkyl, C _3-6 carbocyclyl, C ₁ . ₆ alkyl-C ₃ . ₆ carbocyclyl, C ₁ . ₆ heteroalkyl, C _3-6 heterocyclyl, C ₁ . ₆ αlkyl-C ₃ . ₆ heterocyclyl, C ₁ . ₆ hydroxyalkyl or -CN. In some embodiments, each R ² is independently -C(O)R ⁶ , -C(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ^{7 ,} or -CN. In some embodiments, each R ² is independently -NR4R ⁵ ,

- 33 041590 halogen, -OR ⁶ , C1.6 alkyl, C1.6 fluoroalkyl, C3-6 carbocyclyl, C1.6 heteroalkyl, C3-6 heterocyclyl or -CN. In some embodiments, each R ² is independently -NR4R ⁵ , halo, alkyl, carbocyclyl, alkoxy, or -CN. In some embodiments, each R ² is independently —NR4R ⁵ , halogen, alkyl, or alkoxy. In some embodiments, each R ² is independently methyl, methoxy, ethyl, propyl, isopropyl, cyclopropyl, fluorine, chlorine, or -NMe2. In some embodiments, each R ² is independently methyl, methoxy, isopropyl, cyclopropyl, fluorine, chlorine, or -NMe2. In some embodiments, R ² is methoxy. In some embodiments, R ² is methyl. In some embodiments, R ² is ethyl. In some embodiments, R ² is isopropyl. In some embodiments, R ² is propyl. In some embodiments, R ² is cyclopropyl. In some embodiments, R ² is cyclobutyl. In some embodiments, R ² is fluorine. In some embodiments, R ² is chlorine. In some embodiments, R ² is -NMe2. In some embodiments, R ² is -NH ₂ . In some embodiments, R ² is -NHMe. In some embodiments, R ² is -NMeEt.

In certain embodiments, each R ² is independently optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, each R ² is independently optionally substituted with fluoro or C ₁ . ₆ alkyl. In some embodiments, each R ² is independently optionally substituted with fluorine or methyl.

In some embodiments, R ³ is alkyl, halogen, haloalkyl, deuteroalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, -Si(R ⁶ )3, -OR ⁶ or -S(O)2R ⁷ . In some embodiments, R ³ is alkyl, halogen, haloalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, or heteroalkyl. In some embodiments, R ³ is optionally substituted C1_10 alkyl, halogen, haloalkyl, deuteroalkyl, carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, where R ³ is optionally substituted with halogen, alkyl, alkoxy, hydroxy, -NR4R ⁵ or -S(O) 2R ⁷ . In some embodiments, R ³ is C1.6 alkyl, C1.6 haloalkyl, C1.6 deuteroalkyl, C3_6 carbocyclyl, C3_6 carbocyclyl-C1_6 alkyl, C3_6 heterocyclyl, C3_6 heterocyclyl-C1_6 alkyl. In some embodiments, R ³ is alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, or heteroalkyl. In some embodiments, R ³ is C1. ₆ αkyl, C ₁ . ₆ fluoroalkyl, carbocyclyl or heterocyclylalkyl. In certain embodiments, R ³ is C3-8alkyl or C1.6fluoroalkyl. In some embodiments, R ³ is C 1-6 alkyl. In some embodiments, R ³ is C1.8αkil. In some embodiments, R ³ is C2-8 alkyl. In some embodiments, R ³ is C3_6alkyl. In some embodiments, R ³ is methyl. In some embodiments, R ³ is ethyl. In some embodiments, R ³ is propyl. In some embodiments, R ³ is isopropyl. In some embodiments, R ³ is tert-butyl. In some embodiments, R ³ is butyl. In some embodiments, R ³ is isobutyl. In some embodiments, R ³ is sec-butyl. In some embodiments, R ³ is carbocyclyl. In some embodiments, R ³ is cyclopropyl. In some embodiments, R ³ is cyclobutyl. In some embodiments, R ³ is cyclopentyl. In some embodiments, R ³ is cyclohexyl. In some embodiments, R ³ is halogen. In some embodiments, R ³ is fluorine. In some embodiments, R ³ is chlorine. In some embodiments, R ³ is bromine. In some embodiments, R ³ is trifluoromethyl. In some embodiments, R ³ is hydroxyalkyl. In some embodiments, R ³ is deuteromethyl. In some embodiments, R ³ is -Si(R ⁶ )3. In some embodiments, R ³ is -Si(Me)3. In some embodiments, R ³ is -Si(Ph)3. In some embodiments, R ³ is -OR ⁶ . In some embodiments, R ³ is -S(O)2R ⁷ .

In other embodiments, R ³ is optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, R ³ is phenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,

- 34 041590 pyridazinyl or triazinyl. In some embodiments, R ³ is phenyl optionally substituted with halogen, alkyl, alkoxy, hydroxy, -NR ⁴ R ⁵ or -S(O) 2 R ⁷ . In some embodiments, R ³ is pyridinyl optionally substituted with halogen, alkyl, alkoxy, hydroxy, -NR ⁴ R ⁵ or -S(O) 2 R ⁷ . In some embodiments, R ³ is phenyl. In some embodiments, R ³ is pyridinyl.

In certain embodiments, R ³ is optionally substituted with halogen, alkyl, hydroxy, alkoxy, —NR ⁴ R ⁵ , —S(O)2R ⁷ , or fluoroalkyl. In some embodiments, R ³ is optionally substituted with chlorine, fluorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, dimethylamino, diethylamino, methylamino, amino, -S(O)2Me or trifluoromethyl. In certain embodiments, R ³ is optionally substituted with chlorine, fluorine, methyl, hydroxy, methoxy, dimethylamino, —S(O) ₂ Me, or trifluoromethyl.

In some embodiments, each R ⁴ and R ⁵ is independently -H, optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, -S(O)2R ⁷ or -C(O )N(R ¹³ )2. In some embodiments, each R ⁴ and R ⁵ is independently -H, C1. ₆ alkyl, C ₁ . ₆ fluoroalkyl, C ₃ . ₆ carbocyclyl, C ₁ . ₆ carbocyclylalkyl, C ₂ . ₆ heterocyclyl, C ₁ . ₆ alkyl-C ₃ . ₆ heterocyclyl, -S(O)2R ⁷ or -C(O)N(R ¹³ )2. In some embodiments, each R ⁴ and R ⁵ is independently -H, C1.6alkyl, C1.6fluoroalkyl, C3.6carbocyclyl, C3-5heterocyclyl, or -S(O)2R ⁷ . In some embodiments, each R ⁴ and R ⁵ is independently -H, C1. ₆ alkyl or -S(O)2R ⁷ . In some embodiments, each R ⁴ and R ⁵ is independently —H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, or —S(O) ₂ R ⁷ . In some embodiments, each R ⁴ and R ⁵ is independently —H, methyl, ethyl, propyl, or isopropyl. In some embodiments, R ⁴ and R ⁵ are -H. In some embodiments, R ⁴ and R ⁵ are methyl. In some embodiments, R ⁴ is methyl and R ⁵ is ethyl. In some embodiments, R ⁴ is methyl and R ⁵ is propyl. In some embodiments, R ⁴ is methyl and R ⁵ is isopropyl. In some embodiments, R ⁴ is H and R ⁵ is isopropyl. In some embodiments, each R ⁴ and R ⁵ is independently -H or -C(O)N(R ¹³ )2.

In other embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form a substituted or unsubstituted 4-, 5-, or 6-membered heterocyclic ring further containing 0-3 a heteroatom selected from -O-, -NH-, -NR ⁶ -, -S- and -S(O) ₂ -. In some embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form a 4-, 5-, or 6-membered heterocycle further containing 0 or 1 oxygen in as a heteroatom. In other embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form a substituted or unsubstituted 4-, 5-, or 6-membered heterocyclic ring further containing 1 a heteroatom selected from -O-, -NH-, -NR ⁶ -, -S- and -S(O)2-. In other embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form a 4-, 5-, or 6-membered heterocyclic ring further containing 1 oxygen as heteroatom. In other embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form a 4-, 5-, or 6-membered ring. In some embodiments, the 4-, 5-, or 6-membered ring is

In certain embodiments, each R ⁴ and R ⁵ is independently optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, each R ⁴ and R ⁵ is independently optionally substituted with fluoro or C ₁ . ₆ alkyl. In some embodiments, each R ⁴ and R ⁵ is independently optionally substituted with fluorine or methyl.

In some embodiments, R ⁶ is optionally substituted alkyl, fluoroalkyl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally

- 35 041590 optionally substituted heterocyclyl. In some embodiments, R ⁶ is optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl. In some embodiments, R ⁶ is alkyl, aryl, carbocyclyl, or heterocyclyl. In some embodiments, R ⁶ is alkyl, carbocyclyl, or heterocyclyl. In some embodiments, R ⁶ is alkyl, carbocyclyl, or fluoroalkyl. In some embodiments, R ⁶ is C1_6alkyl, C1.6fluoroalkyl, C3-6carbocyclyl, or C3_6heterocyclyl. In certain embodiments, R ⁶ is C1. ₆ alkyl. In certain embodiments, R ⁶ is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl. In some embodiments, R ⁶ is an optionally substituted phenyl.

In some embodiments, R ⁷ is alkyl, carbocyclyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heterocyclyl. In some embodiments, R ⁷ is C1.6 alkyl, C3_6 carbocyclyl, or aryl optionally substituted with halo or alkyl. In some embodiments, R ⁷ is C1. ₆ alkyl, C ₃ _ ₆ carbocyclyl or phenyl optionally substituted with halogen or alkyl. In some embodiments, R ⁷ is an optionally substituted benzyl. In some embodiments, R ⁷ is C3_6 carbocyclyl. In some embodiments, R ⁷ is phenyl. In some embodiments, R ⁷ is phenyl substituted with 1-4 C1 substituents. ₆ alkyl or fluorine. In some embodiments, R ⁷ is phenyl substituted with a C ₁ substituent. ₆ αkyl or fluorine. In some embodiments, R ⁷ is alkyl, carbocyclyl, aralkyl, or heterocyclyl.

In certain embodiments, R ⁷ is optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R ⁷ is optionally substituted with fluoro or C ₁ . ₆ alkyl. In some embodiments, R ⁷ is optionally substituted with fluorine or methyl.

In some embodiments, each R ¹³ is independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, each R ¹³ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, or optionally substituted aryl. In some embodiments, each R ¹³ is independently optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, or heteroaryl. In some embodiments, each R ¹³ is independently alkyl or aryl. In some embodiments, each R ¹³ is independently hydrogen or C ₁ . ₆ alkyl. In some embodiments, each R ¹³ is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl. In some embodiments, each R ¹³ is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, or t-butyl. In some embodiments, each R ¹³ is independently hydrogen or methyl. In some embodiments, R ¹³ is H. In other embodiments, R ¹³ is alkyl. In other embodiments, R ¹³ is aryl.

In some embodiments, R ¹⁴ is hydrogen or methyl.

In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 3 or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

In some embodiments, Ring A is monocyclic or bicyclic heteroaryl, monocyclic or bicyclic aryl, monocyclic cycloalkyl, or monocyclic heterocyclyl;

R ¹ is -H, -NR4R ⁵ , optionally substituted alkyl-NR4R5, halogen, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted hydroxyalkyl, -C (O)NR4R ⁵ , -S(O) ₂ NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -P(O)(OR ⁶ )2, -CN or -CO2H;

each R ² is independently -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halogen, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocic- 36 041590 lyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted hydroxyalkyl, -C(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -CN or -CO2H;

R ³ is optionally substituted alkyl, halogen, haloalkyl, deuteroalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, -Si(R ⁶ ) ₃ , -OR ⁶ or -S(O)2R ⁷ ;

each R ⁴ and R ⁵ is independently -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -S(O)2R ⁷ , -C(O)N(R ¹³ )2, -C(O)R ⁶ or -C(O)OR ⁶ ; or

R ⁴ and R ⁵ connected to the same N atom are taken together with the N atom to which they are connected to form a substituted or unsubstituted 4-, 5- or 6-membered heterocycle;

R ⁶ is optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

R ⁷ is optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

each R ¹³ is independently H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

R ¹⁴ is hydrogen or methyl; and n is 0, 1, 2, 3, or 4.

In some embodiments, Ring A is monocyclic or bicyclic aryl;

R ¹ is -H, -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halo, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl or optionally substituted carbocyclyl;

each R ² is independently -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halo, -OR ⁶ , -OH, or optionally substituted alkyl;

R ³ is optionally substituted alkyl, halo, haloalkyl, deuteroalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or —S(O)2R ⁷ ;

each R ⁴ and R ⁵ is independently —H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, or —C(O)OR ⁶ ;

R ⁶ is optionally substituted alkyl;

R ⁷ is optionally substituted alkyl;

each R ¹³ is independently H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, or optionally substituted heteroalkyl;

R ¹⁴ is hydrogen or methyl; and n is 0, 1, 2, 3, or 4.

In some embodiments, Ring A is monocyclic or bicyclic heteroaryl, monocyclic or bicyclic aryl; And

R ¹ is -H, -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halogen, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted hydroxyalkyl, -C(O)NR ⁴ R ⁵ , - S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -P(O)(OR ⁶ )2, -CN or -CO2H.

According to some embodiments, the ring

A is monocyclic or bicyclic heteroaryl, monocyclic or bicyclic aryl; And

R ¹ is -H, -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halo, -OR ⁶ , -OH, optionally substituted alkyl, or -CO ₂ H.

In some embodiments, Ring A is monocyclic or bicyclic aryl; And

R ¹ is -H, -NR4R ⁵ , optionally substituted alkyl-NR4R5, halo, -OR ⁶ , -OH, optionally substituted alkyl, or -CO2H.

In some embodiments, Ring A is monocyclic or bicyclic aryl; And

R ¹ is -H, -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halo, -OH or -CO2H.

According to some embodiments

- 37 041590 ring A is monocyclic or bicyclic heteroaryl, monocyclic or bicyclic aryl, monocyclic cycloalkyl or monocyclic heterocyclyl;

R ¹ is -H, -NR ⁴ R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halogen, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted hydroxyalkyl, -C(O)NR ⁴ R ⁵ , -S (O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -P(O)(OR ⁶ )2 , -CN or -CO2H; And

R ³ is optionally substituted alkyl, halogen, haloalkyl, deuteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, -Si(R ⁶ ) ₃ , -OR ⁶ or -S(O)2R ⁷ .

In some embodiments, Ring A is monocyclic or bicyclic aryl;

R ¹ is -H, -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -P(O)(OR ⁶ )2, -CN or -CO2H;

R ³ is optionally substituted alkyl, halogen, optionally substituted heteroaryl, -Si(R ⁶ ) ₃ , -OR ⁶ or -S(O)2R ⁷ ; and each R ⁴ and R ⁵ is independently -H, optionally substituted alkyl, or -C(O)OR ⁶ .

In some embodiments, Ring A is monocyclic aryl;

R ¹ is -H, -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , or -CO2H;

R ³ is optionally substituted alkyl, halogen, or —S(O) ₂ R ⁷ ; and each R ⁴ and R ⁵ is independently -H, optionally substituted alkyl, or -C(O)OR ⁶ .

In some embodiments, Ring A is monocyclic aryl;

R ¹ is -H or -NR ⁴ R ⁵ ;

R ³ is optionally substituted alkyl, halogen, or —S(O) ₂ R ⁷ .

In some embodiments, ring A is phenyl;

R ¹ is -H or -NR ⁴ R ⁵ ;

R ³ is optionally substituted alkyl or halo; and R ⁴ and R ⁵ are each independently —H, optionally substituted alkyl.

In some embodiments, ring A is phenyl;

R ¹ is -H or -NR ⁴ R ⁵ ;

R ³ is alkyl; and each R ⁴ and R ⁵ independently represents alkyl.

In some embodiments, ring A is phenyl;

R ¹ is -NR ⁴ R ⁵ and R ³ is alkyl; and each R ⁴ and R ⁵ independently represents alkyl.

In some embodiments, ring A is phenyl;

R ¹ is -NR4R ⁵ and R ³ is C ₁ . ₆ alkyl; and each R ⁴ and R ⁵ independently represents alkyl.

In some embodiments, ring A is pyridyl;

R ¹ is -H or -NR ⁴ R ⁵ ;

R ³ is alkyl or halo; and each R ⁴ and R ⁵ independently represents alkyl.

In some embodiments, ring A is phenyl;

R ¹ is -NR ⁴ R ⁵ ;

R ³ is alkyl; and each R ⁴ and R ⁵ independently represents alkyl.

In some embodiments, ring A is pyridyl;

R ¹ is -H or -NR ⁴ R ⁵ ;

R ³ is alkyl; and each R ⁴ and R ⁵ independently represents alkyl.

In some embodiments, ring A is pyridyl;

R ¹ is -NR ⁴ R ⁵ and R ³ is alkyl; And

- 38 041590 each R ⁴ and R ⁵ independently represents alkyl.

In some embodiments, ring A is pyridyl;

R ¹ is -NR4R ⁵ and R ³ is C _1-6 alkyl; and each R ⁴ and R ⁵ independently represents alkyl.

In some embodiments, ring A is bicyclic aryl;

R ¹ is -H, -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , or -CO2H;

R ³ is an optionally substituted alkyl, halo, or —S(O)2R ⁷ ; and each R ⁴ and R ⁵ is independently -H, optionally substituted alkyl, or -C(O)OR ⁶ .

In some embodiments, ring A is bicyclic aryl;

R ¹ is -H or -NR ⁴ R ⁵ ;

R ³ is optionally substituted alkyl, halo, or —S(O)2R ⁷ .

In some embodiments, Ring A is benzo-1,4-dioxane;

R ¹ is -H or -NR ⁴ R ⁵ ;

R ³ is an optionally substituted alkyl or halo.

In some embodiments, Ring A is benzo-1,4-dioxane;

R ¹ is -H or -NR ⁴ R ⁵ ;

R ³ is optionally substituted alkyl.

In some embodiments, Ring A is benzo-1,4-dioxane;

R ¹ is -NR ⁴ R ⁵ and R ³ is alkyl.

In some embodiments, Ring A is benzo-1,4-dioxane;

R ¹ is -NR4R ⁵ and R ³ is C _1-6 alkyl.

According to some embodiments

R ¹⁴ is hydrogen;

each R ¹³ is independently H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, or optionally substituted heteroaryl; and n is 0, 1, 2, 3, or 4.

According to some embodiments

R ¹⁴ is hydrogen;

each R ¹³ is independently H, optionally substituted alkyl, haloalkyl, or optionally substituted heteroaryl; and n is 0, 1, or 2.

According to some embodiments

R ¹⁴ is methyl;

each R ¹³ is independently H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, or optionally substituted heteroaryl; and n is 0, 1, 2, 3, or 4.

According to some embodiments

R ¹⁴ is methyl;

each R ¹³ is independently H, optionally substituted alkyl, haloalkyl, or optionally substituted heteroaryl; and n is 0, 1, or 2.

Any combination of the groups described above for various variables is provided herein. In the present description, the groups and their substituents are selected by a person skilled in the art to obtain stable fragments and compounds.

In some embodiments, the compounds described herein are characterized by the following structure of formula (IIa):

he .R ³

Formula (Pa)

- 39 041590

In some embodiments, the compounds described herein have the following structure of formula (IIb):

^R1

Formula (Pb)

In some embodiments, the compounds described herein are characterized by the following structure of formula (IIc):

OH .R ³ Mel n

Formula (Ps)

In some embodiments, the compounds described herein are characterized by the following structure of formula (IId):

^R2

Formula (lid)

According to some embodiments, those described are rasterized by the following structure of formula (IIe):

this document connections ha-

^R3

Formula (Pe)

In some embodiments, the compounds described herein are characterized by the following structure of formula (IIf):

^R1

Formula (Ilf)

In some embodiments, those described in are characterized by the following structure of formula (IIg):

this document connections ha-

Formula (IIg)

In some embodiments, the compounds described herein are characterized by the following structure of formula (IIh):

- 40 041590

In some embodiments provided herein, a compound having the structure of formula (III) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is described:

Formula (Ilh)

Formula (III) wherein ring A is heteroaryl, aryl, cycloalkyl or heterocyclyl;

R ¹ is -NR ^4a R ^5a ;

each R ² is independently -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halogen, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted hydroxyalkyl, -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁴ R ⁵ , -OC(O)OR ⁶ , -OC(O)NR ⁴ R ⁵ , -S(OENR ⁴ R ⁵ , -S(O)2R ⁷ , -S(O)R ⁷ , -SR ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -CN, -CO2H or -NO2 ; or

R ¹ and R ² on adjacent atoms are taken together with the atoms to which they are connected to form an optionally substituted heterocycle;

R ³ is optionally substituted C2-8 alkyl, halogen, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, -Si(R ⁶ )3, -OR ⁶ or -S(O) ₂ R ⁷ ;

R ^4a is C _2-8 alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -S(O)2R ⁷ , -C(O)N(R ¹³ )2, -C(O )R ⁶ or -C(O)OR ⁶ ;

R ^5a is -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -S(O)2R ⁷ , -C(O)N(R ¹³ )2, - C(O)R ⁶ or -C(O)OR ⁶ ; or

R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R ⁴ and R ⁵ is independently -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -S(O)2R ⁷ , -C(O)N(R ¹³ )2, -C(O)R ⁶ or -C(O)OR ⁶ ;

or R ⁴ and R ⁵ are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R ⁶ is independently optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

R ⁷ is optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

each R ⁸ and R ⁹ is independently -H, optionally substituted alkyl, haloalkyl, halogen, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, -OH, -S(O)2R ⁷ , -C(O)2H, -C(O)R ⁶ or -C(O)OR ⁶ ; or

R ⁸ and R ⁹ are taken together with the atom to which they are attached to form an optionally substituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -NR ⁶ -, -S- and -S(O) ₂ -;

- 41 041590 each R ¹⁰ and R ¹¹ independently represents -H, optionally substituted alkyl, halogen, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, -OH, -S(O )2R ⁷ , -C(O)2H, -C(O)R ⁶ or -C(O)OR ⁶ ; or

R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form an optionally substituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -NR ⁶ -, -S and -S (O)2-;

R ¹² is hydrogen, optionally substituted alkyl, haloalkyl, hydroxy, halogen, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroalkyl;

each R ¹³ is independently H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and n is 0, 1, 2, 3, or 4.

In some embodiments of a compound of formula (III), ring A is aryl;

R ¹ is -NR ^4a R ^5a ;

each R ² is independently -NR4R ⁵ , halo or optionally substituted alkyl; or

R ¹ and R ² on adjacent atoms are taken together with the atoms to which they are connected to form an optionally substituted heterocycle;

R ³ is an optionally substituted C ₂ _ ₈ alkyl, haloalkyl, or optionally substituted carbocyclyl;

R ^4a is C _2-8 alkyl;

R ^5a is -H or optionally substituted alkyl; or

R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R ⁴ and R ⁵ is independently —H or optionally substituted alkyl; or

R ⁴ and R ⁵ are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R ⁸ and R ⁹ is independently —H or optionally substituted alkyl; or

R ⁸ and R ⁹ are taken together with the atom to which they are attached to form an optionally substituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -S- and -S(O) 2-;

each R ¹⁰ and R ¹¹ is independently —H or optionally substituted alkyl; or

R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form an optionally substituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -S- and -S(O) _2- ;

R ¹² is hydrogen or optionally substituted alkyl; and n is 0 or 1.

In some embodiments of a compound of formula (III), ring A is aryl;

R ¹ is -NR ^4a R ^5a ;

each R ² is independently halogen or alkyl; or

R ¹ and R ² on adjacent atoms are taken together with the atoms to which they are connected to form an optionally substituted heterocycle;

R ³ is C2-8 alkyl, haloalkyl or carbocyclyl;

R ^4a is C3-6alkyl;

R ^5a is -H or C ₁ . ₆ alkyl; or

R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R ⁸ and R ⁹ is independently —H or methyl;

each R ¹⁰ and R ¹¹ represents -H;

R ¹² is hydrogen or methyl; and n is 0 or 1.

For any possible embodiments of formula (III), the substituents are selected from a subset of the listed alternatives.

In some embodiments, Ring A is monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, or bicyclic heteroaryl. In some embodiments, Ring A is monocyclic heteroaryl or monocyclic aryl. In some embodiments, ring A is bicyclic heteroaryl or bicyclic aryl. According to some embodiments, ring A

- 42 041590 is an N-linked heteroaryl. In some embodiments, ring A is a C-linked heteroaryl. In some embodiments, Ring A is aryl.

In certain embodiments, ring A is phenyl, naphthyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzisoxazolyl, benzothienyl, benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl. In some embodiments, R ¹ is furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. In some embodiments, Ring A is pyrimidinyl, pyridinyl, pyrazinyl, triazinyl, or thiazolyl. In certain embodiments, ring A is a C-linked imidazolyl. In certain embodiments, ring A is an N-linked imidazolyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyrimidinyl optionally substituted with alkyl or alkoxy. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is triazinyl. In some embodiments, ring A is thiazolyl.

In some embodiments, Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ring A is phenyl or pyridinyl. In some embodiments, Ring A is phenyl.

In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C2_8 alkyl, and R ^5a is -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, - S(O)2R ⁷ , -C(O)N(R ¹³ )2, -C(O)R ⁶ or -C(O)OR ⁶ . In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C2_8 alkyl, and R ^5a is -H or optionally substituted alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C2_8 alkyl, and R ^5a is -H or alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C2_8 alkyl, and R ^5a is -H or C1.6 alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is ethyl, isopropyl, or t-butyl, and R ^5a is -H or C1. ₆ alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is ethyl, isopropyl, or tert-butyl, and R ^5a is C ₁ . ₆ alkyl.

In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C3-6 alkyl, and R ^5a is -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl , -S(O)2R ⁷ , -C(O)N(R ¹³ )2, -C(O)R ⁶ or -C(O)OR ⁶ . In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C3_ ₆ alkyl, and R ^5a is -H or optionally substituted alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C3-6 alkyl, and R ^5a is -H or alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C3-6 alkyl, and R ^5a is -H or C1.6 alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a4a is isopropyl or tert-butyl and R ^5a is -H or C1. ₆ alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a4a is isopropyl or tert-butyl and R ^5a is C ₁ . ₆ alkyl.

In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C2_4 alkyl, and R ^5a is -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, - S(O)2R ⁷ , -C(O)N(R ¹³ )2, -C(O)R ⁶ or -C(O)OR ⁶ . In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C2_4 alkyl, and R ^5a is -H or optionally substituted alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C2-4 alkyl, and R ^5a is -H or alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C2-4 alkyl, and R ^5a is -H or C1.6 alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is ethyl, isopropyl, or t-butyl, and R ^5a is -H or C1. ₆ alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is ethyl, isopropyl, or tert-butyl, and R ^5a is C ₁ . ₆ alkyl.

- 43 041590

In some embodiments, R ¹ is -NMeEt. In some embodiments, R ¹ is -NEt2. In some embodiments, R ¹ is -NMeiPr. In some embodiments, R ¹ is -NHEt. In some embodiments, R ¹ is -NHiPr.

In some embodiments, R ¹ is -NR ^4a R ^5a , and R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted heterocycle. In other embodiments, R ¹ is -NR ^4a R ^5a , and R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted 4-, 5-, or 6-membered heterocyclic ring further containing 0 -3 heteroatoms selected from -O-, -NH-, -NR ⁶ -, -S- and -S(O)2-. In some embodiments, R ¹ is -NR ^4a R ^5a , and R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted 4-, 5-, or 6-membered heterocycle further containing 0 or 1 oxygen as a heteroatom. In other embodiments, R ¹ is -NR ^4a R ^5a , and R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted 4-, 5-, or 6-membered heterocyclic ring further containing 1 a heteroatom selected from -O-, -NH-, -NR ⁶ -, -Si and -S(O)2-. In other embodiments, R ¹ is -NR ^4a R ^5a and R ^4a and R ^5a are taken together with the N atom to which they are attached to form a 4-, 5-, or 6-membered ring. In other embodiments, R ¹ is -NR ^4a R ^5a , and R ^4a and R ^5a are taken together with the N atom to which they are attached to form

In other embodiments, R ¹ is -NR ^4a R ^5a , and R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted pyrrolidinyl, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted piperidinyl, or an optionally substituted piperidinyl substituted piperazinyl.

In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 3 or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

In some embodiments, each R ² is independently -NR ⁴ R ⁵ , optionally substituted alkyl-NR4R ⁵ , halo, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted hydroxyalkyl, -C(O)R ⁶ , -C(O)NR ⁴ R ⁵ , -S(O) ₂ NR ⁴ R ⁵ , -S(O)2R ⁷ , - NR ⁴ S(O)2NR ⁴ R ⁵ or -CN. In some embodiments, each R ² is independently -NR4R ⁵ , alkyl-NR ⁴ R ⁵ , halo, -OR ⁶ , -OH, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, -C(O )R ⁶ , -C(O)NR ⁴ R ⁵ , -S(O) ₂ NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ or -CN. In some embodiments, each R ² is independently -NR ⁴ R ⁵ , halogen, -OR ⁶ , optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, -C(O)NR ⁴ R ⁵ . -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -CN or -CO2H. In certain embodiments, each R ² is independently -NR ⁴ R ⁵ , halogen, -OR ⁶ , -OH, optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted hydroxyalkyl, -S( O) _2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ or -CN. In some embodiments, each R ² is independently -NR ⁴ R ⁵ , halogen, -OR ⁶ , alkyl, fluoroalkyl, carbocyclyl, heteroalkyl, heterocyclyl, -S(O) ₂ NR ⁴ R ⁵ , -NR ⁴ S(O) 2NR ⁴ R ⁵ or -S(O)2R ⁷ . In some embodiments, each R ² is independently -NR4R ⁵ , C1.6alkyl-NR ⁴ R ⁵ , halo, -OR ⁶ , -OH, C1. ₆ alkyl, C ₁ . ₆ fluoroalkyl, C ₃ . ₆ carbocyclyl, C ₁ . ₆ alkyl-C ₃ . ₆ carbocyclyl, C ₁ . ₆ heteroalkyl, C _3-6 heterocyclyl, C ₁ . ₆ alkyl-C ₃ . ₆ heterocyclyl, C ₁ . ₆ hydroxyalkyl or -CN. In some embodiments, each R ² is independently -C(O)R ⁶ , -C(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ^{7 ,} or -CN. In some embodiments, each R ² is independently -NR ⁴ R ⁵ , halo, -OR ⁶ , C ₁ . ₆ alkyl, C ₁ . ₆ fluoroalkyl, C ₃ . ₆ carbocyclyl, C ₁ . ₆ heteroalkyl, C ₃ . ₆ heterocyclyl or -CN. In some embodiments, each R ² is independently -NR ⁴ R ⁵ , halo, alkyl, carbocyclyl, alkoxy, or -CN. In some embodiments, each R ² is independently —NR4R ⁵ , halogen, alkyl, or alkoxy. In some embodiments, each R ² is independently methyl, methoxy, ethyl, propyl, isopropyl, cyclopropyl, fluorine, chlorine, or -NMe2. In some embodiments, each R ² is independently methyl, methoxy, isopropyl, cyclopropyl, fluorine, chlorine, or -NMe2. In some embodiments, R ² is methoxy. In some embodiments, R ² is methyl. In some embodiments, R ² is ethyl. In some embodiments, R ² is isopropyl. In some embodiments, R ² is propyl. In some embodiments, R ² is cyclopropyl. In some embodiments, R ² is cyclobutyl. In some embodiments, R ² is fluorine. In some embodiments, R ² is chlorine.

In certain embodiments, each R ² is independently optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, each R ² is independently optionally substituted with fluorine or C ₁ . ₆ alkyl. In some embodiments, each R ² is independently optionally substituted with fluorine or methyl.

In some embodiments, R ¹ and R ² on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted heterocycle. In some embodiments, R ¹ and R ² on adjacent atoms are taken together with the atoms to which they are attached to form a heterocycle. In some embodiments, R ¹ and R ² on adjacent atoms are taken together with the atoms to which they are attached to form 1,4-dioxane or 1,3-dioxolane.

In some embodiments, R ³ is optionally substituted C2-8 alkyl, halo, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, -Si(R ⁶ )3, -OR ⁶ or -S(O)2R ⁷ . In some embodiments, R ³ is C2-8 alkyl, halo, haloalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, heteroalkyl, aryl, optionally substituted heteroaryl, -Si(R ⁶ )3, -OR ⁶ , or -S(O)2R ⁷ . In some embodiments, R ³ is C2_8 alkyl, halo, haloalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, or heteroalkyl. In some embodiments, R ³ is C2-8 alkyl, halogen, haloalkyl, deuteroalkyl, or carbocyclyl, where R ³ is optionally substituted with halogen, alkyl, alkoxy, hydroxy, -NR4R ⁵ or -S(O)2R ⁷ . In some embodiments, R ³ is C2-8 alkyl, C ₁ . ₆ haloalkyl or C ₃ - ₆ carbocyclyl.

In some embodiments, R ³ is CF3, t-butyl, or cyclopropyl. In some embodiments, R ³ is C4-8 alkyl. In some embodiments, R ³ is tert-butyl. In some embodiments, R ³ is haloalkyl. In some embodiments, R ³ is CF3. In some embodiments, R ³ is an optionally substituted carbocyclyl. In some embodiments, R ³ is cyclopropyl.

In certain embodiments, R ³ is optionally substituted with halo, alkyl, hydroxy, alkoxy, —NR ⁴ R ⁵ , —S(O)2R ⁷ , or fluoroalkyl. In some embodiments, R ³ is optionally substituted with chlorine, fluorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, dimethylamino, diethylamino, methylamino, amino, -S(O)2Me or trifluoromethyl. In certain embodiments, R ³ is optionally substituted with chlorine, fluorine, methyl, hydroxy, methoxy, dimethylamino, —S(O) ₂ Me, or trifluoromethyl.

In some embodiments, each R ⁸ and R ⁹ is independently -H, C1.6αkyl, C1.6 haloalkyl, halogen, C3_6 carbocyclyl, C1.6 alkyl-C3.6 carbocyclyl, C1.6 heteroalkyl, C3_6 heterocyclyl, C1.6 alkyl-C3.6 heterocyclyl, -OH, -OR ⁶ , -NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , -CN, -S(O)2R ⁷ , -C(O)2H, -C(O)R ⁶ or - C(O)OR ⁶ or R ⁸ and R ⁹ are taken together with the atom to which they are connected to form a ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -NR ⁶ -, -S- and -S(O)2-. In some embodiments, each R ⁸ and R ⁹ is independently -H, C1.6αkyl, halo, C3-6carbocylyl, methoxy, ethoxy, propoxy, isopropoxy, -NH2, -NMe2, -NHMe, -NEt2, -C(O )NH2, -C(O)NMe2, -C(O)NHMe or -CN. In some embodiments, each R ⁸ and R ⁹ is independently -H, C1. ₆ alkyl, C ₁ . ₆ fluoroalkyl, halogen or C _3-6 carbocyclyl. In some embodiments, each R ⁸ and R ⁹ is independently -H, C1.6αkyl, or C3-6carbocyclyl. In some embodiments, each R ⁸ and R ⁹ is independently -H or C1. ₆ alkyl. In some embodiments, R ⁸ is -H and R ⁹ is C ₁ . ₆ alkyl, C ₁ . ₆ fluoroalkyl or C ₃ _ ₆ carbocyclyl. According to some

- 45 041590 In other embodiments, R ⁸ is -H and R ⁹ is alkyl. In some embodiments, R ⁸ is C1_6 alkyl, C1_6 fluoroalkyl or C3-6 carbocyclyl and R ⁹ is -H. In some embodiments, R ⁸ is methyl and R ⁹ is -H. In some embodiments, R ⁸ and R ⁹ are -H. In some embodiments, R ⁸ and R ⁹ are C1_6 alkyl. In some embodiments, R ⁸ and R ⁹ are methyl.

In other embodiments, R ⁸ and R ⁹ are taken together with the atom to which they are attached to form a 3-, 4-, 5-, or 6-membered ring containing 0-2 heteroatoms selected from the group consisting of -O- , -NH-, -NR ⁶ -, -S- and -S(O) ₂ -. In some embodiments, R ⁸ and R ⁹ are taken together with the atom to which they are attached to form a 3-, 4-, 5-, or 6-membered carbocyclic ring.

In some embodiments, each R ¹⁰ and R ¹¹ is independently -H, alkyl, halogen, haloalkyl, carbocyclyl, heteroalkyl, or -OH. In other embodiments, each R ¹⁰ and R ¹¹ is independently —H, C1-6alkyl, halogen, C1_6alkoxy, or —OH. In certain embodiments, each R ¹⁰ and R ¹¹ is independently —H or C1_6alkyl. In certain embodiments, each R ¹⁰ and R ¹¹ is independently —H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In certain embodiments, each R ¹⁰ and R ¹¹ is independently —H, fluoro, or methyl. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or methyl. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or fluoro. In certain embodiments, both R ¹⁰ and R ¹¹ are —H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or methoxy. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or -OH. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or fluoro. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or chlorine.

In some embodiments, each R ¹⁰ and R ¹¹ is independently -H, alkyl, halo, haloalkyl, carbocyclyl, heteroalkyl, or -OH, where at least one of R ¹⁰ or R ¹¹ is not H. In other embodiments, each R ¹⁰ and R ¹¹ is independently -H, C1_6alkyl, halogen, C1_6alkoxy, or -OH, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or C1_6alkyl, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl or tert-butyl, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H, fluoro, or methyl, where at least one of R ¹⁰ or R ¹¹ is not H. Consent but in certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or methyl, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or fluoro where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or methoxy, where at least one of R ¹⁰ or R ¹¹ is not H. According to In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or -OH, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or fluoro where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or chlorine, where at least one of R ¹⁰ or R ¹¹ is not H.

In some embodiments, R ¹⁰ and R ¹¹ are methyl. In some embodiments, R ¹⁰ and R ¹¹ are ethyl. In some embodiments, R ¹⁰ and R ¹¹ are propyl. In some embodiments, R ¹⁰ and R ¹¹ are fluoro. In some embodiments, R ¹⁰ and R ¹¹ are chlorine. In some embodiments, R ¹⁰ and R ¹¹ are bromine. In some embodiments, R ¹⁰ and R ¹¹ are methoxy. In some embodiments, R ¹⁰ and R ¹¹ are ethoxy. In some embodiments, R ¹⁰ and R ¹¹ are —OH.

In some embodiments, R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form a 3-, 4-, 5-, or 6-membered ring. In some embodiments, R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form cyclopropyl.

In certain embodiments, R ¹⁰ and R ¹¹ are optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R ¹⁰ and R ¹¹ are optionally substituted with fluoro or _{C1_6} alkyl. According to some embodiments of R ¹⁰ and

- 46 041590

R ¹¹ are optionally substituted with fluorine or methyl.

In some embodiments, R ¹² is hydrogen, C1.6 alkyl, C1.6 haloalkyl, C1.6 deuteroalkyl, C3-6 carbocyclyl, C3_6 carbocyclyl-C1_6 alkyl, C3-6 heterocyclyl, C3_6 heterocyclyl-C1_6 alkyl. In some embodiments, R ¹² is hydrogen, alkyl, haloalkyl, hydroxy, halogen, carbocyclyl, or heteroalkyl. In some embodiments, R ¹² is hydrogen, C 1-6 alkyl, C _1-6 fluoroalkyl, carbocyclyl, or heterocyclyl alkyl. In certain embodiments, R ¹² is C1.6αkyl or C1-6fluoroalkyl. In some embodiments, R ¹² is C1. ₆ αkyl, C _1-6 haloalkyl, C _1-6 deuteroalkyl, C _3-6 carbocyclyl, C _3-b- carbocyclyl-C ₁ -balkyl, C _3-6 heterocyclyl, C _3- bheterocyclyl-C _1- balkyl. In some embodiments, R ¹² is alkyl, haloalkyl, hydroxy, halogen, carbocyclyl, or heteroalkyl. In some embodiments, R ¹² is C1.6 alkyl, C1.6 fluoroalkyl, carbocyclyl, or heterocyclylalkyl. In certain embodiments, R ¹² is C1. ₆ alkyl or C ₁ . ₆ fluoroalkyl. In certain embodiments, R ¹² is hydrogen. In some embodiments, R ¹² is C1.6αkyl. In some embodiments, R ¹² is C1. ₃ alkyl. In some embodiments, R ¹² is C2-8 alkyl. In some embodiments, R ¹² is C3-6 alkyl. In some embodiments, R ¹² is methyl. In some embodiments, R ¹² is ethyl. In some embodiments, R ¹² is propyl. In some embodiments, R ¹² is isopropyl. In some embodiments, R ¹² is tert-butyl. In some embodiments, R ¹² is butyl. In some embodiments, R ¹² is isobutyl. In some embodiments, R ¹² is sec-butyl. In some embodiments, R ¹² is carbocyclyl. In some embodiments, R ¹² is cyclopropyl. In some embodiments, R ¹² is cyclobutyl. In some embodiments, R ¹² is cyclopentyl. In some embodiments, R ¹² is cyclohexyl. In some embodiments, R ¹² is trifluoromethyl. In some embodiments, R ¹² is hydroxyalkyl. In some embodiments, R ¹² is deuteromethyl.

In certain embodiments, R ¹² is optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R ¹² is optionally substituted with fluorine or C ₁ . ₆ alkyl. In some embodiments, R ¹² is optionally substituted with fluorine or methyl.

In some embodiments, each R ⁴ and R ⁵ is independently -H, optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, -S(O)2R ⁷ or -C(O )N(R ¹³ )2. In some embodiments, each R ⁴ and R ⁵ is independently -H, C1_6αalkyl, C1_6fluoroalkyl, C3-6carbocyclyl, C1.6carbocyclylalkyl, C2-6heterocyclyl, C1.6alkyl-C3.6heterocyclyl, -S(O)2R ⁷ or -C (O)N(R ¹³ )2. In some embodiments, each R ⁴ and R ⁵ is independently -H, C1_6αkyl, C1.6fluoroalkyl, C3-6carbocyclyl, C3-5heterocyclyl, or -S(O)2R ⁷ . In some embodiments, each R ⁴ and R ⁵ is independently -H, C1. ₆ alkyl or -S(O) ₂ R ⁷ . In some embodiments, each R ⁴ and R ⁵ is independently -H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl, or -S(O)2R ⁷ . In some embodiments, each R ⁴ and R ⁵ is independently —H, methyl, ethyl, propyl, or isopropyl. In some embodiments, R ⁴ and R ⁵ are -H. In some embodiments, R ⁴ and R ⁵ are methyl. In some embodiments, R ⁴ is methyl and R ⁵ is ethyl. In some embodiments, R ⁴ is methyl and R ⁵ is propyl. In some embodiments, R ⁴ is methyl and R ⁵ is isopropyl. In some embodiments, R ⁴ is H and R ⁵ is isopropyl. In some embodiments, each R ⁴ and R ⁵ is independently -H or -C(O)N(R ¹³ ) ₂ .

In other embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form an optionally substituted 4-, 5-, or 6-membered heterocyclic ring further containing 0- 3 heteroatoms selected from -O-, -NH-, -NR ⁶ -, -S- and -S(O) ₂ -. In some embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form a 4-, 5-, or 6-membered heterocycle further containing 0 or 1 oxygen in as a heteroatom. In other embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form an optionally substituted 4-, 5-, or 6-membered heterocyclic ring further containing 1 heteroatom selected from -O-, -NH-, -NR ⁶ -, -S- 47 041590 and -S(O) ₂ -. In other embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form a 4-, 5-, or 6-membered heterocyclic ring further containing 1 oxygen as heteroatom. In other embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form a 4-, 5-, or 6-membered ring.

In certain embodiments, each R ⁴ and R ⁵ is independently optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, each R ⁴ and R ⁵ is independently optionally substituted with fluorine or C ₁ . ₆ alkyl. In some embodiments, each R ⁴ and R ⁵ is independently optionally substituted with fluorine or methyl.

In some embodiments, R ⁶ is optionally substituted alkyl, fluoroalkyl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl. In some embodiments, R ⁶ is optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl. In some embodiments, R ⁶ is alkyl, aryl, carbocyclyl, or heterocyclyl. In some embodiments, R ⁶ is alkyl, carbocyclyl, or heterocyclyl. In some embodiments, R ⁶ is alkyl, carbocyclyl, or fluoroalkyl. In some embodiments, R ⁶ is C1_6alkyl, C1.6fluoroalkyl, C3_6carbocyclyl, or C3_6heterocyclyl. In certain embodiments, R ⁶ is C1. ₆ alkyl. In certain embodiments, R ⁶ is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl. In some embodiments, R ⁶ is an optionally substituted phenyl.

In some embodiments, R ⁷ is alkyl, carbocyclyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heterocyclyl. In some embodiments, R ⁷ is C1.6αalkyl, C3_6carbocyclyl, or aryl optionally substituted with halogen or alkyl. In some embodiments, R ⁷ is C1. ₆ alkyl, C ₃ _ ₆ carbocyclyl or phenyl optionally substituted with halogen or alkyl. In some embodiments, R ⁷ is an optionally substituted benzyl. In some embodiments, R ⁷ is C3_6 carbocyclyl. In some embodiments, R ⁷ is phenyl. In some embodiments, R ⁷ is phenyl substituted with 1-4 C1 substituents. ₆ alkyl or fluoro. In some embodiments, R ⁷ is phenyl substituted with a C ₁ substituent. ₆ alkyl or fluoro. In some embodiments, R ⁷ is alkyl, carbocyclyl, aralkyl, or heterocyclyl.

In certain embodiments, R ⁷ is optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R ⁷ is optionally substituted with fluorine or C ₁ .6 alkyl. In some embodiments, R ⁷ is optionally substituted with fluorine or methyl.

In some embodiments, each R ¹³ is independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, each R ¹³ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, or optionally substituted aryl. In some embodiments, each R ¹³ is independently optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, or heteroaryl. In some embodiments, each R ¹³ is independently alkyl or aryl. In some embodiments, each R ¹³ is independently hydrogen or C ₁ .6 alkyl. In some embodiments, each R ¹³ is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl. In some embodiments, each R ¹³ is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, or t-butyl. In some embodiments, each R ¹³ is independently hydrogen or methyl. In some embodiments, R ¹³ is H. In other embodiments, R ¹³ is alkyl. In other embodiments, R ¹³ is aryl.

Any combination of the groups described above for various variables is provided herein. In the present description, the groups and their substituents are selected by a person skilled in the art to obtain stable fragments and compounds.

In some embodiments, the compounds described herein are characterized by the following structure of formula (IIIa):

R

^R3

Formula (Sha)

In some embodiments, those described are rasterized with the following structure of formula (IIIb):

R ¹ of the present document compounds ha-

^R3

ABOUT

RlO R ¹¹

Formula (SH)

In some embodiments, those described are characterized by the following structure of formula (IIIc):

present paper connections hao

^R3

Formula (Shs)

In some embodiments, those described are rasterized with the following structure of formula (IIId):

xR ² compounds in this document

R

^R3

ABOUT

Rio R

Formula (IIId)

According to some embodiments, those described are rasterized by the following structure of formula (IIIe):

^R3

Formula (She)

According to some embodiments, those described are rasterized by the following structure of formula (IIIf):

document connection document connection haha- 49 041590

In some embodiments, the compounds described herein are ha-

Formula (ΙΠί) is characterized by the following structure of formula (IIIg):

Formula (Illg)

In some embodiments, the compounds described herein are characterized by the following structure of formula (IIIh):

Formula (IIIh)

In some embodiments of a compound of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), or (IIIh), ring A is aryl;

R ¹ is -NR ^4a R ^5a ;

R ² is independently -NR ⁴ R ⁵ , halo or optionally substituted alkyl; or

R ¹ and R ² on adjacent atoms are taken together with the atoms to which they are connected to form an optionally substituted heterocycle;

R ³ is an optionally substituted C _2-8 alkyl, haloalkyl, or optionally substituted carbocyclyl;

R ^4a is C _2-8 alkyl;

R ^5a is -H or optionally substituted alkyl; or

R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R ⁴ and R ⁵ is independently —H or optionally substituted alkyl; or

R ⁴ and R ⁵ are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R ⁸ and R ⁹ is independently —H or optionally substituted alkyl; or

R ⁸ and R ⁹ are taken together with the atom to which they are attached to form an optionally substituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -S- and -S(O) _2- ;

each R ¹⁰ and R ¹¹ is independently —H or optionally substituted alkyl; or

R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form an optionally substituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -S- and -S(O) 2-; And

R ¹² is hydrogen or optionally substituted alkyl.

Certain embodiments provided herein describe a compound having the structure of formula (IV), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

- 50 041590

^R1

Formula (IV) wherein ring A is heteroaryl, aryl, cycloalkyl or heterocyclyl;

R ¹ is -NR ^4a R ^5a ;

each R ² is independently -NR4R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halogen, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted hydroxyalkyl, -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁴ R ⁵ , -OC(O)OR ⁶ , -OC(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -S(O)R ⁷ , -SR ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -CN, -CO2H or -NO2; or

R ¹ and R ² on adjacent atoms are taken together with the atoms to which they are connected to form an optionally substituted heterocycle;

R ³ is optionally substituted alkyl;

R ^4a is C ₂ . ₈ alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -S(O) ₂ R ⁷ , -C(O)N(R ¹³ )2, -C(O)R ⁶ or -C (O)OR ⁶ ;

R ^5a is -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -S(O)2R ⁷ , -C(O)N(R ¹³ )2, - C(O)R ⁶ or -C(O)OR ⁶ ;

each R ⁴ and R ⁵ is independently -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -S(O)2R ⁷ , -C(O)N(R ¹³ )2, -C(O)R ⁶ or -C(O)OR ⁶ ; or

R ⁴ and R ⁵ are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R ⁶ is independently optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

R ⁷ is optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

each R ⁸ and R ⁹ is independently -H, optionally substituted alkyl, haloalkyl, halogen, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, -OH, -S(O)2R ⁷ , -C(O)2H, -C(O)R ⁶ or -C(O)OR ⁶ ; or

R ⁸ and R ⁹ are taken together with the atom to which they are attached to form an optionally substituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -NR ⁶ -, -S- and -S(O) ₂ -;

each R ¹⁰ and R ¹¹ is independently -H, optionally substituted alkyl, halogen, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, -OH, -S(O)2R ⁷ , -C(O)2H, -C(O)R ⁶ or -C(O)OR ⁶ ; or

R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form an optionally substituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -NR ⁶ -, -S and -S (O) _2- ;

R ¹² is hydrogen, optionally substituted alkyl, haloalkyl, hydroxy, halogen, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroalkyl;

each R ¹³ is independently H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and n is 0, 1, 2, 3, or 4.

In some embodiments of a compound of formula (IV), ring A is aryl;

- 51 041590

R ¹ is -NR ^4a R ^5a ;

R ² is independently -NR4R ⁵ , halo or optionally substituted alkyl; or

R ¹ and R ² on adjacent atoms are taken together with the atoms to which they are connected to form an optionally substituted heterocycle;

R ³ is optionally substituted alkyl;

R ^4a is C _2-8 alkyl;

R ^5a is -H or optionally substituted alkyl;

each R ⁴ and R ⁵ is independently —H or optionally substituted alkyl; or

R ⁴ and R ⁵ are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R ⁸ and R ⁹ is independently —H or optionally substituted alkyl; or

R ⁸ and R ⁹ are taken together with the atom to which they are attached to form an optionally substituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -S- and -S(O) _2- ;

each R ¹⁰ and R ¹¹ is independently —H or optionally substituted alkyl; or

R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form an optionally substituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -S- and -S(O) 2-; And

R ¹² is hydrogen or optionally substituted alkyl.

Certain embodiments provided herein describe a compound having the structure of formula (V), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

^R1

Formula (V) wherein Ring A is heteroaryl, aryl, cycloalkyl, or heterocyclyl;

R ¹ is -NR ^4a R ^5a , optionally substituted alkyl-NR ⁴ R ⁵ , halogen, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted hydroxyalkyl, -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁴ R ⁵ , -OC(O)OR ⁶ , -OC(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -S(O)R ⁷ , -SR ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -CN, -CO2H or -NO2;

each R ² is independently -NR ⁴ R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halogen, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted hydroxyalkyl, -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁴ R ⁵ , -OC(O)OR ⁶ , -OC(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -S(O)R ⁷ , -SR ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -CN, - CO2H or -NO2; or

R ¹ and R ² on adjacent atoms are taken together with the atoms to which they are connected to form an optionally substituted heterocycle;

R ³ is an optionally substituted carbocyclyl;

R ^4a is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -S(OhR ⁷ , -C(O)N(R ¹³ )2, -C(O)R ⁶ or -C(O)OR ⁶ ;

R ^5a is -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -S(O)2R ⁷ , -C(O)N(R ¹³ )2, - C(O)R ⁶ or -C(O)OR ⁶ ; or

R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R ⁴ and R ⁵ is independently -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -S(O)2R ⁷ , -C(O)N(R ¹³ )2, -C(O)R ⁶ or -C(O)OR ⁶ ; or

R ⁴ and R ⁵ are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R ⁶ is independently optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

- 52 041590

R ⁷ is optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

each R ⁸ and R ⁹ is independently -H, optionally substituted alkyl, haloalkyl, halogen, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, -OH, -S(O)2R ⁷ , -C(O)2H, -C(O)R ⁶ or -C(O)OR ⁶ ; or

R ⁸ and R ⁹ are taken together with the atom to which they are attached to form an optionally substituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -NR ⁶ -, -S- and -S(O) ₂ -;

each R ¹⁰ and R ¹¹ is independently -H, optionally substituted alkyl, halogen, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, -OH, -S(O)2R ⁷ , -C(O)2H, -C(O)R ⁶ or -C(O)OR ⁶ ; or

R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form an optionally substituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -NR ⁶ -, -S and -S (O)2-;

R ¹² is hydrogen;

each R ¹³ is independently H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and n is 0, 1, 2, 3, or 4.

In some embodiments of a compound of formula (V), ring A is aryl;

R ¹ is -NR ^4a R ^5a ;

each R ² is independently -NR4R ⁵ , halo or optionally substituted alkyl; or

R ¹ and R ² on adjacent atoms are taken together with the atoms to which they are connected to form an optionally substituted heterocycle;

R ³ is an optionally substituted carbocyclyl;

R ^4a is optionally substituted alkyl;

R ^5a is -H or optionally substituted alkyl; or

R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R ⁴ and R ⁵ is independently —H or optionally substituted alkyl; or

R ⁴ and R ⁵ are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R ⁸ and R ⁹ is independently —H or optionally substituted alkyl; or

R ⁸ and R ⁹ are taken together with the atom to which they are attached to form an optionally substituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -S- and -S(O) _2- ;

each R ¹⁰ and R ¹¹ is independently —H or optionally substituted alkyl; or

R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form an optionally substituted ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -S- and S(O)2 -;

R ¹² is hydrogen; and n is 0 or 1.

For any possible embodiments of formulas (IV) and (V), the substituents are selected from a subset of the listed alternatives.

In some embodiments, Ring A is monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, or bicyclic heteroaryl. In some embodiments, Ring A is monocyclic heteroaryl or monocyclic aryl. In some embodiments, ring A is bicyclic heteroaryl or bicyclic aryl. In some embodiments, ring A is an N-linked heteroaryl. In some embodiments, ring A is a C-linked heteroaryl. In some embodiments, ring A is aryl.

In certain embodiments, ring A is phenyl, naphthyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl. In some embodiments, R ¹ is furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. In some embodiments, Ring A is pyrimidinyl, pyridinyl, pyrazinyl, triazinyl, or thiazolyl. In certain embodiments, ring A is a C-linked imidazolyl. In certain embodiments, ring A is an N-linked imidazolyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyrimidinyl optionally substituted with alkyl or alkoxy. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is triazinyl. In some embodiments, ring A is thiazolyl.

In some embodiments, Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ring A is phenyl or pyridinyl. In some embodiments, ring A is phenyl.

In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C2_8 alkyl, and R ^5a is -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, - S(O)2R ⁷ , -C(O)N(R ¹³ )2, -C(O)R ⁶ or -C(O)OR ⁶ . In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C2-8 alkyl, and R ^5a is -H or optionally substituted alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C2_8 alkyl, and R ^5a is -H or alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is _{C2_8} alkyl, and R ^5a is -H or C1.6 alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is ethyl, isopropyl, or t-butyl, and R ^5a is -H or C1. ₆ alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is ethyl, isopropyl, or tert-butyl, and R ^5a is C ₁ . ₆ Alkul.

In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C3-6 alkyl, and R ^5a is -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl , -S(O)2R ⁷ , -C(O)N(R ¹³ )2, -C(O)R ⁶ or -C(O)OR ⁶ . In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C3-6 alkyl, and R ^5a is -H or optionally substituted alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C3-6 alkyl, and R ^5a is -H or alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is _{C3_6} alkyl, and R ^5a is -H or C1.6 alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a4a is isopropyl or tert-butyl and R ^5a is -H or C1. ₆ alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a4a is isopropyl or tert-butyl and R ^5a is C ₁ . ₆ alkyl.

In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C2-4 alkyl, and R ^5a is -H, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl , -S(O)2R ⁷ , -C(O)N(R ¹³ )2, -C(O)R ⁶ or -C(O)OR ⁶ . In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is _C2-4 alkyl, and R ^5a is -H or optionally substituted alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is C2-4 alkyl, and R ^5a is -H or alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is _{C2_4} alkyl, and R ^5a is -H or C1.6 alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is ethyl, isopropyl, or t-butyl, and R ^5a is -H or C1. ₆ alkyl. In some embodiments, R ¹ is -NR ^4a R ^5a , R ^4a is ethyl, isopropyl, or tert-butyl, and R ^5a is C ₁ . ₆ Alkul.

In some embodiments, R ¹ is -NMeEt. In some embodiments, R ¹ is -NEt2. In some embodiments, R ¹ is -NMeiPr. In some embodiments, R ¹ is -NHEt. In some embodiments, R ¹ is -NHiPr.

In some embodiments, R ¹ is -NR ^4a R ^5a , and R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted heterocycle. In other embodiments, R ¹ is -NR ^4a R ^5a , and R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted 4-, 5-, or 6-membered

- 54 041590 heterocyclic ring, additionally containing 0-3 heteroatoms selected from -O-, -NH-, -NR ⁶ -, -S- and -S(O) 2-. In some embodiments, R ¹ is -NR ^4a R ^5a , and R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted 4-, 5-, or 6-membered heterocycle further containing 0 or 1 oxygen as a heteroatom. In other embodiments, R ¹ is -NR ^4a R ^5a , and R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted 4-, 5-, or 6-membered heterocyclic ring further containing 1 a heteroatom selected from -O-, -NH-, -NR ⁶ -, -S and -S(O) ₂ -. In other embodiments, R ¹ is -NR ^4a R ^5a and R ^4a and R ^5a are taken together with the N atom to which they are attached to form a 4-, 5-, or 6-membered ring. In other embodiments, R ¹ is -NR ^4a R ^5a , and R ^4a and R ^5a are taken together with the N atom to which they are attached to form

or

In other embodiments, R ¹ is -NR ^4a R ^5a , and R ^4a and R ^5a are taken together with the N atom to which they are attached to form an optionally substituted pyrrolidinyl, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted piperidinyl, or an optionally substituted piperidinyl substituted piperazinyl.

In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 3 or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

In some embodiments, each R ² is independently -NR ⁴ R ⁵ , optionally substituted alkyl-NR ⁴ R ⁵ , halo, -OR ⁶ , -OH, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted hydroxyalkyl, -C(O)R ⁶ , -C(O)NR ⁴ R ⁵ , -S(O) ₂ NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ or -CN. In some embodiments, each R ² is independently -NR ⁴ R ⁵ , alkyl-NR ⁴ R ⁵ , halogen, -OR ⁶ , -OH, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, -C (O)R ⁶ , -C(O)NR ⁴ R ⁵ , -S(O) ₂ NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , or -CN. In some embodiments, each R ² is independently -NR ⁴ R ⁵ , halogen, -OR ⁶ , optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, -C(O)NR ⁴ R ⁵ . -S(O)2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ , -CN or -CO2H. In certain embodiments, each R ² is independently -NR ⁴ R ⁵ , halogen, -OR ⁶ , -OH, optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted hydroxyalkyl, -S( O) _2NR ⁴ R ⁵ , -S(O)2R ⁷ , -NR ⁴ S(O)2NR ⁴ R ⁵ or -CN. In some embodiments, each R ² is independently -NR ⁴ R ⁵ , halogen, -OR ⁶ , alkyl, fluoroalkyl, carbocyclyl, heteroalkyl, heterocyclyl, -S(O) ₂ NR ⁴ R ⁵ , -NR ⁴ S(O) 2NR ⁴ R ⁵ or -S(O)2R ⁷ . In some embodiments, each R ² is independently -NR4R ⁵ , C1-6alkyl-NR ⁴ R ⁵ , halo, -OR ⁶ , -OH, C1-6alkyl, C _1-6 fluoroalkyl, C _3-6 carbocyclyl, C _{1 -6} alkyl-C _3-6 carbocyclyl, C _1-6 heteroalkyl, C _3-6 heterocyclyl, C _1-6 alkyl-C _3-6 heterocyclyl, C _1-6 hydroxyalkyl or -CN. In some embodiments, each R ² is independently -C(O)R ⁶ , -C(O)NR ⁴ R ⁵ , -S(O)2NR ⁴ R ⁵ , -S(O)2R ^{7 ,} or -CN. In some embodiments, each R ² is independently -NR ⁴ R ⁵ , halo, -OR ⁶ , C _1-6 alkyl, C _1-6 fluoroalkyl, C _3-6 carbocyclyl, C _1-6 heteroalkyl, C _3-6 heterocyclyl or -CN. In some embodiments, each R ² is independently —NR ⁴ R ⁵ , halo, alkyl, carbocyclyl, alkoxy, or —CN.

In some embodiments, each R ² is independently —NR ⁴ R ⁵ , halogen, alkyl, or alkoxy. In some embodiments, each R ² is independently methyl, methoxy, ethyl, propyl, isopropyl, cyclopropyl, fluorine, chlorine, or —NMe ₂ . According to

- 55 041590 in some embodiments, each R ² is independently methyl, methoxy, isopropyl, cyclopropyl, fluorine, chlorine, or -NMe ₂ . In some embodiments, R ² is methoxy. In some embodiments, R ² is methyl. In some embodiments, R ² is ethyl. In some embodiments, R ² is isopropyl. In some embodiments, R ² is propyl. In some embodiments, R ² is cyclopropyl. In some embodiments, R ² is cyclobutyl. In some embodiments, R ² is fluorine. In some embodiments, R ² is chlorine.

In certain embodiments, each R ² is independently optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, each R ² is independently optionally substituted with fluorine or C|- ₆ alkyl. In some embodiments, each R ² is independently optionally substituted with fluorine or methyl.

In some embodiments, R ¹ and R ² on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted heterocycle. In some embodiments, R ¹ and R ² on adjacent atoms are taken together with the atoms to which they are attached to form a heterocycle. In some embodiments, R ¹ and R ² on adjacent atoms are taken together with the atoms to which they are attached to form 1,4-dioxane or 1,3-dioxolane.

In some embodiments, R ³ is optionally substituted C2-8 alkyl, halo, haloalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, -Si(R ⁶ )3, -OR ⁶ or -S(O)2R ⁷ . In some embodiments, R ³ is C2-8 alkyl, halo, haloalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, heteroalkyl, aryl, optionally substituted heteroaryl, -Si(R ⁶ ) ₃ , -OR ⁶ , or -S(O)2R ⁷ . In some embodiments, R ³ is C2-8 alkyl, halo, haloalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, or heteroalkyl. In some embodiments, R ³ is C _2-8 alkyl, halogen, haloalkyl, deuteroalkyl, or carbocyclyl, where R ³ is optionally substituted with halogen, alkyl, alkoxy, hydroxy, -NR4R ⁵ or -S(O)2R ⁷ . In some embodiments, R ³ is C2-8 alkyl, C _1-6 haloalkyl, or C _3-6 carbocyclyl.

In some embodiments, R ³ is CF3, t-butyl, or cyclopropyl. In some embodiments, R ³ is C _4-8 alkyl. In some embodiments, R ³ is tert-butyl. In some embodiments, R ³ is haloalkyl. In some embodiments, R ³ is CF3. In some embodiments, R ³ is an optionally substituted carbocyclyl. In some embodiments, R ³ is cyclopropyl.

In certain embodiments, R ³ is optionally substituted with halogen, alkyl, hydroxy, alkoxy, -NR4R ⁵ , -S(O)2R ⁷ , or fluoroalkyl. In some embodiments, R ³ is optionally substituted with chlorine, fluorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, dimethylamino, diethylamino, methylamino, amino, -S(O)2Me or trifluoromethyl. In certain embodiments, R ³ is optionally substituted with chlorine, fluorine, methyl, hydroxy, methoxy, dimethylamino, S(O)2Me, or trifluoromethyl.

In some embodiments, each R ⁸ and R ⁹ is independently -H, C1-6alkyl, C1-6haloalkyl, halogen, C3-6carbocyclyl, C1_6alkyl-C3_6carbocyclyl, C1-6heteroalkyl, C3_6heterocyclyl, C1_6alkyl-C3_6heterocyclyl, -OH, ^-OR6 , -NR4R ⁵ , -C(O)nR ⁴ R ⁵ , -CN, -S(O)2R ⁷ , -C(O)2H, -C(O)R ⁶ or -C(O)OR ⁶ or R ⁸ and R ⁹ are taken together with the atom to which they are attached to form a ring containing 0-2 heteroatoms selected from the group consisting of -O-, -NH-, -NR ⁶ -, -S- and -S( O)2-. In some embodiments, each R ⁸ and R ⁹ is independently -H, C1-6 alkyl, halo, C3_6 carbocyclyl, methoxy, ethoxy, propoxy, isopropoxy, -NH2, -NMe2, -NHMe, -NEt2, -C(O)NH2 , -C(O)NMe2, -C(O)NHMe or -CN. In some embodiments, each R ⁸ and R ⁹ is independently -H, C 1-6 alkyl, C _1-6 fluoroalkyl, halogen, or C _3-6 carbocyclyl. In some embodiments, each R ⁸ and R ⁹ is independently -H, C1-6 alkyl, or C3-6 carbocyclyl. In some embodiments, each R ⁸ and R ⁹ is independently -H or C1-6 alkyl. In some embodiments, R ⁸ is -H and R ⁹ is C1-6alkyl, C1-6fluoroalkyl, or C3-6carbocyclyl. In some embodiments, R ⁸ is -H and R ⁹ is alkyl. In some embodiments, R ⁸ is C 1-6 alkyl, C _1-6 fluoroalkyl, or C ₃ _ ₆ carbocyclyl, and R ⁹ is -H. In some embodiments, R ⁸ is methyl,

- 56 041590 and R ⁹ is -H. In some embodiments, R ⁸ and R ⁹ are

-N. In some embodiments, R ⁸ and R ⁹ are C1. ₆ alkyl. In some embodiments, R ⁸ and R ⁹ are methyl.

In other embodiments, R ⁸ and R ⁹ are taken together with the atom to which they are attached to form a 3-, 4-, 5-, or 6-membered ring containing 0-2 heteroatoms selected from the group consisting of -O- , -NH-, -NR ⁶ -, -S- and -S(O) ₂ -. In some embodiments, R ⁸ and R ⁹ are taken together with the atom to which they are attached to form a 3-, 4-, 5-, or 6-membered carbocyclic ring.

In some embodiments, each R ¹⁰ and R ¹¹ is independently -H, alkyl, halogen, haloalkyl, carbocyclyl, heteroalkyl, or -OH. In other embodiments, each R ¹⁰ and R ¹¹ is independently —H, C1-6alkyl, halogen, C1_6alkoxy, or —OH. In certain embodiments, each R ¹⁰ and R ¹¹ is independently —H or C1_6alkyl. In certain embodiments, each R ¹⁰ and R ¹¹ is independently —H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In certain embodiments, each R ¹⁰ and R ¹¹ is independently —H, fluoro, or methyl. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or methyl. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or fluorine. In certain embodiments, both R ¹⁰ and R ¹¹ are —H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or methoxy. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or -OH. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or fluorine. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or chlorine.

In some embodiments, each R ¹⁰ and R ¹¹ is independently -H, alkyl, halo, haloalkyl, carbocyclyl, heteroalkyl, or -OH, where at least one of R ¹⁰ or R ¹¹ is not H. In other embodiments, each R ¹⁰ and R ¹¹ is independently -H, C^alkyl, halogen, C1_6alkoxy, or -OH, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently - H or C1_6alkyl, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , sec-butyl, or tert-butyl, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently —H, fluoro, or methyl, where at least one of R ¹⁰ or R ¹¹ is not H. According to in certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or methyl, wherein at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or fluoro, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or methoxy, where at least one of R ¹⁰ or R ¹¹ is not H. According to certain in embodiments, each R ¹⁰ and R ¹¹ is independently -H or -OH, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or fluorine, where at least one of R ¹⁰ or R ¹¹ is not H. In certain embodiments, each R ¹⁰ and R ¹¹ is independently -H or chlorine, where at least one of R ¹⁰ or R ¹¹ is not H.

In some embodiments, R ¹⁰ and R ¹¹ are methyl. In some embodiments, R ¹⁰ and R ¹¹ are ethyl. In some embodiments, R ¹⁰ and R ¹¹ are propyl. In some embodiments, R ¹⁰ and R ¹¹ are fluorine. In some embodiments, R ¹⁰ and R ¹¹ are chlorine. In some embodiments, R ¹⁰ and R ¹¹ are bromine. In some embodiments, R ¹⁰ and R ¹¹ are methoxy. In some embodiments, R ¹⁰ and R ¹¹ are ethoxy. In some embodiments, R ¹⁰ and R ¹¹ are —OH.

In some embodiments, R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form a 3-, 4-, 5-, or 6-membered ring. In some embodiments, R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R ¹⁰ and R ¹¹ are taken together with the atom to which they are attached to form cyclopropyl.

In certain embodiments, R ¹⁰ and R ¹¹ are optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R ¹⁰ and R ¹¹ are optionally substituted with fluoro or _{C1_6} alkyl. In some embodiments, R ¹⁰ and R ¹¹ are optionally substituted with fluorine or methyl.

In some embodiments, R ¹² is hydrogen, _{C1_6} alkyl, _{C1_6} haloalkyl _{, C1_6} deuteroalkyl, _{C3_6} carbocyclyl, _{C3_6} carbocyclyl _{- C1_6} alkyl _{, C3_6 heterocyclyl} ,

- 57 041590

From ₃ . ₆ heterocyclyl-C ₁ . ₆ alkyl. In some embodiments, R ¹² is hydrogen, alkyl, haloalkyl, hydroxy, halogen, carbocyclyl, or heteroalkyl. In some embodiments, R ¹² is hydrogen, C1-balkyl, C1-bfluoroalkyl, carbocyclyl, or heterocyclylalkyl. In certain embodiments, R ¹² is C1-bαkyl or C1 _-b fluoroalkyl. In some embodiments _, R ¹² is C _1-b αkyl, C _1-b haloalkyl, C _1-b deuteroalkyl, C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-6 alkyl, C _3-6 heterocyclyl, C _3-6 heterocyclyl-C _1-6 alkyl. In some embodiments, R ¹² is alkyl, haloalkyl, hydroxy, halogen, carbocyclyl, or heteroalkyl. In some embodiments, R ¹² is C1.6 alkyl, C1.6 fluoroalkyl, carbocyclyl, or heterocyclylalkyl. In certain embodiments, R ¹² is C1. ₆ alkyl or C ₁ . _b fluoroalkyl. In certain embodiments, R ¹² is hydrogen. In some embodiments, R ¹² is C ₁ . ₆ alkyl. In some embodiments, R ¹² is _C1-3 alkyl. In some embodiments, R ¹² is C2-8 alkyl. In some embodiments, R ¹² is _C3-6 alkyl. In some embodiments, R ¹² is methyl. In some embodiments, R ¹² is ethyl. In some embodiments, R ¹² is propyl. In some embodiments, R ¹² is isopropyl. In some embodiments, R ¹² is tert-butyl. In some embodiments, R ¹² is butyl. In some embodiments, R ¹² is isobutyl. In some embodiments, R ¹² is sec-butyl. In some embodiments, R ¹² is carbocyclyl. In some embodiments, R ¹² is cyclopropyl. In some embodiments, R ¹² is cyclobutyl. In some embodiments, R ¹² is cyclopentyl. In some embodiments, R ¹² is cyclohexyl. In some embodiments, R ¹² is trifluoromethyl. In some embodiments, R ¹² is hydroxyalkyl. In some embodiments, R ¹² is deuteromethyl.

In certain embodiments, R ¹² is optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R ¹² is optionally substituted with fluorine or C ₁ _ _b alkyl. In some embodiments, R ¹² is optionally substituted with fluorine or methyl.

In some embodiments, each R ⁴ and R ⁵ is independently -H, optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, -S(O)2R ⁷ or -C(O )N(R ¹³ )2. In some embodiments, each R ⁴ and R ⁵ is independently -H, C1.6alkyl, C1.6fluoroalkyl, C3-6carbocyclyl, C1.6carbocyclylalkyl, C2-6heterocyclyl, C1.6alkyl-C3.6heterocyclyl, -S(O)2R ⁷ or -C(O)N(R ¹³ )2. In some embodiments, each R ⁴ and R ⁵ is independently -H, C1_balkyl, C1.6fluoroalkyl, C3-bcarbocyclyl, C3-5heterocyclyl, or -S(O)2R ⁷ . In some embodiments, each R ⁴ and R ⁵ is independently -H, C1_ _b alkyl, or -S(O) ₂ R ⁷ . In some embodiments, each R ⁴ and R ⁵ is independently -H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl, or -S(O)2R ⁷ . In some embodiments, each R ⁴ and R ⁵ is independently —H, methyl, ethyl, propyl, or isopropyl. In some embodiments, R ⁴ and R ⁵ are -H. In some embodiments, R ⁴ and R ⁵ are methyl. In some embodiments, R ⁴ is methyl and R ⁵ is ethyl. In some embodiments, R ⁴ is methyl and R ⁵ is propyl. In some embodiments, R ⁴ is methyl and R ⁵ is isopropyl. In some embodiments, R ⁴ is H and R ⁵ is isopropyl. In some embodiments, each R ⁴ and R ⁵ is independently -H or -C(O)N(R ¹³ )2.

In other embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form an optionally substituted 4-, 5-, or 6-membered heterocyclic ring further containing 0- 3 heteroatoms selected from -O-, -NH-, -NR ⁶ -, -S- and -S(O)2-. In some embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form a 4-, 5-, or 6-membered heterocycle further containing 0 or 1 oxygen in as a heteroatom. In other embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form an optionally substituted 4-, 5-, or 6-membered heterocyclic ring further containing 1 heteroatom selected from -O-, -NH-, -NR ⁶ -, -S and -S(O)2-. In other embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form a 4-, 5-, or 6-membered heterocyclic ring further containing 1 oxygen as heteroatom. In other embodiments, R ⁴ and R ⁵ bonded to the same N atom are taken together with the N atom to which they are bonded to form a 4-, 5-, or 6-membered ring.

In certain embodiments, each R ⁴ and R ⁵ is independently optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, each R ⁴ and R ⁵ is independently optionally substituted with fluorine or C ₁ . ₆ alkyl. In some embodiments, each R ⁴ and R ⁵ is independently optionally substituted with fluorine or methyl.

In some embodiments, R ⁶ is optionally substituted alkyl, fluoroalkyl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl. In some embodiments, R ⁶ is optionally substituted alkyl, fluoroalkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl. In some embodiments, R ⁶ is alkyl, aryl, carbocyclyl, or heterocyclyl. In some embodiments, R ⁶ is alkyl, carbocyclyl, or heterocyclyl. In some embodiments, R ⁶ is alkyl, carbocyclyl, or fluoroalkyl. In some embodiments, R ⁶ is C1_6alkyl, C1.6fluoroalkyl, C3_6carbocyclyl, or C3_6heterocyclyl. In certain embodiments, R ⁶ is C1. ₆ alkyl. In certain embodiments, R ⁶ is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl. In some embodiments, R ⁶ is an optionally substituted phenyl.

In some embodiments, R ⁷ is alkyl, carbocyclyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heterocyclyl. In some embodiments, R ⁷ is C1.6 alkyl, C3-6 carbocyclyl, or aryl optionally substituted with halo or alkyl. In some embodiments, R ⁷ is C1. ₆ alkyl, C ₃ - ₆ carbocyclyl or phenyl optionally substituted with halogen or alkyl. In some embodiments, R ⁷ is an optionally substituted benzyl. In some embodiments, R ⁷ is C3_6 carbocyclyl. In some embodiments, R ⁷ is phenyl. In some embodiments, R ⁷ is phenyl substituted with 1-4 C1 substituents. ₆ alkyl or fluoro. In some embodiments, R ⁷ is phenyl substituted with a C ₁ substituent. ₆ αlkyl or fluorine. In some embodiments, R ⁷ is alkyl, carbocyclyl, aralkyl, or heterocyclyl.

In certain embodiments, R ⁷ is optionally substituted with halogen, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R ⁷ is optionally substituted with fluoro or C ₁ . ₆ alkyl. In some embodiments, R ⁷ is optionally substituted with fluorine or methyl.

In some embodiments, each R ¹³ is independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, each R ¹³ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, or optionally substituted aryl. In some embodiments, each R ¹³ is independently optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted aryl, or heteroaryl. In some embodiments, each R ¹³ is independently alkyl or aryl. In some embodiments, each R ¹³ is independently hydrogen or C ₁ . ₆ alkyl. In some embodiments, each R ¹³ is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl. In some embodiments, each R ¹³ is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, or t-butyl. In some embodiments, each R ¹³ is independently hydrogen or methyl. In some embodiments, R ¹³ is H. In other embodiments, R ¹³ is alkyl. In other embodiments, R ¹³ is aryl.

Any combination of the groups described above for various variables is provided herein. In the present description, the groups and their substituents are selected by a person skilled in the art to obtain stable fragments and compounds.

In some embodiments, the substituted steroid derivative described by the formulas provided herein has the structure shown in Table 1. 1.

- 59 041590

Table 1

No. Structure Mass, [M+H] ⁺ No. Structure Mass, [M+N] ⁺ 1 ⁿ X ⁿ F/ \ f aT n 500.5 2 hSh / 'x. 1 nt and f y f T yTn 502.4 3 1 mch o (__ ^x o o 489.4 4 / hh ⁿ T ⁿ F/ f TjTy _O <H/HH 518.5 5 i o*HH LF 0^0 o 475.4 6 1 ⁿ X ⁿ fu G TaJ a 488.5 7 with about z— ^/ about '--ν' ¹ / φΤθ I 516.3 8 / ⁿ T ⁿ Tch - g t ^A J ^{1 \u003d 1} _O <HH\H 516.5 9 V ° Fb V7O I 502.4 10 / XLchtL'^^ ⁿ X ⁿ Tch G T^T ^A ₀ <hhhh 488.4 eleven X1chF.fL nfnfr f Ta J i sg'HHHH 516.5 12 X X / O ΙΖ ^x o \ -- 13 I NJ About 2 LF fTo ΐ 446.3 14 'T ^F HN^T / CX/-TT^' I T N f U g T ^A T ⁿ _o <hhhh 506.5 15 1 Λ U\ ° 520.4 16 h 4T Fr fTo 1 516.5 17 1 ,N. Γ 11 ι °Τ=—-\ < τ η τ / Γ ΦαΤ ⁿ ₀ <hh<h 476.4 18 υ44 4^ . F ⁿ f / G T a t y _o <hhhh 486.4

- 60 041590

19 474.4 20 XX^xLg ⁿ X ⁿ X / X fnTy 529.4 21 l , X ⁿ X y G ^A 500.5 22 o / ¹⁴ X ⁿ X/ X X ^Y X ^y 564.3 23 n . χκχχ G T n T n 432.4 24 o Χ'Ν'^η ⁿ X ⁿ X / G T y T a 557.5 25 ⁿ d ⁿ > \ 1 ychr 615.3 26 ζ O <m X 418.3 27 o Ίρ ^N X ^N XX G T n T n 593.4 28 । X ⁿ X / G T a T y 498.4 29 V ⁰ mH τι D -4 - x/^o 1 "P 526.3 thirty + /H nR XX § 460.4 31 iShD^ i X n χ 5 G T n T n 468.4 32 1 f !Х ^Н XX/ χ Х^Хй -

In some embodiments, the substituted steroid derivative described by the formulas provided herein has the structure shown in Table 1. 2.

-61 041590

table 2

No. Structure la f About Z-S V ___/ f Up ξ-οξ f f 2a 't' ^F Χ1 ^FH X ^H jO f T^Th Behind 1 °*w /—V ¹ ( ^T /—\ / ^—x 1/04 1° ° 4a T. _: /—\ ^x \ ^T /--\ /—\ ^ll=l= / 04 IZ O 5a H ₂ N_^ / i X ^H X / Г ТнТh 6a ., a V___. .___/ o pd '—V ¹ / \4<o t 7a 1 /—\ ^II=E )--QU ) 04 0 ° °4

- 62 041590

Preparation of substituted steroid derivatives of compounds.

The compounds used in the reactions described herein are prepared according to organic synthetic procedures known to those skilled in the art, starting from commercially available chemicals and/or from compounds described in the chemical literature. Commercially available chemicals are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (WestChester, PA), Crescent Chemical Co. (Haapauj, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Wyndham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CT), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, Oregon), Trans World Chemicals, Inc. (Rockville, MD) and Wako Chemicals USA, Inc. (Richmond, Virginia).

Suitable reference literature and scientific writings that detail the synthesis of reagents useful in the preparation of the compounds described herein, or which provide links to articles that describe the preparation, include, for example, Synthetic Organic Chemistry, John Wiley & Sons, Inc. ., NY; S.R. Sandier et al., Organic Functional Group Preparations, 2nd edition, Academic Press, New York, 1983; H.O. House, Modern Synthetic Reactions, 2nd edition, W.A. benjamin,

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Inc. Menlo Park, California, 1972; T.L. Gilchrist, Heterocyclic Chemistry, 2nd edition, John Wiley & Sons, New York, 1992; J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Edition, Wiley-Interscience, New York, 1992 compounds document, or which provide links to articles that describe the preparation, include, for example, Fuhrhop J. and Penzlin G. Organic Synthesis: Concepts, Methods, Starting Materials, second revised and expanded edition (1994), John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. Organic Chemistry, An Intermediate Text (1996), Oxford University Press, ISBN 0-19-509618-5; Larock, R.C. Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th edition (1992), John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (ed.) Modern Carbonyl Chemistry (2000), Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. Patai's 1992 Guide to the Chemistry of Functional Groups (1992) Interscience ISBN: 0-471-93022-9; Solomons, T.W.G. Organic Chemistry, 7th edition (2000), John Wiley & Sons, ISBN: 0-471-19095-0; Stowell J.C. Intermediate Organic Chemistry, 2nd edition (1993), Wiley-Interscience, ISBN: 0-471-57456-2; Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia (1999) John Wiley & Sons, ISBN: 3-52729645-X, in 8 volumes; Organic Reactions (1942-2000), John Wiley & Sons, in over 55 volumes; and Chemistry of Functional Groups John Wiley & Sons, in 73 volumes.

Specific and similar reagents are optionally identified using the American Chemical Society's Chemical Abstracts Index of Known Chemicals, available from most public and university libraries, and online databases (for more information, refer to the American Chemical Society, Washington, DC) . Chemicals that are known but not commercially available in catalogs are optionally custom-made from chemical synthesis firms in cases where many standard chemical supply firms (such as those listed above) provide services for individual synthesis. Reference regarding the preparation and selection of pharmaceutical salts of the substituted steroid derivatives of the compounds described herein is P.H. Stahl & C.G. Wermuth Handbook of Pharmaceutical Salts, Verlag Helvetica Chimica Acta, Zurich, 2002.

Pharmaceutical compositions of substituted steroid derivatives of compounds.

In certain embodiments, the substituted steroid derivative described herein is administered as a chemically pure substance. In other embodiments, the substituted steroid derivative described herein is combined with a pharmaceutically acceptable or acceptable carrier (also referred to herein as a pharmaceutically acceptable (or acceptable) excipient, a physiologically acceptable (or acceptable) excipient, or a physiologically acceptable (or acceptable) carrier) selected based on the chosen route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition. Mack Pub. Co., Easton, PA (2005) ).

Provided herein is a pharmaceutical composition comprising at least one substituted steroid derivative, or stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or appropriate if the carrier is compatible with the other ingredients of the composition and does not adversely affect the recipient (ie, subject) receiving the composition.

One embodiment relates to a pharmaceutical composition comprising a compound of any of the formulas provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In certain embodiments, the substituted steroid derivative compound described by any of the formulas provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1% other organic small molecules, such as unreacted intermediates or synthetic by-products, which are formed, for example, in one or more of their synthetic process steps.

Suitable dosage forms for oral administration include, for example, tablets, pills, sachets or capsules of hard or soft gelatin, methylcellulose or other suitable material readily soluble in the gastrointestinal tract. In some embodiments, suitable non-toxic solid carriers are used which include, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. pharmaceutical grade, (see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition. Mack Pub. Co., Easton, PA (2005)).

The dosage of a composition containing at least one substituted steroid derivative described herein differs depending on the condition of the patient (eg, human), i.e. stage of the disease, general health, age and other factors.

The pharmaceutical compositions are administered in a manner suitable for the disease being treated (or prevented). The appropriate dose and appropriate duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the route of administration. In general, an appropriate dose and treatment regimen will deliver the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., improved clinical outcome such as more complete or partial remissions, or longer relapse-free survival and/or or overall survival or improvement in symptom severity.Optimal doses are generally determined using experimental models and/or clinical trials.The optimal dose depends on the body weight, weight, or blood volume of the patient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times or more per day.

The use of substituted steroid derivatives of compounds.

Modulators of glucocorticoid receptors.

Mifepristone is a non-selective modulator of several nuclear receptors. Mifepristone has been referred to in the scientific literature as a GR antagonist, progesterone receptor (PR) antagonist, GR partial agonist, androgen receptor (AR) antagonist, and AR partial agonist. The activity observed on several hormone receptors leads to various undesirable side effects and, in some cases, the development of cancer. Thus, AR agonistic activity is an undesirable property of GR antagonists used in the treatment of cancer (eg, AR-positive or AR-dependent cancers, including castration-resistant prostate cancer (CRPC), breast cancer, or ovarian cancer). There is a need for GR antagonists, which are characterized by a minimized ability to bind to other hormone receptors, such as the androgen receptor (AR), for effective treatment of the diseases described herein, with reduced side effects.

Certain embodiments provided herein describe compounds that are glucocorticoid receptor (GR) modulators. In some embodiments, the compounds alter the level and/or activity of GR. In some embodiments, the compounds described herein are GR inhibitors. In some embodiments, GR inhibitors are GR antagonists. In some cases, glucocorticoid receptor antagonists bind to the receptor and prevent the binding of glucocorticoid receptor agonists and the occurrence of GR-mediated events, including transcription. Thus, in some embodiments, the compounds described herein inhibit the activity of GR in relation to transcriptional activation. In some embodiments, the compounds described herein are selective GR antagonists. In some embodiments, the compounds described herein are not GR agonists. In some embodiments, the compounds described herein are not partial GR agonists. In some embodiments, GR inhibitors reduce the activity of cortisol in cells and make secondary therapeutics more effective.

GR antagonists are useful in the treatment or prevention of weight gain (eg, olanzapine-induced weight gain), uterine fibrosis, alcoholism, alcohol dependence disorders, cocaine addiction, bipolar depression, adrenocortical hypercortisolism, post-traumatic stress disorder , anxiety neurosis, affective disorders, hyperglycemia and for the induction of abortion.

In some embodiments, the GR inhibitors described herein are also inhibitors of androgen receptor (AR) signaling. In certain embodiments, AR signaling inhibitors are AR antagonists. In some cases, AR antagonists bind to the AR and prevent the binding of AR agonists and the occurrence of AR-mediated events, including transcription. In other embodiments, the GR inhibitors are not inhibitors of androgen receptor (AR) signaling. In such cases, GR inhibitors do not significantly reduce AR levels and/or activity. In some embodiments, the GR inhibitors are not AR agonists.

In some embodiments, the GR inhibitors described herein are characterized by a minimized androgen receptor (AR) binding ability. In some embodiments, the compounds described herein are not AR agonists. In some embodiments, the compounds described herein are not partial AR agonists. In some embodiments, the compounds described herein are characterized by a minimized partial AR agonist activity compared to mifepristone.

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In some embodiments, the GR inhibitors described herein are not AR partial agonists or GR partial agonists.

In some embodiments, the GR inhibitors described herein do not modulate progesterone receptors. In some embodiments, the GR inhibitors described herein are not progesterone receptor (PR) inhibitors. In such cases, GR inhibitors do not significantly reduce PR levels and/or activity. In some embodiments, GR inhibitors are not PR agonists. In some embodiments, GR inhibitors are not partial PR agonists. In some embodiments, GR inhibitors are not PR antagonists.

In some embodiments, GR inhibitors (eg, GR antagonists) are selective inhibitors. In some embodiments, the use of GR inhibitors in a patient does not cause or cause vaginal bleeding, spasm, nausea, vomiting, diarrhea, dizziness, back pain, weakness, fatigue, or combinations thereof. In certain embodiments, the use of GR inhibitors in a patient does not cause or cause vaginal bleeding. In certain embodiments, the use of GR inhibitors in a patient does not cause or cause spasm. In some embodiments, the use of GR inhibitors in a patient does not cause or cause allergic reactions, low blood pressure, unconsciousness, shortness of breath, palpitations, or combinations thereof.

Methods of treatment.

Cancer.

One embodiment relates to a method of treating cancer in a subject in need, comprising administering to the subject a compound of any of the formulas provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, a GR inhibitor as described herein is used in combination with a second therapeutic agent (eg, an anti-cancer agent) to treat cancer. In some embodiments, the combination of a GR inhibitor with a second therapeutic agent (eg, an anticancer agent) provides a more effective first line therapy in the treatment of cancer compared to a second therapeutic agent (eg, an anticancer agent) administered alone. In some embodiments, a GR inhibitor as described herein is used in combination with one or more additional therapeutic agents (eg, anti-cancer agents) to treat cancer. In some embodiments, the combination of a GR inhibitor with one or more additional therapeutic agents (eg, anti-cancer agents) provides a more effective first line therapy for treating cancer compared to one or more therapeutic agents (eg, anti-cancer agents) administered alone.

In some embodiments, the cancer is chemotherapy-resistant cancer, radiation therapy-resistant cancer, or refractory cancer. In some embodiments, the cancer is recurring cancer, persistent cancer, or recurrent cancer. According to another embodiment presented herein, a method for reducing the incidence of cancer recurrence is described. Also in some embodiments, provided herein is a method for treating chemotherapy-resistant cancer.

Prostate cancer.

Prostate cancer is the second leading cause of cancer death among men in the United States, and approximately one in six American men will be diagnosed with the disease during their lifetime. Treatment aimed at destroying the tumor is unsuccessful in 30% of men.

One embodiment relates to a method of treating prostate cancer in a subject in need, comprising administering to the subject a compound of any of the formulas provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, a GR inhibitor as described herein is used in combination with a second therapeutic agent (eg, an anti-cancer agent) for the treatment of prostate cancer. In some embodiments, the combination of a GR inhibitor with a second therapeutic agent (eg, an anticancer agent) provides a more effective first line therapy in the treatment of prostate cancer compared to a second therapeutic agent (eg, an anticancer agent) administered alone. In some embodiments, a GR inhibitor as described herein is used in combination with one or more additional therapeutic agents (eg, anti-cancer agents) to treat prostate cancer. In some embodiments, the combination of a GR inhibitor with one or more additional therapeutic agents (e.g., anti-cancer agents) provides a more effective first-line therapy for the treatment of prostate cancer compared to one or more therapeutic agents (e.g., anti-cancer agents), entered separately.

In some embodiments, the prostate cancer is chemotherapy-resistant cancer, radiation therapy-resistant cancer, antiandrogen-resistant, or refractory cancer. In some embodiments, the prostate cancer is recurring cancer, persistent cancer, or recurrent cancer.

In some embodiments, the prostate cancer is an acinar adenocarcinoma, an atrophy-like carcinoma, a foam cell carcinoma, a mucus-forming carcinoma, or a cricoid cell carcinoma. In some embodiments, the prostate cancer is ductal adenocarcinoma, transitional cell carcinoma, urothelial cancer, squamous cell carcinoma, carcinoid, small cell carcinoma, sarcoma, or sarcomatoid cancer. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer, doubly resistant prostate cancer, castration-resistant prostate cancer, hormone-resistant prostate cancer, androgen-independent, or androgen-refractory cancer.

In some cases, antiandrogens are useful in the treatment of prostate cancer in its early stages. In some cases, prostate cancer cells depend on the androgen receptor (AR) for their proliferation and survival. Some patients with prostate cancer undergo surgical castration or chemical castration with agents that block testosterone production (eg, GnRH agonists), alone or in combination with antiandrogens that counteract the effects of any residual testosterone.

In some cases, prostate cancer enters a hormone-refractory phase, in which the disease progresses despite ongoing androgen ablation or antiandrogen therapy. The hormone-refractory phase, to which most patients eventually progress in the presence of ongoing androgen ablation or antiandrogen therapy, is known as castration-resistant prostate cancer (CRPC). CRPC is associated with AR overexpression. AR is expressed in most prostate cancer cells, and overexpression of AR is necessary and sufficient for androgen-independent growth of prostate cancer cells. The failure of hormone therapy, due to the development of androgen-independent growth, is an obstacle to the successful fight against advanced prostate cancer.

While a small minority of CRPCs bypass the need for AR signaling, the great majority of CRPCs, although often referred to as androgen-independent prostate cancer or hormone-refractory prostate cancer, retain their direction of differentiation dependence on AR signaling.

Recently approved therapeutic drugs that target androgen receptor (AR) signaling, such as abiraterone and enzalutamide, have been used to treat CRPC. Despite these successes, sustained response with these agents is limited to acquired resistance, which usually develops within 6-12 months. Doubly resistant prostate cancer is characterized by tumor cells becoming castration resistant and overexpressing AR, which is a hallmark of CRPC. At the same time, cells remain resistant to treatment with second-generation antiandrogens. Cells of doubly resistant prostate cancer are characterized by the fact that when they are exposed to second-generation antiandrogens, there is no efficacy in inhibiting tumor growth.

As discussed above, resistant prostate cancer (eg, doubly resistant and castration resistant prostate cancer) occurs when cancer cells overexpress androgen receptors (AR). Expression of the AR target gene is inhibited when cells are treated with a second-generation antiandrogen. In some cases, enhanced signaling through the glucocorticoid receptor (GR) compensates for the inhibition of androgen receptor signaling in resistant prostate cancer. Doubly resistant prostate cancer develops when a subset of these AR target genes is re-expressed. In some cases, GR activation is responsible for the activation of this target gene. In some embodiments, GR transcription is upregulated in patients with or predisposed to resistant prostate cancer (eg, doubly resistant and castration resistant prostate cancer). In some cases, an increase in the level of GR expression in cancer cells causes resistance to antiandrogens.

Some embodiments provided herein describe the use of GR inhibitors for the treatment of prostate cancer in a subject in need thereof, including doubly resistant prostate cancer and castration resistant prostate cancer. In some embodiments, the subject in need has an increased level of GR expression in the tumor. In some embodiments, the GR inhibitor is also an AR signaling inhibitor or an antiandrogen.

In some embodiments, the GR inhibitor is used in combination with a second

- 67 041590 therapeutic agent. In some embodiments, the GR inhibitor is used in combination with one or more additional therapeutic agents. In some embodiments, the second or additional agent is an anticancer agent. In certain embodiments, the anticancer agent is useful in AR positive or AR negative prostate cancer.

In some embodiments, the second or additional agent is a signal transduction inhibitor or an antiandrogen. In certain embodiments, the AR signaling inhibitor is an AR antagonist. In some embodiments, the second or additional therapeutic agent is selected from finasteride, dutasteride, alphatradiol, cyproterone acetate, spironolactone, danazol, gestrinone, ketoconazole, abiraterone acetate, enzalutamide, ARN-509, danazol, gestrinone, danazol, simvastatin, aminoglutethimide, atorvastatin, simvastatin , прогестерона, ципротерона ацетата, медроксипрогестерона ацетата, мегестрола ацетата, хлормадинона ацетата, спиронолактона, дроспиренона, эстрадиола, этинилэстрадиола, диэтилстилбестрола, конъюгированных конских эстрогенов, бусерелина, деслорелина, гонадорелина, гозерелина, гистрелина, лейпрорелина, нафарелина, трипторелина, абареликса, цетрореликса, дегареликса , ganirelix or any combinations thereof or any salts. In some embodiments, the second or additional therapeutic agent is selected from flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, cyproterone acetate, megestrol acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, cimetidine, or any combinations or any salts thereof. In some embodiments, the AR signaling inhibitor is 3,3'-diindolylmethane (DIM), abiraterone acetate, ARN-509, bexlosteride, bicalutamide, dutasteride, epristeride, enzalutamide, finasteride, flutamide, isonsteride, ketoconazole, N-butylbenzenesulfonamide, nilutamide, megestrol , steroidal antiandrogens, turosteride, or any combination thereof. In some embodiments, the AR signaling inhibitor is flutamide, nilutamide, bicalutamide, or megestrol. In some embodiments, the AR signaling inhibitor is ARN-509. In other embodiments, the AR signaling inhibitor is enzalutamide.

In some embodiments, the anticancer agent is mitoxantrone, estramustine, etoposide, vinblastine, carboplatin, vinorelbine, paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel, or doxorubicin. In some embodiments, the anticancer agent is paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel, or doxorubicin. In certain embodiments, the anticancer agent is docetaxel.

Mammary cancer.

Breast cancer is the second most common cancer among women in the United States. Forms of triple negative breast cancer are among the most aggressive and difficult to treat of all types of breast cancer. Triple-negative breast cancer is a form of the disease in which the three receptors that primarily promote breast cancer growth, estrogen, progesterone, and HER-2, are absent. Because tumor cells lack these receptors, drugs that target estrogen, progesterone, and HER-2 receptors are ineffective. Approximately 40,000 women are diagnosed with triple-negative breast cancer each year. More than half of the tumor cells in these women are estimated to express significant amounts of GR.

In some cases, GR expression is associated with a poor prognosis in early stage estrogen receptor (ER) negative breast cancer. In some cases, GR activation in triple-negative breast cancer cells initiates an anti-apoptotic gene expression profile that is associated with inhibition of chemotherapy-induced tumor cell death. GR activity in such cancer cells correlates with resistance to chemotherapy and an increased rate of cancer recurrence.

In some embodiments, provided herein are methods for treating breast cancer, the method comprising administering to a subject in need thereof a compound of any of the formulas provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, a GR inhibitor as described herein is used in combination with a second therapeutic agent (eg, a chemotherapeutic agent) to treat breast cancer. In some embodiments, the combination of a GR inhibitor with a second therapeutic agent (eg, a chemotherapeutic agent) provides a more effective first line therapy in the treatment of breast cancer compared to a second therapeutic agent (eg, a chemotherapeutic agent) administered alone. In some embodiments, a GR inhibitor as described herein is used in combination with one or more additional therapeutic agents (eg, anti-cancer agents) to treat breast cancer. In some embodiments, the combination of a GR inhibitor with one or more additional therapeutic agents (e.g., anti-cancer agents) provides a more effective first-line therapy for the treatment of breast cancer compared to one or more therapeutic agents (e.g., anti-cancer agents) entered separately.

In some embodiments, the breast cancer is chemotherapy-resistant cancer, radiation therapy-resistant cancer, or refractory cancer. In some embodiments, the breast cancer is recurring cancer, persistent cancer, or recurrent cancer. Forms of breast cancer may include, without limitation, ductal carcinoma, infiltrating ductal carcinoma, tubular carcinoma of the breast, medullary carcinoma of the breast, mucoid carcinoma of the breast, papillary carcinoma of the breast, cribriform carcinoma of the breast, infiltrating lobular carcinoma, edematous infiltrative breast cancer , lobular carcinoma in situ, male breast cancer, Paget's disease of the nipple, foliar cystosarcoma of the breast, recurrent and metastatic breast cancer, triple negative breast cancer, or combinations thereof.

In some embodiments, the breast cancer is recurrent and metastatic breast cancer, triple negative breast cancer, or combinations thereof. In some embodiments, the breast cancer is chemotherapy-resistant triple negative breast cancer or estrogen receptor (ER) negative breast cancer. In some embodiments, the breast cancer is chemotherapy-resistant triple negative breast cancer. In some embodiments, the breast cancer is estrogen receptor (ER) negative breast cancer. In some embodiments, the breast cancer is GR+ triple negative breast cancer. In some embodiments, the breast cancer is GR+ estrogen receptor (ER) negative breast cancer.

Certain embodiments provided herein describe the use of GR inhibitors to treat breast cancer in a patient, including triple negative breast cancer or ER negative breast cancer. In some embodiments, GR inhibitors inhibit anti-apoptotic GR signaling pathways and increase the cytostatic efficacy of secondary chemotherapeutic agents. In some embodiments, the GR inhibitors described herein enhance the efficacy of chemotherapy in patients with breast cancer, such as patients with triple negative breast cancer. In some embodiments, the breast cancer patient has an increased level of GR expression in the tumor.

In some embodiments, the GR inhibitor described herein is used in combination with a second therapeutic agent, such as chemotherapy or immunotherapy. In some embodiments, a GR inhibitor described herein is used in combination with one or more additional therapeutic agents. In some embodiments, the second or additional chemotherapeutic agent is cisplatin, carboplatin, cyclophosphamide, capecitabine, gemcitabine, paclitaxel, nab-paclitaxel, altretamine, docetaxel, epirubicin, melphalan, methotrexate, mitoxantrone, ixabepilone, ifosfamide, irinotecan, eribulin, etoposide, doxorubicin , doxorubicin in liposomes, camptothecin, pemetrexed, topotecan, vinorelbine, daunorubicin, fluorouracil, mitomycin, thiotepa, vincristine, everolimus, veliparib, glembatumumab vedotin, pertuzumab, trastuzumab, or any combination or any salt thereof. In some embodiments, the second or additional therapeutic agent is an anti-PD-L1 antibody agent. In certain embodiments, the anti-PD-L1 antibody agent is MPDL3280A or avelumab. In some embodiments, the second or additional therapeutic agent is an anti-PD1 antibody agent. In certain embodiments, the anti-PD1 antibody agent is nivolumab or pembrolizumab.

In some embodiments provided herein, methods for treating estrogen receptor positive breast cancer are described. In some cases, patients with estrogen receptor positive breast cancer develop resistance to estrogen receptor modulators. In some embodiments, the GR inhibitors described herein increase the efficacy of estrogen receptor modulators in patients with estrogen receptor positive breast cancer. In some embodiments, the breast cancer patient has an increased level of GR expression in the tumor. In some embodiments, a GR inhibitor as described herein is used in combination with an estrogen receptor modulator. In some embodiments, the estrogen receptor modulator is tamoxifen, raloxifene, toremifene, tibolone, fulvestrant, lasofoxifene, clomiphene, ormeloxifene

- 69 041590 or ospemifene. In some embodiments, the estrogen receptor modulator is tamoxifen, raloxifene, toremifene, tibolone, or fulvestrant. In some embodiments, the estrogen receptor modulator is tamoxifen, raloxifene, or toremifene. In certain embodiments, the estrogen receptor modulator is tamoxifen.

Ovarian cancer.

Ovarian cancer is the leading cause of death from gynecological malignancies. Some forms of ovarian cancer (eg, high-grade serous ovarian cancer) are initially sensitive to platinum-based therapy, but the recurrence rate remains high.

One embodiment relates to a method of treating ovarian cancer in a patient in need thereof, comprising administering to the patient a compound of any of the formulas provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has an increased level of GR expression in the tumor. In some embodiments, a GR inhibitor as described herein is used in combination with a second therapeutic agent (eg, a chemotherapeutic agent) to treat ovarian cancer. In some embodiments, the combination of a GR inhibitor with a second therapeutic agent (eg, a chemotherapeutic agent) provides a more effective first line therapy in the treatment of ovarian cancer compared to a second therapeutic agent (eg, a chemotherapeutic agent) administered alone. In some embodiments, a GR inhibitor as described herein is used in combination with one or more additional therapeutic agents (eg, anti-cancer agents) to treat ovarian cancer. In some embodiments, the combination of a GR inhibitor with one or more additional therapeutic agents (eg, anti-cancer agents) provides a more effective first-line therapy for the treatment of ovarian cancer compared to one or more therapeutic agents (eg, anti-cancer agents) administered alone.

In some cases, GR activation leads to increased resistance to chemotherapy in ovarian cancer (eg, high-grade serous ovarian cancer). In some cases, GR activation leads to a significant inhibition of chemotherapy-induced apoptosis of ovarian cancer cells. In some embodiments, provided herein are methods of treating ovarian cancer in a subject, the method comprising treating the subject with a GR inhibitor (eg, a GR antagonist) to improve response to chemotherapy. In some embodiments, the ovarian cancer has become resistant to chemotherapy. In some embodiments, the ovarian cancer cells are resistant to cisplatin, paclitaxel, carboplatin, gemcitabine, alone or in combination. In some embodiments, the GR inhibitor or antagonist reverses the cell survival effect.

Forms of ovarian cancer may include, without limitation, forms of epithelial ovarian cancer such as serous epithelial ovarian cancer, endometrioid epithelial ovarian cancer, clear cell epithelial ovarian cancer, mucinous epithelial ovarian cancer, undifferentiated or unclassified epithelial ovarian cancer, refractory ovarian cancer, genital stromal tumors. cord, Sertoli and Sertoli-Leydig cell tumors, germ cell tumors such as dysgerminoma and non-dysgerminoma tumors, Brenner tumors, primary peritoneal carcinoma, fallopian tube cancer, or combinations thereof.

In some embodiments, the GR inhibitor is used in combination with at least a second therapeutic agent, such as chemotherapy or immunotherapy. In some embodiments, the GR inhibitor is used in combination with one or more additional therapeutic agents. In some embodiments, the second or additional chemotherapeutic agent is cisplatin, carboplatin, cyclophosphamide, capecitabine, gemcitabine, paclitaxel, nab-paclitaxel, altretamine, docetaxel, epirubicin, melphalan, methotrexate, mitoxantrone, ixabepilone, ifosfamide, irinotecan, eribulin, etoposide, doxorubicin , doxorubicin in liposomes, camptothecin, pemetrexed, topotecan, vinorelbine, daunorubicin, fluorouracil, mitomycin, thiotepa, vincristine, everolimus, veliparib, glembatumumab vedotin, pertuzumab, trastuzumab, or any combination or any salt thereof. In some embodiments, the second or additional chemotherapeutic agent is gemcitabine. In some embodiments, the second or additional chemotherapeutic agent is carboplatin. In some embodiments, the second or additional chemotherapeutic agent is cisplatin. In some embodiments, the second or additional agent is paclitaxel. In some embodiments, the GR inhibitor is used in combination with gemcitabine and carboplatin. In some embodiments, the GR inhibitor is used in combination with carboplatin and cisplatin. In some embodiments, the second or additional therapeutic agent is an anti-PD-L1 antibody. In certain embodiments, the anti-PD-L1 antibody agent is MPDL3280A or avelumab. In some embodiments, the second or additional therapeutic agent is an anti-PD1 antibody agent. In certain embodiments, the anti-PD1 antibody agent is nivolumab or pembrolizumab.

Non-small cell lung cancer.

One embodiment relates to a method of treating non-small cell lung cancer (NSCLC) in a patient in need thereof, comprising administering to the patient a compound of any of the formulas provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has an increased level of GR expression in the tumor. In some embodiments, a GR inhibitor described herein is used in combination with a second therapeutic agent (eg, a chemotherapeutic agent) to treat NSCLC. In some embodiments, the combination of a GR inhibitor with a second therapeutic agent (eg, a chemotherapeutic agent) provides a more effective first line therapy in the treatment of NSCLC compared to a second therapeutic agent (eg, a chemotherapeutic agent) administered alone. In some embodiments, a GR inhibitor described herein is used in combination with one or more additional therapeutic agents (eg, anti-cancer agents) to treat NSCLC. In some embodiments, the combination of a GR inhibitor with one or more additional therapeutic agents (eg, anti-cancer agents) provides a more effective first-line therapy for the treatment of NSCLC compared to one or more therapeutic agents (eg, anti-cancer agents) administered alone.

In some embodiments, the GR inhibitor is used in combination with at least a second therapeutic agent, such as a chemotherapeutic agent or immunotherapy. In some embodiments, the GR inhibitor is used in combination with one or more additional therapeutic agents. In some embodiments, the second or additional chemotherapeutic agent is cisplatin, carboplatin, cyclophosphamide, capecitabine, gemcitabine, paclitaxel, nab-paclitaxel, altretamine, docetaxel, epirubicin, melphalan, methotrexate, mitoxantrone, ixabepilone, ifosfamide, irinotecan, eribulin, etoposide, doxorubicin , doxorubicin in liposomes, camptothecin, pemetrexed, topotecan, vinorelbine, vinblastine, daunorubicin, fluorouracil, mitomycin, thiotepa, vincristine, everolimus, veliparib, glembatumumab vedotin, pertuzumab, trastuzumab, or any combination or salt thereof. In some embodiments, the second or additional chemotherapeutic agent is gemcitabine. In some embodiments, the second or additional chemotherapeutic agent is carboplatin. In some embodiments, the second or additional chemotherapeutic agent is cisplatin. In some embodiments, the second or additional agent is paclitaxel. In some embodiments, the GR inhibitor is used in combination with gemcitabine and carboplatin. In some embodiments, the GR inhibitor is used in combination with carboplatin and cisplatin. In some embodiments, the second or additional therapeutic agent is an anti-PD-L1 antibody agent. In certain embodiments, the anti-PD-L1 antibody agent is MPDL3280A or avelumab. In some embodiments, the second or additional therapeutic agent is an anti-PD1 antibody agent. In certain embodiments, the anti-PD1 antibody agent is nivolumab or pembrolizumab.

Hypercortisolism/Cushing's disease.

One embodiment relates to a method of treating hypercortisolism or Cushing's disease in a patient in need thereof, comprising administering to the patient a compound of any of the formulas provided herein, or a pharmaceutically acceptable salt thereof.

Types of Cushing's disease include, without limitation, recurrent Cushing's disease, refractory Cushing's disease, persistent Cushing's disease, endogenous Cushing's disease, spontaneous hypercortisolism, corticotropin-dependent, corticotropin-independent, or combinations thereof.

Causes of hypercortisolism may include, without limitation, prolonged exposure to cortisol, a tumor that produces excess cortisol, a tumor that causes excess production of cortisol, or combinations thereof.

Other embodiments and uses will be apparent to those skilled in the art in light of the present disclosure. The following examples are provided solely as an illustration of various embodiments and should not be construed as limiting the present invention in any way.

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Examples

I. Chemical synthesis.

Unless otherwise indicated, reagents and solvents were used as received from commercial suppliers. For synthetic transformations sensitive to moisture and/or oxygen, anhydrous solvents and oven-dried glassware were used. The outputs are not optimized. Response times are approximate and have not been optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted.

Example 1

Compound 17 13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3Hcyclopenta[a]phenanthren-3-one.

Step A. (8'S,9'S,10'R,13'S,14S)-10',13'-dimethyl-1',2',4',7',8',9',10',12',13 ',14',15',16'-dodecahydro11'H-dispiro[[1,3]dioxolane-2,3'-cyclopenta[a]phenanthrene-17',2-[1,3]dioxolane]-11' -He.

VW Ίη I) o^T Gaj a

Vo

Adrenosterone (50.2 g, 1 eq) was dissolved in 390 ml DCM with 91 g trimethylorthoformate (5.2 eq) and 119 g ethylene glycol (11.5 eq). Toluenesulfonic acid (1.9 g, 0.06 eq.) was added. The reaction mixture was heated to 40° C. for 18 hours. The dark solution was quenched with 4 ml of pyridine. The reaction mixture was concentrated to remove the solvents. The residue was dissolved in DCM and washed with water. The organic layer was dried over MgSO ₄ , filtered and concentrated to give 74.3 g of a mushy solid. The solid was purified to give 42.2 g (65%) of the title compound, m/z (ESI, positive ion) 389.3 (M+H)+.

Stage B. (8'S,9'S,10'R,13'R,14'S)-10',13'-dimethyl-1',4',7',8',9',10',13',14' ,15',16'-decahydro-2Ήdispiro[[1,3]dioxolan-2,3'-cyclopenta[a]phenanthrene-17',2-[1,3]dioxolane]-11'-yl 1,1, 2,2,3,3,4,4,4 nonafluorobutane-1-sulfonate.

C4F ₉ SO ₂ O^ _?; i\TV - o < T ⁿ JT / o. G GnJ A

Vo

A solution of lithium diisopropylamide was prepared as follows. In an oven-dried 500 ml flask in a dry ice/acetone bath, a solution of 125 ml of THF and anhydrous diisopropylamine (5.77 ml, 4.1 eq.) was cooled. N-butyl lithium (25.1 mL, 4 eq, 1.6 M in hexanes) was added slowly and the reaction mixture was stirred for 25 minutes.

The starting bis-ketal (step A) (3.9 g, 1 equiv.) was charged to a separate flask, azeotropically distilled with toluene, dried in vacuo, purged with Ar, and the balloon with Ar was left. 40 ml of THF was added to dissolve the bis-ketal. This solution was slowly added to a freshly prepared LDA solution stored at -78°C. The reaction mixture was stirred for 30 minutes, then perfluorobutanesulfonyl fluoride (5.4 ml, 3 eq.) was added. The reaction mixture was maintained in a cold bath for another hour. The bath was removed and the mixture was stirred at rt overnight. After 24 hours, an additional 2.5 ml of perfluorobutanesulfonyl fluoride was added and the reaction mixture was again stirred overnight. Saturated aq. NH ₄ Cl, followed by extraction with EtOAc. The organic layer was washed with brine and dried over MgSO ₄ . After concentration in vacuo, the residue was purified by silica gel chromatography to give the desired product as a light yellow solid (3.7 g, 55%). m/z (ESI, positive ion) 671.2 (M+H) ⁺ .

- 72 041590

Step C. tert-butyl-(4-((8'S,9'S,10'R,13'R,14'S)-10',13'-dimethyl-1',4',7',8',9', 10',13',14',15',16'decahydro-2'H-dispiro[[1,3]dioxolane-2,3'-cyclopenta[a]phenanthrene-17',2-[1,3] dioxolane]-11'yl)phenyl)(methyl)carbamate.

The flask was loaded with (8'S,9'S, 10'R, 13'R,14'S)-10', 13'-dimethyl-1',4',7',8',9', 10',13',14' , 15',16'-decahydro2'H-dispiro[[1,3]dioxolan-2,3'-cyclopenta[a]phenanthrene-17',2-[1,3]dioxolane]-11'-yl 1, 1,2,2,3,3,4,4,4 nonafluorobutane-1-sulfonate (step B) (1.4 g, 1 eq.), (4-((tert-butoxycarbonyl)(methyl)amino)phenyl)boronic acid (5.2 g, 10 eq.), lithium chloride (177 mg, 2 eq.) and Pd(PPh ₃ ) ₄ (193 mg, 0.08 eq.). Then toluene (36 ml), ethanol (18 ml) and Na ₂ CO ₃ (2 M, 7.8 ml, 7.5 eq.) were added successively and the reaction mixture was degassed with argon. After heating the reaction mixture under reflux for 42 h, it was cooled to rt, quenched aq. NaHCO ₃ solution and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. Purification by flash column chromatography on silica gel gave the title compound (1.1 g, 92%) as a white solid.

Step D. tert-Butyl-(4-((4a'R,5a'S,6a'S,6b'S,9a'R, 11a'R, 11b'R)-9a', 11b'-dimethyl1',5a',6' ,6a',6b',7',8',9a', 11a',11b'-decahydro-2Ή,4Ή-dispiro[[1,3]dioxolane-2,3'-cyclopenta[ 1,2]phenanthro[ 8а,9b]oxirene-9',2-[1,3]dioxolane]-11'-yl)phenyl)(methyl)carbamate.

To a solution of tert-butyl-(4-((8'S,9'S,10'R,13'R,14'S)-10',13'-dimethyl-1',4',7',8',9',10 ',13',14',15',16'decahydro-2'H-dispiro[[1,3]dioxolane-2,3'-cyclopenta[a]phenanthrene-17',2-[1,3]dioxolane ]-1Hyl)phenyl)(methyl)carbamate (step C) (520 mg, 0.9 mmol) in DCM (10 ml) at 0°C was added 1,1,1,3,3,3hexafluoropropan-2-one ( 0.14 ml, 0.99 mmol) followed by the addition of 30% aqueous hydrogen peroxide (0.37 ml, 4.5 mmol) and sodium hydrogen phosphate (383.3 mg, 2.7 mmol). The reaction mixture was stirred at 0°C for 10 min and rt overnight. Additional aliquots of reagents (380 mg sodium hydrogen phosphate, 0.13 ml CF3COCF3, 0.35 mLof 30% H ₂ O ₂ ) were added at time points 24 and 48 hours. The reaction mixture was quenched with 10% Na2S2O3 and extracted with EtOAc. After washing with brine, the organic layer was separated, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography to give 470 mg (88%) of the desired epoxide as a white foamy solid.

Step E. tert-butyl-(4-((5'R,8'S,9'R, 10'R, 13'R,14'S)-5'-hydroxy-10', 13'-dimethyl1',4', 5',6',7',8',9', 10', 13',14',15',16'-dodecahydro-2'H-dispiro[[1,3]dioxolane-2,3'- cyclopenta[a]phenanthrene 17',2-[1,3]dioxolane]-11'-yl)phenyl)(methyl)carbamate.

The flask was charged with tert-butyl-(4-((4a'R,5a'S,6a'S,6b'S,9a'R,11a'R,11b'R)-9a',11b'-dimethyl1',5a',6', 6a',6b',7',8',9a',11a',11b'-decahydro-2Ή,4Ή-dispiro[[1,3]dioxolane-2,3'cyclopenta[1,2]phenanthro[8a, 9-b]oxirene-9',2-[1,3]dioxolan]-11'-yl)phenyl)(methyl)carbamate (step D) (2.98 g, 6.02 mmol) and azeotropically distilled with toluene. THF (30 ml) was added under argon and the solution was cooled in an ice bath, followed by the dropwise addition of lithium aluminum hydride (1M solution in THF, 6.02 ml). After 5 min, the ice bath was removed and the reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with a few drops of methanol, followed by sat. Rochelle's salt solution and EtOAc. The mixture was stirred for 15 min and the organic layer was separated, washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-50% EtOAc in hexanes to give the title compound (2.63 g, 88%) as a white solid.

Step F. tert-butyl-(4-((3a'S,3b'S,5a'R,9a'R,9b'S,9c'R, 10a'R, 10b'R)-5a'-hydroxy-9a', 10b'dimethyltetradecahydro -9cΉ-dispiro[[1,3]dioxolan-2,1'-cyclopenta[1,2]phenanthro[3,4-b]oxiren-7',2[1,3]dioxolan]-9c'-yl) phenyl)(methyl)carbamate.

To a solution of tert-butyl-(4-((5'R,8'S,9'R, 10'R, 13'R,14'S)-5'-hydroxy-10', 13'-dimethyl1',4',5 ',6',7',8',9', 10',13',14', 15',16'-dodecahydro-2'H-dispiro[[1,3]dioxolane-2,3'-cyclopenta [a]phenanthrene 17',2-[1,3]dioxolane]-11'-yl)phenyl)(methyl)carbamate (step E) (1.93 g, 3.88 mmol) in DCM (60 ml) was added 3 -chlorobenzenecarboperoxic acid (75%, 3.57 g, 15.5 mmol). The reaction mixture was stirred at rt for 20 h and treated with sat. NaHCO ₃ and also extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0-45% EtOAc in hexanes to give the more polar isomer (530 mg, 27%) as the desired product. The less polar isomer was also isolated (910 mg, 46%).

Step G 'H-dispiro[[1,3]dioxolane-2,3'-cyclopenta[a]phenanthrene-17',2[ 1,3]dioxolane]-5', 12'(4'H)-diol.

An oven-dried 250 ml 3-neck flask was fitted with a cold finger condenser and an argon bottle. Both the 3-necked flask and the cold finger were cooled with dry ice in acetone. Liquid ammonia from the feed tank was condensed into the flask until the required volume of 25 ml was reached. Lithium metal (109 mg, 13.7 mmol) was added and the color of the solution changed to dark blue. The dry ice bath was quickly removed for 2 min to speed up the lithium dissolution process, then the flask was returned to the cooling bath. After approximately 4 minutes, a solution of tert-butyl-(4-((3a'S,3b'S,5a'R,9a'R,9b'S,9c'R,10a'R,10b'R)-5a 'hydroxy-9а', 10b'-dimethyltetradecahydro-9сΉ-dispiro[[1,3]dioxolane-2,1'-cyclopenta[1,2]phenanthro[3,4b]oxirene-7',2-[1,3 ]dioxolane]-9c'-yl)phenyl)(methyl)carbamate (1.05 g, 1.72 mmol) (step F) in THF (20 mL). The reaction continued for 50 minutes and the color remained deep blue. At this time, 0.5 ml of ethanol was added, stirred for 1 min, then the cooling bath was removed and water was slowly added to quench the reaction. EtOAc was added and the ammonia was allowed to evaporate. The reaction mixture was extracted with EtOAc and washed with brine. The organic layer was dried, concentrated and the residue was purified by silica gel chromatography to give 715 mg of the desired product (81%). m/z (ESI, positive ion) 514.4 (M+H)+.

Step H dispiro[[1,3]dioxolane-2,3'-cyclopenta[a]phenanthrene-17',2-[1,3]dioxolane]5',12'(4'H)-diol.

The flask was loaded with (5'R,8'S,9'R,10'R,11'S,12'S,13'R,14'S)-10',13'-dimethyl-11'-(4(methylamino)phenyl)dodecahydro-2 'H-dispiro[[1,3]dioxolane-2,3'-cyclopenta[a]phenanthrene-17',2[1,3]dioxolane]-5',12'(4'H)-diol (609 mg , 1.19 mmol) (Step G) and DCM (12 mL) was added followed by acetic acid (0.68 mL, 11.9 mmol). Formaldehyde (0.45 ml, 5.93 mmol) was then added and the mixture was stirred for 6 minutes. Sodium triacetoxyborohydride (276 mg, 1.30 mmol) was added. The reaction mixture was stirred for 1 h and quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was dried, concentrated and purified by chromatography on

- 74 041590 silica gel to obtain 575 mg of the title compound (92%). m/z (ESI, positive ion) 528.3 (M+H)+.

Step I. (8S,9R,10R,11S,12S,13R,14S)-11-(4-(dimethylamino)phenyl)-12-hydroxy-10,13-dimethyl1,6,7,8,9,10, 11,12,13,14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione.

The flask was loaded with (5'R,8'S,9'R,10'R,11'S,12'S,13'R,14'S)-11'-(4-(dimethylamino)phenyl)-10',13'dimethyldodecahydro-2'N-dispiro[[1,3]dioxolane-2,3'-cyclopenta[a]phenanthrene-17',2-[1,3]dioxolane]5',12'(4'H)-diol (step H) (940 mg, 1.78 mmol) and acetone (26 ml) was added followed by 4 N hydrogen chloride (1.78 ml, 7.13 mmol). The resulting clear mixture was stirred at rt for 2 h. The reaction was quenched with sat. NaHCO ₃ and extracted with EtOAc. The EtOAc layer was washed with brine, dried over _MgSO4 , and concentrated in vacuo. The residue was purified by silica gel chromatography to give 411 mg (55%) of the desired product, m/z (ESI, positive ion) 422.3 (M+H)+.

Step J ,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-12-yl)-1H-imidazole-1carbothioate.

(8S,9R,10R,11S,12S,13R,14S)-11-(4-(dimethylamino)phenyl)-12-hydroxy-10,13dimethyl-1,6,7,8,9,10, 11,12,13,14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (step I) (411 mg, 0.97 mmol) and azeotrope distilled with toluene . DCM (24 ml) was added followed by triethylamine (0.27 ml, 1.95 mmol) and di(imidazol-1-yl)methanethione (2.8 g, 15.6 mmol). After stirring the reaction mixture under argon at rt for 4 days, it was quenched with dilute HCl and the crude product was extracted with EtOAc. The organic layer was washed twice with brine, dried and concentrated. The residue was purified by silica gel chromatography to give the title compound (427 mg, 82%).

Step K. (8S,9R,10R,11S,13S,14S)-11-(4-(dimethylamino)phenyl)-10,13-dimethyl1,6,7,8,9,10,11,12,13, 14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione.

O-((8S,9R,10R,12S,13R,14S)-11-(4-(dimethylamino)phenyl)-10,13-dimethyl-3,17dioxo-2,3,6,7,8 ,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-12-yl)-1Himidazole-1-carbothioate (step J) (420 mg, 0, 79 mmol) and purged the contents with argon. Toluene (19 ml) was added followed by tributyltin hydride (0.42 ml, 1.58 mmol). After heating the reaction mixture under reflux for 3 h, it was cooled to rt and concentrated. The residue was purified by silica gel chromatography to give the title compound (168 mg, 84%) as a colorless oil, m/z (ESI, positive ion) 406.4 (M+H)+.

Step L. (8S,9R,10R,11S,13S,14S)-11-(4-(dimethylamino)phenyl)-3-ethoxy-10,13-dimethyl1,2,7,8,9,10,11, 12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one.

(8S,9R,10R,11S,13S,14S)-11-(4-(dimethylamino)phenyl)-10,13-dimethyl1,6,7,8,9,10,11,12,13, 14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (step K) (210 mg,

- 75 041590

0.52 mmol) and subjected the contents to azeotropic distillation with toluene. p-Toluenesulfonic acid monohydrate (118.2 mg, 0.62 mmol) was added to the flask and the flask was purged with argon. Ethanol (8 ml) was added and the reaction mixture was cooled in an ice bath. Triethyl orthoformate (0.26 ml, 1.55 mmol) was added. The reaction mixture was stirred in an ice bath for 1 hour. Triethylamine (0.72 ml) was added to neutralize the acid. The reaction mixture was concentrated and then directly purified by silica gel chromatography to give the desired monoketone (66 mg, 29%). The remaining overprotected and alternative monoprotected products were reused by hydrolysis with HCl as in step I. m/z (ESI, positive ion) 434.4 (M+H)+.

Step M. (8S,9R, 10R, 11S,13S,14S,17S)-11-(4-(dimethylamino)phenyl)-17-hydroxy-17-(3methoxyprop-1-yn-1-yl)-10, 13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3Hcyclopenta[a]phenanthren-3-one.

The flask was charged with 3-methoxyprop-1-yne (0.1 ml, 1.2 mmol) and THF (2 ml). The reaction mixture was cooled at -78° C. and n-butyllithium (0.71 ml, 1.14 mmol) was added dropwise. The resulting mixture was stirred at -78°C for 10 min, and then it was added to a solution of (8S,10R,11S,13S,14S)-11-[4(dimethylamino)phenyl]-3-ethoxy-10.13 -dimethyl-1,2,7,8,9,11,12,14,15,16-decahydrocyclopenta[a]phenanthren17-one (step L) (29 mg, 0.07 mmol) in THF (2 ml) at -78°C. After the reaction mixture was stirred at -78°C for 60 min, it was quenched with saturated NH ₄ Cl and extracted with EtOAc. The organic layer was dried, filtered and concentrated. The residue was dissolved in THF (1.5 ml), 1.2 ml water (1.2 ml) and 4 N HCl (0.75 ml) and the solution was stirred at rt for 1 h. The solution was quenched with saturated NaHCO ₃ solution and extracted EtOAc. The organic layer was concentrated and the residue was purified by preparative reverse phase HPLC to give the title compound as a TFA salt (23 mg, 72%).

¹ H NMR (400 MHz, chloroform-d) δ ppm 7.05-7.25 (2H, m), 6.48-6.75 (2H, m), 5.68 (1H, d, J=1 .17 Hz), 4.09-4.22(2H, m), 3.41-3.45(1H, m), 3.40(3H, s), 2.94(6H, s), 2 .45 (1H, m), 2.20-2.35 (4H, m), 2.10-2.15 (1H, m), 1.85-2.00 (3H, m), (3H, br d, J=4.53 Hz), 1.68-1.85 (2H, m), 1.36-1.53 (4H, m), 1.02 (3H, s), 0.90 ( 3H, s); m/z (ESI, positive ion) 476.4 [M+H] ⁺ .

Example 2

Compound 9 13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthrene-3-one.

X / ⁿ X ^H jT/ G T A T A

Step A. (8S,13S,14S)-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'- [1,3]dioxolane]-17-ol.

he oX Ύ j ^a Vo

To a solution of (8S,13S,14S)-13-methyl-l,4,6,7,8,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene3,2'-[1,3] dioxolane]-17(2H)-one (100 g, 318 mmol) in THF (500 ml) and MeOH (50 ml) sodium borohydride (6.14 g, 159 mmol) was added in portions at 0°C. The mixture was stirred at 0° C. for 30 min and then at rt for 1 h. NaHCO ₃ solution and concentrated to remove MeOH. The residue was dissolved in EtOAc, the organic phase was washed with sat. NaHCO ₃ solution, brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (99.5 g, 100% yield) as a colorless oil. The crude material was used for the next reaction without further purification, m/z (ESI, positive ion) 317.3 [M+H] ⁺ .

- 76 041590

Stage B. (5'R,8'S,10'R,13'S,14'S)-13'-methyl-1',2',7',8',12',13',14',15',16' ,17'-decahydro-4Ή,6Ήspiro[[1,3]dioxolan-2,3'-[5,10]epoxycyclopenta[a]phenanthrene]-17'-ol.

To a solution of (88,138,148)-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3] dioxolan]-17-ol (43.0 g, 136 mmol, step A) in DCM (320 ml) at 0°C was added Na ₂ HPO ₄ (9.65 g, 68.0 mmol), followed by the addition of trihydrate 1 ,1,1,3,3,3-hexafluoropropan-2-one (11.2 ml, 81.5 mmol) and H ₂ O ₂ (35% aqueous solution, 34.2 ml, 408 mmol). The mixture was stirred at 0°C for 10 min and then at rt for 3 h. ). The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound (43.0 g) as a 4:1 mixture of epoxides as a white solid. The crude material was used for the next step without further purification.

Step C. (8S,11R,13S,14S)-11-(4-(diethylamino)phenyl)-17-hydroxy-13-methyl1,2,6,7,8,11,12,13,14,15, 16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one.

The dried flask was charged with magnesium chips (2.04 g, 83.9 mmol) and crystalline iodine. The flask was purged with Ar and the contents were heated briefly with a hot air dryer and then placed in a 60° C. oil bath. A small portion of a solution of 4-bromo-N,N-diethylaniline (18.5 g, 81.2 mmol, pre-azeotropically distilled with toluene) in THF (80 ml) (approximately 5 ml) was added. After the disappearance of the iodine color, the remaining solution was added dropwise over 20 min and the mixture continued to stir at 60°C for 2 h.

The Grignard reagent prepared above was cooled to rt and added to a solution of (5'R,8'S,10'R,13'S,14'S)-13'-methyl-1',2',7',8',12',13', 14',15',16',17'-decahydro-4Ή,6Ή-spiro[[1,3]dioxolan-2,3'[5,10]epoxycyclopenta[a]phenanthrene]-17'-ol (9, 00 g, 27.1 mmol, azeotropically distilled with toluene, step B) and copper(I) iodide (2.60 g, 13.5 mmol) in THF (100 ml) at 0°C. The resulting mixture was allowed to warm to rt and stirred for 1 h. The reaction mixture was quenched (sat. aq. NH ₄ Cl), extracted (2xEtOAc) and washed (brine). The combined organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Purification of the residue with a combi-flash system (220 g SiO ₂ , 20 to 80% EtOAc/hexanes mixture) gave (5R,8S,11R,13S,14S)-11-(4(diethylamino)phenyl)-13-methyl -1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene3,2'-[1,3]dioxolane]-5,17(4Н) -diol (6.50 g, 13.5 mmol, 50% yield) as an off-white foam.

A solution of (5R,8S,11R,13S,14S)-11-(4-(diethylamino)phenyl)-13-methyl-1,2,6,7,8,11,12,13,14,15,16, 17dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dioxolane]-5,17(4H)-diol (6.50 g, 13.5 mmol) in 70% acetic acid in water (109 mL ) was stirred at 55° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to remove most of the AcOH. The residue was then diluted (EtOAc), basified (sat. aq. NaHCO ₃ ), extracted (2xEtOAc) and washed (brine). The combined organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Purification of the residue with a combi-flash system (220 g SiO ₂ , 20 to 60% EtOAc/hexanes) gave the title compound (6.80 g, 16.2 mmol, 80% yield) as a white solid.

Ή NMR (400 MHz, chloroform-d) δ 6.98 (d, J=8.33 Hz, 2H), 6.54-6.66 (m, 2H), 5.75 (s, 1H), 4 .28 (d, J=6.72 Hz, 1H), 3.66 (brt, J=8.04 Hz, 1H), 3.25-3.38 (m, 4H), 2.68-2, 83 (m, 1H), 2.32-2.61 (m, 7H), 1.98-2.16 (m, 2H), 1.60-1.74 (m, 3H), 1.30- 1.49 (m, 3H), 1.14 (t, J=7.09 Hz, 6H), 0.48 (s, 3H).

- 77 041590

Stage D

(8S,9R, 11S,13S,14S)-11 -(4-(diethylamino)phenyl)-17-hydroxy-13-methyl1,2,4,6,7,8,9,11,12,13,14 ,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one.

Lithium (283 g, 40.8 mmol) was added in portions to liquid ammonia (157 ml) at -78°C under Ar atmosphere. If the color changed to dark blue, a solution of (8S,11R,13S,14S)-11-(4-(diethylamino)phenyl)17-hydroxy-13-methyl-1,2,6,7,8,11, 12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one (4.50 g, 10.7 mmol, step C) in THF (100 mL) for 15 min ( keeping the internal temperature below -60°C) followed by the addition of a solution of tert-butanol (2.50 ml, 25.7 mmol) in THF (50 ml) over 1 min (dark purple color remained after addition). The reaction mixture was quenched with solid ammonium chloride (12.0 g, 225 mmol). Both the dry ice bath and the cold finger condenser were removed and most of the ammonia was allowed to evaporate by stirring the slurry at rt for 1 h. The reaction mixture was diluted (saturated aq. NH4Cl) and extracted (2xEtOAc). The combined organic layer was washed (saturated aq. NH4Cl), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Purification of the residue with a combi-flash system (220 g SiO ₂ , 20 to 60% EtOAc/hexanes) gave the title compound (2.60 g, 6.17 mmol, 58% yield). m/z (ESI, positive ion) 422.3 [M+H]+.

Step E. (8R,9S,10R,11S,13S,14S)-11-(4-(diethylamino)phenyl)-17-hydroxy-13-methyl1,2,6,7,8,9,10,11, 12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one.

To a solution of (8S,9R,11S,13S,14S)-11-[4-(diethylamino)phenyl]-17-hydroxy-13-methyl2,4,6,7,8,9,11,12,14,15 ,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-one (2.60 g, 6.17 mmol, step D) in toluene (50 ml) was added 4-methylbenzenesulfonic acid hydrate (3.52 g, 18.5 mmol) under Ar atmosphere and the resulting solution was heated at 80° C. for 1 h. The reaction mixture was quenched with TEA (3 ml), cooled, diluted (EtOAc and sat. aq. NaHCO ₃ ) and extracted (2xEtOAc ). The combined organic layer was washed (brine), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Purification of the residue with a combi-flash system (120 g, 40 to 60% EtOAc/hexanes) gave the title compound (1.50 g, 3.56 mmol, 58% yield) as a white foam; m/z (ESI, positive ion) 422.3 [M+H] ⁺ .

Step F. (8R,9S,10R,11S,13S,14S)-11-(4-(diethylamino)phenyl)-13-methyl1,2,6,7,8,9,10,11,12,13, 14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolane]-17-ol.

To a solution of (8R,9S,10R,11S,13S,14S)-11-(4-(diethylamino)phenyl)-17-hydroxy-13-methyl1,2,6,7,8,9,10,11,12 ,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (1.50 g, 3.56 mmol, step E) and p-toluenesulfonic acid monohydrate (1.35 g, 7.11 mmol) in acetic acid (15 ml) was added ethane-1,2-dithiol (3.00 ml, 35.6 mmol). After the solution was stirred at rt for 1 h under Ar, the reaction mixture was quenched (ice-cold 2.5 N aq. NaOH) and extracted (2xEtOAc). The combined organic layer was washed (brine), dried (MgSO ₄ ) and concentrated under reduced pressure. Purification of the residue with a combi-flash system (120 g SiO2, 20 to 40% EtOAc/hexanes) gave the title compound (740 mg, 1.49 mmol, 42% yield) as a white solid.

Ή NMR (400 MHz, chloroform-d) δ 7.21 (d, J=8.62 Hz, 2H), 6.58 (d, J=8.92 Hz, 2H), 5.61 (s, 1H ), 3.56 (br t, J=7.97 Hz, 1H), 3.25-3.41 (m, 7H), 3.16-3.25 (m, 2H), 2.42-2 .57 (m, 1H), 2.27 (td, J=3.27, 13.63 Hz, 1H), 1.93-2.15 (m, 6H), 1.81-1.92 (m , 2H), 1.50-1.73 (m, 2H), 1.21-1.38 (m, 2H), 1.08-1.18 (m, 7H), 0.79-1.05 (m, 3H), 0.54 (s, 3H); m/z (ESI, positive ion) 498.4 [M+H] ⁺ .

- 78 041590

Step G 15,16-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolane]-17(2H)-one.

To a solution of (8R,9S, 10R, 11S,13S,14S)-11 -(4-(diethylamino)phenyl)-13-methyl1,2,6,7,8,9,10,11,12,13,14 ,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolane]-17ol (740 mg, 1.49 mmol, step F) in toluene (15 mL) cyclohexanone was added successively (0.44 ml, 4.28 mmol) and aluminum propane-2-olate (410 mg, 2.00 mmol). After heating the reaction to 105° C. for 4 hours, it was cooled to rt and quenched with a saturated aqueous solution of Rochelle's salt. The mixture was stirred for 10 min and extracted (2xEtOAc). The combined organic layer was washed (brine), dried (MgSO ₄ ) and concentrated under reduced pressure. Purification of the residue with a combi-flash system (40 g SiO ₂ , 10 to 50% EtOAc/hexanes) gave the title compound (430 mg, 0.87 mmol, 58% yield) as a white solid.

1H NMR (400 MHz, chloroform-d) δ 7.20 (d, J=7.63 Hz, 2H), 6.57 (d, J=8.92 Hz, 2H), 5.60-5.70 (s, 1H), 3.24-3.41 (m, 8H), 3.16-3.24 (m, 1H), 2.37-2.58 (m, 2H), 2.33 (m , 1H), 1.93-2.20 (m, 6H), 1.83 (dt, J=2.78, 13.08 Hz, 1H), 1.66-1.76 (m, 2H), 1.50-1.66 (m, 2H), 1.25-1.37 (m, 3H), 1.02-1.21 (m, 7H), 0.67 (s, 3H); m/z (ESI, positive ion) 496.4 [M+H]+.

Step H 1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolane]17- ol.

To a solution of isopropyl magnesium chloride (2 M solution in THF, 0.76 ml, 1.51 mmol) in THF (1 ml) was added dropwise under Ar atmosphere 3,3-dimethylbut-1-yne (0.19 ml, 0. 61 mmol) at 0°C. After stirring the solution at rt for 10 min, the mixture was stirred at 50° C. for 1 h (using a condenser). The Grignard reagent was cooled to 0°C, and a solution of (8R,9S,10R,11S,13S,14S)-11-[4(diethylamino)phenyl]-13-methyl-spiro[1,2,6,7 ,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthrene 3,2'-1,3-dithiolan]-17-one (100 mg, 0.20 mmol, step G) in THF (2 ml). After the reaction mixture was stirred at 0° C. for 30 min, it was allowed to warm to rt and stirred overnight. The reaction mixture was quenched (sat. aq. NH ₄ Cl) and was extracted (2xEtOAc). The combined organic layers were washed (brine), dried (MgSO ₄ ) and concentrated under reduced pressure. Purification of the residue with a combi-flash system (12 g SiO ₂ , 15 to 35% EtOAc/hexanes) gave the title compound (110 mg, 0.19 mmol, 94% yield) as a white solid; m/z (ESI, positive ion) 578.5 [M+H] ⁺ .

Step I. (8R,9S, 10R, 11S,13S,14S,17S)-11-(4-(diethylamino)phenyl)-17-(3,3-dimethylbut-1-yn-1-yl)17-hydroxy - 13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthrene-3 he.

To a solution of (8R,9S,10R,11S,13S,14S,17S)-11-(4-(diethylamino)phenyl)-17-(3,3-dimethylbut-1-yn-1-yl)-13methyl-1 ,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthren-3,2'-[1,3]dithiolane]17-ol (110 mg, 0.19 mmol, Step H) in acetic acid (4 mL) glyoxylic acid monohydrate (876 mg, 9.52 mmol) was added at rt and the mixture was stirred at rt for 10 min. Then 4N HCl in water (0.86 ml, 3.43 mmol) was added and the resulting solution was stirred at rt for 20 h.

The reaction mixture was quenched (sat. aq. NaHCO ₃ ), extracted (2xEtOAc) and washed (brine). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Purification of the residue with a combi-flash system (12 g SiO ₂ , 20 to 40% EtOAc/hexane mixture) gave the title compound (33 mg, 0.066 mmol, 38% yield) as a white foam.

- 79 041590

1H NMR (400 MHz, chloroform-d) δ 7.23 (br d, J=8.33 Hz, 2H), 6.60 (br d, J=8.77 Hz, 2H), 5.86 (br s, m),

3.33 (br d, J=6.87 Hz, 5H), 2.86 (br s, m), 2.53 (br d, J=15.05 Hz, 1H), 2.38 (m, 1H), 2.01-2.30 (m, 5H), 1.92 (m,

3H), 1.71 (br s, 1H), 1.46-1.64 (m, 5H), 1.21-1.28 (s, 9H), 1.17 (m, 7H), 0. 67(s, 3H); m/z (ESI, positive ion) 502.4 [M+H] ⁺ .

Compounds from examples 3-10 were prepared using procedures similar to those described in example 2, replacing 4-bromo-N,N-diethylaniline with the appropriate bromide in step C and 3,3-dimethylbut-1ine with the appropriate alkyne in step H.

Example 3

Compound 1 pyrrolidin-1-yl)phenyl)-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3one.

1H NMR (400 MHz, chloroform-d) δ 7.24-7.29 (m, 2H), 6.50 (d, J=8.77 Hz, 2H), 5.86 (s, 1H), 3 .22-3.41(m, 4H), 2.86(m, 1H), 2.53(m, 1H), 2.37(m, 2H), 2.21-2.29(m, 1H ), 1.99-2.20 (m, 7H), 1.89-1.96 (m, 2H), 1.61-1.81 (m, 6H), 1.23-1.43 (m , 11H), 1.01-1.21 (m, 1H), 0.68 (s, 3H); m/z (ESI, positive ion) 500.5 [M+H] ⁺ .

Example 4

Compound 3 -in-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3Hcyclopenta[a] phenanthrene-3-one.

1H NMR (400 MHz, chloroform-d) δ 6.93 (d, J=1.90 Hz, 1H), 6.83-6.91 (m, 1H), 6.78 (d, J=8, 33 Hz, 1H), 5.87 (s, 1H), 4.23-4.32 (m, 4H), 3.33 (br t, J=5.85 Hz, 1H), 2.86 (br s, m), 2.53 (br d, J=14.18 Hz, 1H), 2.36-2.42 (m, 1H), 2.11-2.29 (m, 4H), 2, 02-2.09 (m, 2H), 1.84-1.99 (m, 3H), 1.69-1.81 (m, 1H), 1.44-1.55 (m, 2H), 1.23-1.41 (m, 11H), 1.01-1.15 (m, 1H), 0.67 (s, 3H); m/z (ESI, positive ion) 489.4 [M+H] ⁺ .

Example 5

Compound 5 -yl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthrene3- He.

1H NMR (400 MHz, chloroform-d) δ ppm 6.86-6.94 (2H, m), 6.74 (1H, d, J=8.0 Hz), 5.94-6.00 (2H , m), 5.87 (1H, s), 3.35 (1H, br t, J=6.0 Hz), 2.80-2.90 (1H, m), 2.50-2.57 (1H, m), 2.36-2.42 (1H, m), 2.24-2.35 (2H, m), 1.96-2.23 (5H, m), 1.87-1 .95 (3H, m), 1.69-1.80 (1H, m), 1.44-1.55 (2H, m), 1.38 (1H, td, J=12.0.5, 7 Hz), 1.26-1.33 (1H, m), 1.24 (9H, s), 1.11 (1H, br dd, J=12.1, 3.7 Hz), 0.68 (3H, s); m/z (ESI, positive ion) 475.4 [M+H]+.

Example 6

Compound 4 in-1-yl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3Hcyclopenta[a]phenanthren-3-one .

1H NMR (400 MHz, chloroform-d) δ 7.25 (br d, J=8.6 Hz, 2H), 6.71 (br d, J=8.77 Hz, 2H), 5.86 (s , 1H), 4.08 (td, J=6.56, 13.34 Hz, 1H), 3.37 (s, 3H), 3.33 (br t, J=5.41 Hz, 1H), 2.85 (br m, 1H), 2.73 (s, 3H), 2.53 (br d, J=14.32 Hz, 1H), 2.18-2.43 (m, 4H), 1 .89-2.16 (m, 6H), 1.67-1.80 (m, 2H), 1.37-1.55 (m, 8H), 1.26 (dt, J=5.55,

- 80 041590

11.40 Hz, 1H), 1.05-1.21 (m, 7H), 0.69 (s, 3H); m/z (ESI, positive ion) 518.5 [M+H] ⁺ .

Example 7

Compound 7 -1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren3-one.

1H NMR (400 MHz, chloroform-d) δ 7.33 (br d, J=8.33 Hz, 2H), 6.84 (br d, J=7.45 Hz, 2H), 5.87 (s , 1H), 3.88 (br s, 4H), 3.26-3.48 (m, 1H), 3.17 (br s, 4H), 2.82 (br s, 1H), 2.54 (br d, J=14.03 Hz, 1H), 2.33-2.46 (m, 1H), 2.03-2.31 (m, 5H), 1.82-1.99 (m, 3H), 1.67-1.80 (m, 1H), 1.45-1.65 (m, 3H), 1.21-1.42 (m, 11H), 1.07-1.18 ( m, 1H), 0.64 (s, 3H); m/z (ESI, positive ion) 516.3 [M+H] ⁺ .

Example 8

Compound 6 13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthrene-3one.

1H NMR (400 MHz, chloroform-d) δ ppm 7.27 (2H, s), 6.67 (2H, br d, J=6.4 Hz), 5.86 (1H, s), 3.34 (1H, br s), 2.95 (3H, br), 2.95 (3H, br), 2.83 (1H, br d, J=10.8 Hz), 2.49-2.57 ( m, 1H), 2.37 (1H, td, J=14.1, 4.3 Hz), 2.27 (2H, dt, J=16.3, 3.9 Hz), 2.19 (1H , ddd, J=13.8, 9.6, 5.7 Hz), 2.02-2.14 (3H, m), 1.87-1.99 (3H, m), 1.69-1 .78 (m, 1H), 1.63 (1H, s), 1.48-1.54 (2H, m), 1.44 (2H, q, J=7.6 Hz), 1.33- 1.41 (m, 1H), 1.22-1.31 (m, 1H), 1.19 (3H, s), 1.19 (3H, s), 1.10 (1H, br d, J =12.0 Hz), 0.99 (3H, t, J=7.6 Hz), 0.66 (3H, s); m/z (ESI, positive ion) 488.5 [M+H] ⁺ .

Example 9

Compound 11 )-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3Hcyclopenta[a]phenanthren-3-one.

1H NMR (400 MHz, chloroform-d) δ 7.25-7.30 (m, 2H), 7.01-7.05 (m, 2H), 5.85 (s, 1H), 3.37 ( s, 1H), 2.81-2.93 (m, 1H), 2.74 (s, 3H), 2.50 (m, 1H), 2.31-2.41 (m, 1H), 1 .98-2.31 (m, 5H), 1.86-1.96 (m, 3H), 1.64-1.74 (m, 1H), 1.43-1.53 (m, 2H) , 1.16-1.38 (m, 12H), 1.04-1.14 (m, 10H), 0.56 (s, 3H); MS (ESI)=516.5 [M+H] ⁺ .

Example 10

Compound 2 amino)phenyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3Hcyclopenta[a]phenanthren-3-one.

1H NMR (400 MHz, chloroform-d) δ ppm 7.23 (2H, br d, J=8.3 Hz), 6.71 (2H, br d, J=8.3 Hz), 5.86 ( 1H, s), 4.04-4.11 (1H, m), 3.33 (1H, br s), 2.86 (1H, br s), 2.72 (3H, s), 2.53 (1H, br d, J=14.3 Hz), 2.33-2.43 (1H, m), 2.07-2.31 (5H, m), 2.03 (1H, br s), 1.88-1.97(3H, m), 1.68-1.78(1H, m), 1.63(1H, s), 1.46-1.55(2H, m), 1, 34-1.42(1H, m), 1.26-1.30(1H, m), 1.24(9H, s), 1.17(3H, d, J=5.6Hz), 1 .15 (3H, d, J=5.6 Hz), 1.06-1.12 (1H, m), 0.67 (3H, s); m/z (ESI, positive ion) 502.4 [M+H]+.

- 81 041590

Example 11.

Compound 10 -13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3Hcyclopenta[a]phenanthren-3-one.

Step A. (8S,11R,13S,14S)-11-(4-aminophenyl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16 ,17 dodecahydro-3H-cyclopenta[a]phenanthren-3-one.

The title compound was prepared from (5'R,8'S,10'R,13'S,14'S)-13'-methyl-1',2',7',8',12',13',14',15',16 ',17'decahydro-4H,6H-spiro[[1,3]dioxolane-2,3'-[5,10]epoxycyclopenta[a]phenanthrene]-17'-ol (Example 2, step B) using the procedure , similar to that described in example 2, stage C, with the replacement of bromide (4-(diethylamino)phenyl)magnesium bromide (4-(bis(trimethylsilyl)amino)phenyl)magnesium.

Step B. tert-butyl-(4-((8S,11R,13S,14S)-17-hydroxy-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14 ,15,16,17dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)carbamate.

In a flask loaded with (8S,11R,13S,14S)-11-(4-aminophenyl)-17-hydroxy-13-methyl1,2,6,7,8,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one (4.00 g, 11.0 mmol, azeotropically distilled with toluene, step A) was added di-tert-butyl dicarbonate (12.0 g, 55. 0 mmol) and MeCN (72 ml). The reaction mixture was stirred overnight. The solid was then filtered and washed (v/v=5/1, hep/EtOAc). The filtrate was purified with a combi-flash system (80 g SiO ₂ , 25 to 50% EtOAc/hexanes) to give the title compound (4.90 g, 10.6 mmol, 96% yield) as a yellow solid.

Step C. (8R,9S,10R,11S,13S,14S)-11-(4-aminophenyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14 ,15,16,17tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolane]-17-ol.

The title compound was prepared from tert-butyl-(4-((8S,11R,13S,14S)-17-hydroxy-13-methyl-3-oxo2,3,6,7,8,11,12,13,14, 15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)carbamate (Step B) using procedures similar to those described in Example 2, Steps D, E and F.

Step D. (8R,9S,10R,11S,13S,14S)-11-(4-(isopropylamino)phenyl)-13-methyl1,2,6,7,8,9,10,11,12,13, 14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolane]-17-ol.

To a solution of acetone (86.4 µl, 1.18 mmol) and (8'R,11'S,13'S,14'S)-11'-(4-aminophenyl)-13'-methylspiro[1,3-dithiolan-2,3 '-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1H-cyclonent[a]phenanthrene]-17'-ol (19.2 ml, 0.12 mmol, step C) in DCE (1.1 ml) sodium triacetoxyborohydride (62.4 mg, 0.29 mmol) was added at rt. After stirring the reaction mixture at rt, it was made basic (sat. aq.

NaHCO ₃ ), was extracted (2xDCM) and washed (with water). The combined organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Purification of the residue with a combiflash system (12 g SiO ₂ , 30 to 50% EtOAc/hexane mixture) gave the title compound (51.0 mg, 0.105 mmol,

- 82 041590 yield 90%) as an almost white solid; m/z (ESI, positive ion) 486.4 [M+H]+.

Step E. (8R,9S,10R,11S,13S,14S,17S)-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-11-(4(isopropylamino)phenyl) - 13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3Hcyclopenta[a]phenanthren-3-one.

The title compound was prepared from (8R,9S,10R,11S,13S,14S)-11-(4-(isopropylamino)phenyl)-13methyl-1,2,6,7,8,9,10,11,12,13 ,14,15,16,17-Tetradecahydrospiro[cyclopenta[a]phenanthren-3,2'[1,3]dithiolan]-17-ol (Step D) using procedures similar to those described in Example 2, Step G , H and I.

¹ H NMR (400 MHz, chloroform-d) δ ppm 7.19 (d, J=7.89 Hz, 2H), 6.52 (d, J=7.75 Hz, 2H), 5.85 (s , 1H), 3.57-3.64 (m, 1H), 3.28-3.32 (m, 1H), 2.79-2.86 (m, 1H), 2.49-2.55 (m, 1H), 2.30-2.40 (m, 1H), 2.01-2.29 (m, 6H), 1.86-1.97 (m, 3H), 1.69-1 .74 (m, 1H), 1.63 (s, 1H), 1.37-1.55 (m, 3H), 1.30-1.40 (m, 1H), 1.20-1.28 (m, 15H), 0.66 (s, 3H); m/z (ESI, positive ion) 488.4 [M+H] ⁺ .

Example 12.

Compound 13 -1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one.

Step A. Tert-butyl-(4-((8R,9S,10R,11S,13S,14S)-17-hydroxy-13-methyl1,2,6,7,8,9,10,11,12,13 ,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolane]-11yl)phenyl)carbamate.

Vos ⁿ X ⁿ XI/ sJ^jXj ^A Vs

The flask was loaded with (8R,9S,10R,11S,13S,14S)-11-(4-aminophenyl)-13-methyl1,2,6,7,8,9,10,11,12,13,14,15 ,16,17-tetradecahydrospiro[cyclopenta[a]phenanthren-3,2'-[1,3]dithiolane]-17-ol (358 mg, 0.81 mmol, azeotropically distilled with toluene, Example 11, Step C) , di-tert-butyl dicarbonate (885 mg, 4.05 mmol) and MeCN (6 mL) was added. After the reaction mixture was stirred overnight, the solid was filtered and washed with heptane:EtOAc 5:1. The filtrate was purified with a combi-flash system (40 g SiO ₂ , 25 to 50% EtOAc/hexanes) to give the title compound (420 mg, 0.780 mmol, 95% yield).

Step B. tert-butyl-(4-((8R,9S, 10R, 11S,13S,14S,17S)- 17-(3,3-dimethylbut-1-yn-1-yl)- 17-hydroxy13-methyl -3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[α]phenαntren-11yl)phenyl)carbamate.

Vos /

s T and V 2

G T n T y

The title compound was prepared from tert-butyl-(4-((8R,9S,10R,11S,13S,14S)-17-hydroxy-13-methyll,2,6,7,8,9,10,l 1.12 ,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthren-3,2'-[1,3]dithiolane]-11yl)phenyl)carbamate (step A) using procedures similar to those described in example 2, steps G, H and I.

Step C. (8R,9S,10R,11S,13S,14S,17S)-11-(4-aminophenyl)-17-(3,3-dimethylbut-1-yn-1-yl)-17hydroxy-13-methyl -1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one.

The flask was loaded with tert-butyl-(4-((8R,9S,10R,11S,13S,14S,17S)-17-(3,3-dimethylbut-1-yn-1-yl)-17hydroxy-13-methyl -3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-11yl)phenyl)carbamate (39 mg, 0.07 mmol, step B) in acetone (1 ml) followed by the addition of 4 N HCl in

- 83 041590 dioxane (0.09 ml, 0.36 mmol). After stirring the resulting clear mixture at rt for 5 h, it was quenched with sat. NaHCO ₃ solution and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified using a combi-flash system (4 g SiO2, 0 to 70% EtOAc/hexanes) to give the title compound (8.0 mg, 0.018 mmol, 25%) as an off-white solid.

¹ H NMR (400 MHz, dichloromethane-d2) δ ppm 7.12 (d, J=8.33 Hz, 2H), 6.49-6.55 (d, 2H), 5.71 (s, 1H) , 3.22 (br t, J=5.92 Hz, 1H), 2.71-2.77 (m, 1H), 2.40-2.45 (m, 1H), 2.23-2, 33 (m, 1H), 1.91-2.19 (m, 6H), 1.70-1.85 (m, 3H), 1.54-1.69 (m, 2H), 1.34- 1.48 (m, 3H), 1.22-1.34 (m, 1H), 1.14 (s, 9H), 0.54 (s, 3H); m/z (ESI, positive ion) 446.3 [M+H]+.

Example 13

Compounds 14 and 15 phenyl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3Hcyclopenta[a]phenanthren-3-one (14) and (8R,9S,10R,11S,13S,14S,17S)-17-(3,3-dimethylbut-1-yn-1-yl)-11-(3fluoro-4-(isopropyl(methyl) amino)phenyl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17tetradecahydro-3H-cyclopenta[a]phenanthrene-3 -on (15).

Compound 14

Compound 15

(8R,9S,11S,13S,14S,17S)-17-(3,3-dimethibut-1-ynyl)-17-hydroxy-11-[4[isopropyl(methyl)amino]phenyl]- 13-methyl-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren3-one (300 mg, 0.60 mmol, example 10) and DCM ( 8 ml). The contents of the flask were cooled to 0° C. and 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (294 mg, 1.02 mmol) was added. After stirring the reaction mixture at 0° C. for 60 min, it was heated to rt and stirred for another 30 min. The reaction mixture was quenched with NaHCO ₃ solution (6 ml) and extracted with EtOAc (200 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified using a combi-flash system eluting with EtOAc/hexanes 1:9 to give a mixture of 14 and 15. contain 0.1% formic acid, 30 min process) to give (8R,9S,10R,11S,13S,14S,17S)-17-(3,3-dimethibut-1-yn-1-yl)-11 -(3-fluoro-4(isopropyl(methyl)amino)phenyl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16 ,17-tetradecahydro-3Hcyclopenta[a]phenanthren-3-one (15) as the isomer of the first elution and (8R,9S,10R,11S,13S,14S,17S)-17(3,3-dimethylbut-1-yne -1-yl)-11-(3-fluoro-4-(isopropylamino)phenyl)-17-hydroxy-13-methyl1,2,6,7,8,9,10,11,12,13,14,15 ,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (14) as the second elution isomer.

Connection 14.

¹ H NMR (400 MHz, chloroform-d) δ ppm 6.99-7.22 (m, 2H), 6.62 (t, J=8.62 Hz, 1H), 5.87 (s, 1H) , 3.47-3.75 (m, 1H), 3.22-3.46 (m, 1H), 2.76-2.86 (br dd, J=3.00, 1.68 Hz, 1H ), 2.530-2.58 (br d, J=14.32 Hz, 1H), 2.34-2.43 (m, 1H), 2.21-2.35 (m, 2H), 2.14 -2.211 (m, 1H), 2.05-2.14 (m, 1H), 2.02-2.05 (m, 1H), 1.83-2.00 (m, 2H), 1.68 -1.78 (m, 1H), 1.64-1.68 (m, 1H), 1.45-1.55 (m, 3H), 1.32-1.42 (m, 1H), 1 .24-1.27 (d, J=4 Hz, 3H), 1.20-1.24 (m, 12H), 1.05-1.15 (m, 2H), 0.57-0.68 (m, 3H); m/z (ESI, positive ion) 506.5 (M+H)+.

Compound 15.

¹ H NMR (400 MHz, chloroform-d) δ ppm 6.98-7.17 (m, 2H), 6.84 (t, J=8.84 Hz, 1H), 5.87 (s, 1H) , 3.66-3.81 (m, 1H), 3.35 (br t, J=5.12 Hz, 1H), 2.84 (br dd, J=3.29, 1.53 Hz, 1H), 2.69 (s, 3H), 2.50-2.59 (m, 1H), 2.38-2.43 (m, 1H), 2.22-2.36 (m, 2H) , (dt, J=1.97, 1.06 Hz, 1H), 2.10-2.22 (m, 2H), 2.01-2.12 (m, 2H), 1.84-2, 00 (m, 2H), 1.69-1.81 (m, 1H), 1.66 (s, 1H), 1.43-1.56 (m, 2H), 1.34-1.44 ( m, 1H), 1.25-1.33 (m, 3H), 1.24 (9 s, H), 1.07-1.18 (m, 6H), 0.63 (s, 3H); m/z (ESI, positive ion) 520.4 (M+H)+.

Example 14

Compound 8 methyl)amino)phenyl)-13,16-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3Hcyclopenta[a]phenanthrene-3 -one or (8R,9S,10R,11S,13S,14S,16S,17S)-17-(3,3-dimethylbut-1-yn-1-yl)-17hydroxy-11-(4-(isopropyl(methyl )amino)phenyl)-13,16-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17tetradecahydro-3H-cyclopenta[a]phenanthrene-3- He.

- 84 041590

Step A. (8R,9S,10R,11S,13S,14S,16R)-11-(4-(isopropyl(methyl)amino)phenyl)-13,16-dimethyl1,6,7,8,9,10, 11,12,13,14,15,16-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolane]-17(2H)-one or

(8R,9S,10R, 11S,13S,14S,16S)-11-(4-(isopropyl(methyl)amino)phenyl)-13,16-dimethyl

1,6,7,8,9,10,11,12,13,14,15,16-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolane]-17(2Н)- He.

To a solution of (8S,13S, 14S)-13-methyl-l,4,6,7,8,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene3,2'-[1,3] [bis(trimethylsilyl) amino]lithium (50.9 ml, 50.9 mmol). After 30 minutes of stirring, iodomethane (7.92 ml, 127 mmol) was added. The reaction mixture was stirred at -20°C for 1 h and quenched with sat. NH ₄ Cl, extracted with EtOAc, washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified using a combi-flash system (10-20% EtOAc/hexanes) to give the title compound (6.70 g, 20.4 mmol, 80% yield).

Step B. (8R,9S,10R,11S,13S,14S,16R,17S)-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-11-(4(isopropyl( methyl)amino)phenyl)-13,16-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3Hcyclopenta[a]phenanthrene-3 -one or (8R,9S,10R,11S,13S,14S,16S,17S)-17-(3,3-dimethylbut-1-yn-1-yl)-17hydroxy-11-(4-(isopropyl(methyl )amino)phenyl)-13,16-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17tetradecahydro-3H-cyclopenta[a]phenanthrene-3- He.

The title compound was prepared from (8R,9S,10R,11S,13S,14S,16R)-11-(4-(isopropyl(methyl)amino)phenyl)13,16-dimethyl-1,6,7,8,9, 10,11,12,13,14,15,16-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolan]17(2H)-one or (8R,9S, 10R,11S, 13S, 14S, 16S)-11-(4-(isopropyl(methyl)amino)phenyl)-13,16-dimethyl1,6,7,8,9,10,11,12,13,14,15,16- dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolan]-17(2H)-one (Step A) using procedures similar to those described in Example 2, Steps H and I.

¹ H NMR (400 MHz, chloroform-d) δ 7.24 (d, J=8.77 Hz, 2H), 6.71 (d, J=8.92 Hz, 2H), 5.85 (s, 1H), 4.02-4.13(m, 1H), 3.27-3.37(m, 1H), 2.77-2.92(m, 1H), 2.67-2.73( m, 3H), 2.47-2.58 (m, 1H), 2.36 (m, 1H), 1.85-2.31 (m, 8H), 1.57-1.75 (m, 1H), 1.44-1.57 (m, 2H), 1.19-1.30 (m, 11H), 1.16 (dd, J=5.12, 6.58 Hz, 6H), 1 .11 (m, 4H), 0.73 (s, 3H); m/z (ESI, positive ion) 516.5 [M+H] ⁺ .

Example 15

Compound 21 ,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3Hcyclopenta[a]phenanthren-3-one.

Example 15 was prepared from (8'S,9'S,10'R,13'R,14 ^, S)-10',13'-dimethyl-1',4',7',8',9',10',13',14',15',16'decahydro-2'H-dispiro[[1,3]dioxolane-2,3'-cyclopenta[a]phenanthrene-17',2-[1,3]dioxolane]-11' -yl 1,1,2,2,3,3,4,4,4-nonafluorobutan-1-sulfonate (example 1, step B) using procedures similar to those described in example 1, steps C-M, with replacing formaldehyde with acetone in step H and replacing 3-methoxyprop-1-yne with ethynylcyclopropane in step M.

1H NMR (400 MHz, chloroform-d) δ ppm 7.20-7.40 (m, 2H), 6.64 (d, J=8.77 Hz, 2H), 5.68 (d, J=1 .32 Hz, 1H), 4.05 (m, 1H), 3.50 (s, 1H), 3.40 (m, 1H), 2.71 (s, 3H), 2.50 (m, 1H ), 2.20-2.40 (m, 5H), 2.10-2.20 (m, 2H), 1.95 (m, 3H), 1.73 (m, 2H), 1.43 ( m, 3H), 1.30 (m, 2H), 1.16 (dd, J=6.58, 1.17 Hz, 6H), 1.02 (s, 3H), 0.87 (s, 3H ), 0.74-0.84 (m, 2H), 0.60-0.73 (m, 2H); m/z (ESI, positive ion) 486.4 [M+H]+.

- 85 041590

Example 16

Compound 26 1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one.

Example 16 was prepared from (8'S,9'S,10'R,13'R,14'S)-10',13'-dimethyl-1',4',7',8',9',10',13',14 ',15',16'-decahydro2H-dispiro[[1,3]dioxolan-2,3'-cyclopenta[a]phenanthrene-17',2-[1,3]dioxolane]-11'-yl 1,1 ,2,2,3,3,4,4,4 nonafluorobutane-1-sulfonate (Example 1, Step B) using procedures similar to those described in Example 1, Steps C-G, replacing (4-((tert-butoxycarbonyl )(methyl)amino)phenyl)boronic acid (4-((tert-butoxycarbonyl)aminophenyl)boronic acid in step C, and then using procedures similar to those described in example 1, step 1-M, with the replacement of 3- methoxyprop-1-yne prop-1-yne at stage M.

1H NMR (400 MHz, chloroform-d) δ ppm 7.26-7.05 (br s, 2H), 6.54-6.62 (m, 2H), 5.69 (d, J=1.32 Hz, 1H), 3.59 (br s, 2H), 3.41 (t, J=5.55 Hz, 1H), 2.46-2.59 (m, 1H), 2.11-2, 33 (m, 7H), 1.86-1.99 (m, 3H), 1.89 (s, 3H), 1.64-1.81 (m, 3H), 1.36-1.56 ( m, 3H), 1.10-1.23 (m, 1H), 1.03 (s, 3H), 0.87 (s, 3H); m/z (ESI, positive ion) 418.3 [M+H]+.

Example 17.

Compound 30 )-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren3-one.

Example 17 was prepared from 8S,9R,10R,11S,13S,14S,17S)-11-(4-aminophenyl)-17-hydroxy-10,13-dimethyl-17(prop-1-yn-1-yl)- 1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (Example 16) using a procedure similar to as described in example 1, step H, replacing the formaldehyde with acetone.

1H NMR (400 MHz, chloroform-d) δ ppm 7.25-7.05 (br s, 2H), 6.46 (d, J=8.77 Hz, 2H), 5.68 (d, J= 1.17 Hz, 1H), 3.61 (quin, J=6.29 Hz, 1H), 3.33-3.43 (m, 2H), 2.47-2.56 (m, 1H), 2.10-2.34 (m, 7H), 1.86-1.99 (m, 3H), 1.89 (s, 3H), 1.70-1.84 (m, 3H), 1, 36-1.51 (m, 3H), 1.22 (d, J=4.0 Hz, 1H), 1.21 (d, J=4.0 Hz, 1H), 1.09-1.18 (m, 1H), 1.03 (s, 3H) 0.88 (s, 3H); m/z (ESI, positive ion) 460.4 [M+H] ⁺ .

Example 18.

Compound 31 -in-1-yl)-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one.

Example 18 was prepared from 8S,9R,10R,11S,13S,14S,17S)-11-(4-aminophenyl)-17-hydroxy-10,13-dimethyl-17(prop-1-yn-1-yl)- 1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (Example 16) using a procedure similar to as described in example 1, stage H, with the replacement of formaldehyde with 2,5-dimethoxytetrahydrofuran.

1H NMR (400 MHz, chloroform-d) δ ppm 7.40-7.65 (br s, 2H), 7.23-7.27 (m, 2H), 7.10 (t, J=2.19 Hz, 2H), 6.35 (t, J=2.19 Hz, 2H), 5.71 (d, J=1.02 Hz, 1H), 3.55 (brt, J=5.85 Hz, 1H), 2.54 (td, J=14.47, 4.53 Hz, 1H), 2.15-2.39 (m, 7H), 1.94-2.01 (m, 3H), 1 .91 (s, 3H), 1.70-1.85 (m, 3H), 1.41-1.58 (m, 3H), 1.12-1.23 (m, 1H), 1.07 (s, 3H), 0.86 (s, 1H); m/z (ESI, positive ion) 468.4 [M+H] ⁺ .

II. Biological assessment.

Example A Luciferase assay for GR in vivo.

Cell line: expressing the CHO/GR/MMTV luciferase gene.

Culture medium: DMEM (with phenol red) + 10% FBS.

Analysis medium: DMEM (no phenol red) + 10% CSS.

Cells from 1x10 cm dishes were divided into 2x15 cm dishes in assay medium (CSS). After 4 days, cells in assay medium were collected and counted.

Antagonist assay: 1.5 x 104 cells/well were plated in a 384-well white-walled TC well plate in 20 μl of assay medium containing 12.5 nM dexamethasone (final concentration=10 nM).

The plates were covered with foil to prevent evaporation and placed in a TC incubator. Media/drug dilutions were prepared in assay media in 96-well sterile plates.

100 μl of assay medium was aliquoted into 96-well plates using an 8-channel pipette (20-200 μl). Using an 8-channel pipette (0.5-10 µl), 0.5 µl of compounds at 1000x concentration was added to the plates. The plates were shaken for 15 seconds to mix. The film was removed from the 384-well assay cell plates. 5 μl medium/drug dilutions were added to appropriate wells. The plates were covered with foil to prevent evaporation and placed in a TC incubator overnight. After 16-18 hours in the incubator, the plates were removed and left at room temperature for 10 minutes to equilibrate. The reagent dispenser was set up to dispense 25 µl aliquots of OneGlo luciferase reagent (at room temperature) into each well of a 384-well plate using a standard cassette. After being added to OneGlo plates, the plates were shaken briefly, then incubated in the dark at room temperature for approximately 3 minutes. Plates were read using a Tecan or Promega luminometer.

The ability of the compounds disclosed herein to inhibit GR activity was quantified and the corresponding IC ₅₀ value determined. In table. 3 shows the cellular IC ₅₀ values of various substituted steroid compounds disclosed herein.

Table 3

No. 1X50 FOR GR (nM) No. 1X50 FOR GR (nM) 1 A 17 IN 2 A 18 A 3 A 19 IN 4 A 20 A 5 A 21 A 6 A 22 A 7 A 23 IN 8 A 24 A 9 A 25 A 10 A 26 IN eleven A 27 A 12 IN 28 IN 13 A 29 A 14 IN thirty IN 15 A 31 A 16 IN 32 IN

Note. Data on IC ₅₀ cell analysis indicated in the following ranges: A<100 nm, B>100 nm.

Example B In vitro AR agonist assay.

An AR agonist assay was performed using the LNAR reporter gene-expressing cell line, which overexpresses the AR and 4XARE-Luc genes. This cell line is sensitive to even minor partial agonist

Claims (16)

biological activity against AR in a hormone-deprived medium (CSS). Assays were performed in RPMI (no phenol red)+10% CSS using 6000 LNAR cells/well in 384-well plates and compounds were incubated with cells in a 37° C. incubator for 18-24 hours. OneGlo reagent (25 μl/well) was added ) and the plates were read with a luminometer for 3 min. Mifepristone has shown strong partial AR agonist activity at concentrations below 10 nM and is known to significantly promote CRPC growth both in vivo and in vitro. Mifepristone is included as a standard in the assay to measure partial agonist AR activity. The results of the analysis of agonist action against AR were quantified by determining the ratio of the maximum response for individual compounds and the maximum response for mifepristone (conventionally taken as 1). Values from the table. 4 are shown as relative maximum response to mifepristone. This general trend of AR agonistic activity has been shown for the class of compounds described herein. Note. The relative maximum response to mifepristone based on AR agonist response analysis data is indicated in the following ranges: A<0.4, B>0.4. CLAIM 1. Connection, which is or a pharmaceutically acceptable salt thereof. 2. A pharmaceutical composition containing a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 3. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the treatment of cancer in a subject in need thereof, said cancer expressing a glucocorticoid receptor (GR). 4. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to reduce the incidence of cancer recurrence in a subject in cancer remission, said cancer expressing the glucocorticoid receptor (GR). 5. The use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the treatment of - 88 041590 stent for cancer chemotherapy in a subject in need thereof, said cancer expressing the glucocorticoid receptor (GR). 6. Use according to any one of claims 3 to 5, wherein the cancer is breast cancer. 7. Use according to any one of claims 3 to 5, wherein the cancer is ovarian cancer. 8. Use according to any one of claims 3 to 5, wherein the cancer is prostate cancer. 9. Use according to any one of claims 6 to 8, wherein the subject in need has increased expression of glucocorticoid receptors in the tumor. 10. Use according to any one of claims 3 to 5, wherein the cancer is triple negative breast cancer, high grade serous ovarian cancer, castration resistant prostate cancer, or double resistant prostate cancer. 11. Use according to any one of claims 3 to 5, wherein the cancer is castration-resistant prostate cancer. 12. Use according to any one of claims 3 to 11 in combination with a second therapeutic agent, wherein the second therapeutic agent is an androgen receptor inhibitor. 13. Use according to claim 12, wherein the androgen receptor inhibitor is enzalutamide. 14. Use according to any one of claims 3-11 in combination with a second therapeutic agent, wherein the second therapeutic agent is cisplatin, carboplatin, paclitaxel, gemcitabine, doxorubicin, camptothecin, topotecan, or any combination thereof. 15. Use according to any one of claims 3 to 11 in combination with a second therapeutic agent, wherein the second therapeutic agent is nab-paclitaxel. 16. Use according to any one of claims 3 to 11 in combination with a second therapeutic agent, wherein the second therapeutic agent is an anti-PD-L1 antibody agent or an anti-PD1 antibody agent. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2