CANCER THERAPY USING A COMBINATION OF A CDK7 INHIBITOR WITH AN ORAL SERD

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] The present application claims priority to and benefit of U.S. Provisional Pat. Appl. No. 63/342,470, filed on May 16, 2022, which application is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] This invention pertains to methods for treating cancer in a subject, comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an oral selective estrogen receptor degrader (SERD).

BACKGROUND

[0003] Cyclin-dependent kinase (CDK7) is necessary for transcription and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 also modulates regulated gene expression by phosphorylating transcription factors, including p53, retinoid receptors, androgen receptor, and estrogen receptor. Ligand-dependent phosphorylation of serine 118 (Seri 18), important for ERa function and turnover, is mediated by CDK7 (Oncogene; 2002; 21:4921). Hence pharmacological modulation of CDK7 kinase activity is considered to be an important approach to treat cancers that are critically dependent on transcription to maintain their oncogenic state. CDK7, which complexes with cyclin H and MAT1, phosphorylates the cell cycle CDKs in the activation of T-loop, to promote their activities (Fisher et al., Cell., Aug 26;78(4):713-24, 1994). Recent genetic and biochemical studies have confirmed the importance of CDK7 for cell cycle progression (Larochelle et al., Mol Cell., Mar 23;25(6):839-50. 2007; Ganuza et al., EMBO J., May 30; 31(11): 2498-510, 2012).

[0004] Breast cancer is the most frequently diagnosed cancer in women, with estrogen receptor positive (ER+) breast cancer making up approximately 75% of all breast cancers diagnosed. Given the dependence on active ER signaling in these tumors, the predominant treatment strategy has been to inhibit various aspects of this pathway including directly antagonizing ER, for example with selective estrogen receptor degraders (SERDs). Interestingly, the dependence on ER for breast cancer growth is often retained even after progression through several lines of antiestrogen therapy, making ER a bona fide biomarker for this cancer subtype and driving the continued research and development of novel ER- targeted therapeutics to treat this patient population. This, combined with the continuous discovery of mechanisms underlying endocrine resistance, is resulting in a continually evolving treatment landscape for ER+ breast cancer. Oral SERDs, having SERD activity with good oral bioavailability, are being developed to allow for convenient oral administration for treatment of cancers, including ER+ breast cancer. Oral SERDs are also being investigated in other cancers such as ovarian cancer and endometrial cancer.

[0005] In recent times, promising drug targets have been identified for their effective use in the cancer treatment. These chemotherapies are effective in certain types of cancer; but their effectiveness has always been restricted due to drug resistance and side effects on normal tissues and cells. The development of multidrug resistance to chemotherapy remains a major challenge in treating cancer. Therefore, the continual advancement of novel anticancer therapy remains to be a prime public health demand, despite of the present available anticancer drugs in the market.

SUMMARY

[0006] The present invention provides methods and compositions for treating cancer using a compound of formula (I) or a pharmaceutically acceptable salt thereof, including combination therapy with an oral selective estrogen receptor degrader (SERD).

[0007] Provided herein is a method of treating cancer in a subject, comprising administering to the subject a compound of formula (I): or a pharmaceutically acceptable salt or a stereoisomer thereof, in combination with an oral SERD; wherein, ring A is cycloalkyl, aryl, heteroaryl or heterocyclyl; ring B is aryl, cycloalkyl, heterocyclyl or absent;

Ri is hydrogen or alkyl;

R2 is hydrogen, alkyl or cycloalkyl;

R3 is hydrogen, alkyl or heteroaryl; alternatively, R2 together with Ri or R3 along with the ring atoms to which they are attached forms a 5- to 7-membered ring;

R4 at each occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro, cyano or haloalkyl; ^or wherein R5' is hydrogen, halo, alkyl, alkoxy, alkoxyalkyl or -(CH2)I-3- NR _a R _b ; R ₅ " is H or alkyl;

R _a and Rb are each independently hydrogen, alkyl, alkoxy or alkoxyalkyl ; alternatively, R _a and Rb together with the nitrogen atom to which they are attached form an optionally substituted ring containing 0-2 additional heteroatoms independently selected from N, O or S; wherein the optional substituent is independently one or more halo, alkyl, acyl, hydroxy, cyano, cyanoalkyl, haloalkyl, alkoxy, alkoxyalkyl, -COOH or -COO-alkyl;

R6 at each occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro, cyano or haloalkyl;

L1 is *-CRcRd -C(O)-, *-NReC(O)- or absent; wherein * is the point of attachment with ring A;

R _c and Rd independently are hydrogen, alkyl or haloalkyl; alternatively, R _c and Rd together with the carbon atom to which they are attached form a cycloalkyl ring;

R _e is hydrogen or alkyl;

L2 is -C(O)NH-, — C(O)O- or absent; m is 0, 1 or 2; p is 0 or 1 ; and q is 0 to 3.

[0008] In some embodiments, disclosed herein is a use of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof in combination with an oral SERD for the treatment of cancer. [0009] In some embodiments, disclosed herein is a use of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, including combinations thereof in all ratios, as a medicament for treating cancer in combination with an oral SERD.

[0010] In some embodiments, the oral SERD is elacestrant, rintodestrant, giredestrant, amcenestrant, camizestrant, imlunestrant, or LSZ-102, or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the cancer is breast cancer, prostate cancer, head and neck cancer, squamous cell carcinoma, stomach cancer, ovarian cancer, soft-tissue sarcoma, adenocarcinoma, or lung cancer.

[0012] In some embodiments, the cancer is breast cancer.

[0013] In some embodiments, the cancer is metastatic breast cancer.

[0014] In some embodiments, the cancer is metastatic hormone resistant breast cancer.

[0015] In some embodiments, the cancer is ER-positive (estrogen receptor positive), HRpositive (hormone receptor positive, i. c. , ER-positive and progesterone receptor (PR)- positive) or HER2 -negative (human epidermal growth factor receptor 2 negative), advanced or metastatic breast cancer.

[0016] In some embodiments, the cancer is non-small cell lung cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Fig. 1 is a cell viability matrix for CPD-44A + amcenestrant in a MCF7 cell line.

[0018] Fig. 2 is a cell viability matrix for CPD-44A + giredestrant in a MCF7 cell line.

[0019] Fig. 3 is a cell viability matrix for CPD-44A + camizestrant in a MCF7 cell line.

[0020] Fig. 4 is a cell viability matrix for CPD-44A + elacestrant in a MCF7 cell line.

[0021] Fig. 5 is a cell viability matrix for CPD-44A + amcenestrant in a BT474 cell line.

[0022] Fig. 6 is a cell viability matrix for CPD-44A + giredestrant in a BT474 cell line.

[0023] Fig. 7 is a cell viability matrix for CPD-44A + camizestrant in a BT474 cell line.

[0024] Fig. 8 is a cell viability matrix for CPD-44A + elacestrant in a BT474 cell line.

[0025] Fig. 9 is a cell viability matrix for CPD-44A + amcenestrant in a T47D cell line. [0026] Fig. 10 is a cell viability matrix for CPD-44A + giredestrant in a T47D cell line.

[0027] Fig. 11 is a cell viability matrix for CPD-44A + camizestrant in a T47D cell line.

[0028] Fig. 12 is a cell viability matrix for CPD-44A + elacestrant in a T47D cell line.

[0029] Fig. 13 is a Loewe synergy score matrix for CPD-44A + amcenestrant in a MCF7 cell line.

[0030] Fig. 14 is a Loewe synergy score matrix for CPD-44A + elacestrant in a MCF7 cell line.

[0031] Fig. 15 is a Loewe synergy score matrix for CPD-44A + giredestrant in a MCF7 cell line.

[0032] Fig. 16 is a Loewe synergy score matrix for CPD-44A + camizestrant in a MCF7 cell line.

[0033] Fig. 17 is a plot of median tumor volume in a MCF7 mouse xenograft model following dosing of CPD-44A, elacestrant, or a combination thereof.

DETAILED DESCRIPTION

[0034] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated to facilitate the understanding of the present invention.

[0035] As used herein, unless otherwise defined the term “alkyl” alone or in combination with other term(s) means saturated aliphatic hydrocarbon chains, including Ci-Cio straight or C3-C10 branched alkyl groups. Examples of “alkyl” include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, isopentyl or neopentyl and the like.

[0036] As used herein, the term “halo” or “halogen” alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine.

[0037] As used herein, the term “haloalkyl” means alkyl substituted with one or more halogen atoms independently, wherein the alkyl groups are as defined above. The term “halo” is used herein interchangeably with the term “halogen” means F, Cl, Br or I. Examples of “haloalkyl” include but are not limited to fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and the like.

[0038] As used herein, the term “hydroxy” or “hydroxyl” alone or in combination with other term(s) means -OH.

[0039] As used herein, the term “alkoxy” refers to the group alkyl-O- or -O-alkyl, where alkyl groups are as defined above. Exemplary alkoxy- groups include but are not limited to methoxy, ethoxy, n-propoxy, n-butoxy, t-butoxy and the like. An alkoxy group can be unsubstituted or substituted independently with one or more suitable groups.

[0040] As used herein, the term “alkoxyalkyl” refers to the group alkyl-O-alkyl-, wherein alkyl and alkoxy groups are as defined above. Exemplary alkoxyalkyl- groups include but are not limited to methoxymethyl, ethoxymethyl, methoxyethyl, isopropoxymethyl and the like.

[0041] As used herein, the term “cyano” refers to -CN; and the term “cyanoalkyl” refers to alkyl substituted with -CN; wherein the alkyl groups are as defined above.

[0042] As used herein, the term “amino” refers to -NH2;

[0043] As used herein, the term “nitro” refers to -NO2;

[0044] As used herein, the term “acyl” refers to the group -C(O)-alkyl, wherein alkyl groups are as defined above. Exemplary acyl- groups include but are not limited to acetyl, propanoyl and acrylyl. An acyl group can be unsubstituted or substituted independently with one or more suitable groups.

[0045] As used herein the term “cycloalkyl” alone or in combination with other term(s) means C3-C10 saturated cyclic hydrocarbon ring. A cycloalkyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms. Examples of single-ring cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. A cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused and spirocyclyls and the like.

[0046] As used herein, the term “aryl” is optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms. Examples of a C6-C14 aryl group include, but are not limited to phenyl, naphthyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl and acenaphthyl. An aryl group can be unsubstituted or substituted independently with one or more suitable groups. [0047] The term “heterocycloalkyl” refers to a non-aromatic, saturated or partially saturated monocyclic or polycyclic ring system of 3 to 15 members having at least one heteroatom or hetero group selected from O, N, S, S(O), S(O)2, NH or C(O) with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. A monocyclic heterocycloalkyl may typically contain 4 to 7 ring atoms. Examples of “heterocycloalkyl” include, but are not limited to azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, azepanyl and N-oxides thereof. Attachment of a heterocycloalkyl substituent can occur via either a carbon atom or a heteroatom. A heterocycloalkyl group can be optionally independently substituted with one or more suitable groups selected from one or more aforesaid groups.

[0048] As used herein, the term “heteroaryl” alone or in combination with other term(s) means a completely unsaturated ring system containing a total of 5 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms/groups being independently selected from the group consisting of carbon, oxygen, nitrogen or sulfur. A heteroaryl may be a single-ring (monocyclic) or polycyclic ring system. Examples of “heteroaryl” include but are not limited to pyridyl, indolyl, benzimidazolyl, benzothiazolyl and the like.

[0049] As used herein, the term “heterocyclyl” alone or in combination with other term(s) includes both “heterocycloalkyl” and “heteroaryl” groups which are as defined above.

[0050] The term “heteroatom” as used herein designates a sulfur, nitrogen or oxygen atom.

[0051] As used in the above definitions, the term “optionally substituted” or “substituted” or “optionally substituted with suitable groups” refers to replacement of one or more hydrogen radicals in a given structure with a radical of a specified substituent including, but not limited to halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl and heteroaryl. It is understood that the substituent may be further substituted.

[0052] As used herein, the term “comprise” or “comprising” is generally used in the sense of include, that is to say permitting the presence of one or more features or components.

[0053] As used herein, the term “or” means “and/or” unless stated otherwise.

[0054] As used herein, the term “including” as well as other forms, such as “include", “includes” and “included” is not limiting.

[0055] The term “treatment”/“treating” means any treatment of a disease in a mammal, including (a) Inhibiting the disease, i.e., slowing or arresting the development of clinical symptoms; and/or (b) Relieving the disease, i.e., causing the regression of clinical symptoms and/or (c) Alleviating or abrogating a disease and/or its attendant symptoms.

[0056] "Pharmaceutically acceptable” means that, which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

[0057] The term “pharmaceutically acceptable salt” refers to a product obtained by reaction of the compound of the present invention with a suitable acid or a base. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic/organic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate or p-toluenesulfonate salts, and the like. Certain compounds of the invention (can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc, salts.

[0058] The term “stereoisomers” refers to any enantiomers, diastereomers, or geometrical isomers of the compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) and (IG), wherever they are chiral or when they bear one or more double bonds. When the compounds of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF) and (IG) are chiral, they can exist in racemic or in optically active form. The invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as tZ-isomers and l- isomers and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis/trans, syn/anti, entgegen (E) / zusammen (Z), (R)/(S) isomers as well as the appropriate mixtures thereof.

[0059] In some embodiments, the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as ² H (“D”), ³ H, ⁿ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³⁵ S, ¹⁸ F, ³⁶ C1, ¹²³ I and ¹²⁵ I. Isotopically labeled compounds of the present inventions can generally be prepared by following procedures well known in the art, such as by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0060] As used herein, the term “subject” refers to an animal, preferably a mammal, and most preferably a human.

[0061] As used herein, the term, “therapeutically effective amount” refers to an amount of a compound of the present invention or a pharmaceutically acceptable salt or a stereoisomer thereof; or a composition comprising the compound of the present invention or a pharmaceutically acceptable salt or a stereoisomer thereof, effective in producing the desired therapeutic response in a particular patient suffering from cancer. Particularly, the term “therapeutically effective amount” includes the amount of the compound of the present invention or a pharmaceutically acceptable salt or a stereoisomer thereof, when administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject. In respect of the therapeutic amount of the compound, the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment can also be considered. The therapeutically effective amount of the compound or composition will be varied with the condition being treated, the severity of the condition being treated, the duration of the treatment, the nature of concurrent therapy, the age and physical condition of the end user, the specific compound or composition employed the particular pharmaceutically acceptable carrier utilized.

[0062] As used herein, the term, “oral SERD” refers to a therapeutic compound that possesses biological activity as a selective estrogen receptor degrader and has adequate oral bioavailability to be suitable for oral administration. For example, an oral SERD has oral bioavailability that is greater than SERDs that are not suitable for oral administration due to their poor oral bioavailability (e.g., fulvestrant).

[0063] In some embodiments, compounds of the invention may be used in combination with another therapeutic agent. As used herein, administering a first agent (e.g., a compound of formula (I)) in combination with a second agent (e.g., an oral SERD) refers to any form of administration of two or more different therapeutic compounds such that the second agent is administered while the first agent is still effective in the body (e.g., the two compounds are simultaneously effective in the subject, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. In some embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. In some embodiments, the second agent is administered within about 5 minutes to within about 168 hours prior to or after administration of the first agent. Thus, a subject who receives such treatment can benefit from a combined effect of the administered therapeutic compounds. [0064] In some embodiments, the present invention provides methods wherein an oral SERD is administered within about 5 minutes to within about 168 hours prior to or after administration of a compound of formula (I). In some embodiments, the present invention provides methods wherein an oral SERD is administered within 0.5 hours to 72 hours prior to or after administration of a compound of formula (I). In some embodiments, the present invention provides methods wherein an oral SERD is administered within 0.5 hours to 24 hours prior to or after administration of a compound of formula (I). In some embodiments, the present invention provides methods wherein an oral SERD is administered within 2 hours prior to or after administration of a compound of formula (I).

[0065] In some embodiments, the present invention provides methods comprising administering a compound of formula (I) prior to administering an oral SERD. In some embodiments, the present invention provides methods comprising administering a compound of formula (1) 2 hours prior to administering an oral SERD. In some embodiments, the present invention provides methods comprising administering a compound of formula (I) within 0.5 hours to 72 hours after administering an oral SERD. In some embodiments, the present invention provides methods comprising administering a compound of formula (I) about 2 hours after administering an oral SERD. In some embodiments, the present invention provides methods comprising administering a compound of formula (I) at least 1 hour after an oral SERD.

[0066] In some embodiments, combination therapy of compounds of the invention with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) provide improved efficacy relative to each individual administration of the compound of the invention or the one or more additional therapeutic agent(s). In certain such embodiments, the combination therapy provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the invention and the one or more additional therapeutic agent(s).

[0067] Provided herein is a method of treating cancer in a subject, comprising administering to the subject a compound of formula (I): or a pharmaceutically acceptable salt or a stereoisomer thereof, in combination with an oral SERD; wherein, ring A is cycloalkyl, aryl, heteroaryl or heterocyclyl; ring B is aryl, cycloalkyl, heterocyclyl or absent;

Ri is hydrogen or alkyl;

R2 is hydrogen, alkyl or cycloalkyl;

R3 is hydrogen, alkyl or heteroaryl; alternatively, R2 together with Ri or R3 along with the ring atoms to which they are attached forms a 5- to 7-membered ring;

R4 at each occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro, cyano or haloalkyl;

O ; wherein R5 is hydrogen, halo, alkyl, alkoxy, alkoxyalkyl or -(CH2)i-3- NR _a Rb; R ₅ " is H or alkyl;

R _a and Rb are each independently hydrogen, alkyl, alkoxy or alkoxyalkyl; alternatively, R _a and Rb together with the nitrogen atom to which they are attached form an optionally substituted ring containing 0-2 additional heteroatoms independently selected from N, O or S; wherein the optional substituent is independently one or more halo, alkyl, acyl, hydroxy, cyano, cyanoalkyl, haloalkyl, alkoxy, alkoxyalkyl, -COOH or -COO-alkyl;

R ₅ at each occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro, cyano or haloalkyl;

Li is *-CRcRd-C(O)-, *- -NReC(O)- or absent; wherein * is the point of attachment with ring A;

R _c and Ri independently are hydrogen, alkyl or haloalkyl; alternatively, R _c and Rd together with the carbon to which they are attached form a cycloalkyl ring;

R _e is hydrogen or alkyl;

L2 is -C(O)NH- — C(O)O- or absent; m is 0, 1 or 2; p is 0 or 1; and q is 0 to 3. [0068] In some embodiments, the present methods include administering a compound of formula (I) represented by formula (IA): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, ring A is cycloalkyl, aryl, heteroaryl or heterocyclyl; ring B is aryl, cycloalkyl, heterocyclyl or absent;

Ri is hydrogen or alkyl;

R2 is hydrogen, alkyl or cycloalkyl;

R3 is hydrogen, alkyl or heteroaryl; alternatively, R2 together with Ri or R3 along with the ring atoms to which they are attached forms a 5- to 7-membered ring;

R4 at each occurrence is halo, alkyl, hydroxy or alkoxy; ; wnerem KS IS nyarogen, naio, aiKyi, aiKoxy, aiKoxyaucyi or - (CH ₂ )i-3-NR _a Rb; R ₅ " is H or alkyl;

R _a and Rb are each independently hydrogen or alkyl; alternatively, Ra and Rb together with the nitrogen atom to which they are attached form an optionally substituted ring containing 0- 2 additional heteroatoms independently selected from N, O or S; wherein the optional substituent is independently one or more halo, alkyl, hydroxy, haloalkyl or alkoxy;

Li is *-CRcRd-C(O)-, *-NR _e C(O)- or absent; wherein * is the point of attachment with ring A;

R _c and Rd independently are hydrogen, alkyl or haloalkyl; alternatively, R _c and Rd together with the carbon atom to which they are attached form a cycloalkyl ring;

R _e is hydrogen or alkyl;

L2 is -C(O)NH-, -C(O)O- or absent; m is 0, 1 or 2; and p is 0 or 1.

[0069] In some embodiments, the present methods include administering a compound of formula (1) represented by formula (IB): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0070] In some embodiments, the present methods include administering a compound of formula (I) represented by formula (IC): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0071] In some embodiments, the present methods include administering a compound of formula (I) represented by formula (ID): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. [0072] In some embodiments, the present methods include administering a compound of formula (I) represented by formula (IE):

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein Li is ; and wherein * is the point of attachment with phenyl ring.

[0073] In some embodiments, the present methods include administering a compound of formula (I) represented by formula (IF): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein Li is and wherein * is the point of attachment with phenyl ring.

[0074] In some embodiments, the present methods include administering a compound of formula (I) represented by formula (IG): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0075] In some embodiments, provided herein is a method of treating breast cancer in a subject, comprising administering to the subject a compound of formula (I): or a pharmaceutically acceptable salt or a stereoisomer thereof, in combination with an oral SERD; wherein, ring A is cycloalkyl, aryl, heteroaryl or heterocyclyl; ring B is aryl, cycloalkyl, heterocyclyl or absent;

Ri is hydrogen or alkyl;

R2 is hydrogen, alkyl or cycloalkyl;

R3 is hydrogen, alkyl or heteroaryl; alternatively, R2 together with Ri or R3 along with the ring atoms to which they are attached forms a 5- to 7-membered ring;

R4 at each occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro, cyano or haloalkyl; ^or wherein R5' is hydrogen, halo, alkyl, alkoxy, alkoxyalkyl or -(CH2)I-3- NR _a Rb; R ₅ " is H or alkyl;

R _a and Rb are each independently hydrogen, alkyl, alkoxy or alkoxyalkyl; alternatively, R _a and Rb together with the nitrogen atom to which they are attached form an optionally substituted ring containing 0-2 additional heteroatoms independently selected from N, O or S; wherein the optional substituent is independently one or more halo, alkyl, acyl, hydroxy, cyano, cyanoalkyl, haloalkyl, alkoxy, alkoxyalkyl, -COOH or -COO-alkyl;

R ₅ at each occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro, cyano or haloalkyl;

Li is *-CRcR<i-C(O)-, *-NR«C(O)- or absent; wherein * is the point of attachment with ring A;

R _c and Ri independently are hydrogen, alkyl or haloalkyl; alternatively, R _c and Rd together with the carbon to which they are attached form a cycloalkyl ring;

R _e is hydrogen or alkyl; L2 is -C(O)NH-, -C(0)0- or absent; m is 0, 1 or 2; p is 0 or 1; and q is 0 to 3.

[0076] In some embodiments, the present methods include administering a compound of formula (I) wherein ring A is aryl or heteroaryl.

[0077] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is aryl.

[0078] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is 1,3-phenylene.

[0079] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is monocyclic or bicyclic, cycloalkyl, aryl, heterocycloalkyl or heteroaryl.

[0080] In some embodiments, the present methods include administering compounds of formula (I), wherein ring B is aryl. Preferably the aryl is phenyl.

[0081] In some embodiments, the present methods include administering compounds of formula (I), wherein ring B is heterocyclyl. Preferably the heterocyclyl is piperidinyl, pyridinyl, piperazinyl, pyrazolyl, morpholinyl, indolinyl or pyrrolidinyl.

[0082] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is cycloalkyl.

[0083] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₅ is:

[0084] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₅ ' is -(CH2)i-3-NRaRb.

[0085] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R _a and Rb together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring having 0-2 additional heteroatoms selected from O, S or N.

[0086] In some embodiments, the present methods include administering a compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein Li is *-CR _c Rd-C(O)-; wherein * is the point of attachment with ring A.

[0087] According to the preceding embodiment, specifically provided are methods which include administering a compound of formula (I), wherein Rc and Rd are independently hydrogen or alkyl, wherein the alkyl is methyl, ethyl or isopropyl.

[0088] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L2 is absent.

[0089] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein when Li is present, L2 is absent.

[0090] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is alkyl or cycloalkyl. Preferably the alkyl is ethyl and the cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl.

[0091] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen and alkyl; wherein the alkyl is methyl.

[0092] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R4 is halo. Preferably the halo is fluoro.

[0093] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R5 is: wherein R5' is hydrogen or -CH2-NR _a Rb.

[0094] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₅ is: when R ₅ is attached to hetero atom of ring B; R ₅ ' is hydrogen or -CH2-NR _a Rb.

[0095] According to the preceding two embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the R _a and Rb are each independently hydrogen or alkyl. Preferably the alkyl is methyl.

[0096] According to the preceding embodiment, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the Ra and Rb together with the nitrogen atom to which they are attached form an optionally substituted ring containing 0-2 additional heteroatoms independently selected from N, O or S; wherein the optional substituent is independently one or more halo, hydroxy, haloalkyl or alkoxy.

[0097] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is meta-substituted with respect to Li and L2.

[0098] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is monocyclic or bicyclic, cycloalkyl, aryl, heterocycloalkyl or heteroaryl.

[0099] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is heterocyclyl. In another embodiment, the heterocyclyl is piperidinyl, pyridinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, pyrazinyl, pyrazolyl, morpholinyl, indolinyl or pyrrolidinyl.

[0100] In some embodiments, the present methods include administering a compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.

[0101] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0102] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

[0103] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 1. [0104] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is cycloalkyl; in another embodiment, the cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl.

[0105] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 and Ri together with the atoms to which they are attached form a 5 or 6 membered ring.

[0106] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together with the atoms to which they are attached form a 5 or 6 membered ring.

[0107] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together with the atoms to which they are attached form a 6 membered aromatic ring.

[0108] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₅ is: wherein R ₅ ' is hydrogen, halo, alkyl, alkoxy or alkoxyalkyl; and R ₅ " is H or alkyl.

[0109] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₅ is: wherein R ₅ ' is -CH2-NR _a Rb; R ₅ " is H or alkyl; R _a and Rb are each independently hydrogen, alkyl, alkoxy or alkoxyalkyl.

[0110] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₅ is: wherein R ₅ ' is -CH2-NR _a Rb; R ₅ " is H or alkyl; R _a and Rb together with the nitrogen atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl ring containing 0-2 additional heteroatoms independently selected from N, O or S; wherein the optional substituent is independently one or more halo, alkyl, acyl, hydroxy, cyano, cyanoalkyl, haloalkyl, alkoxy, alkoxyalkyl, -COOH or -COO-alkyl.

[0111] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₅ is: wherein p is 1 , Ra and Rb are as defined in formula (I).

[0112] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₅ is: wherein '- is a point of attachment.

[0113] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₅ ' is -(CH2)i-3-NRaRb; wherein R _a and Rb are as defined in formula (I).

[0114] In some embodiments, the present methods include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein when Li is -CR _c Ra-C(O)- or -NR _e C(O)-, L2 is absent.

[0115] In some embodiments, the present methods include administering a compound of formula (I) selected from Table 1 below:

Table 1: or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0116] In some embodiments, the compound of formula (I) is selected from:

(E)-N-(5 -(3 -( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)- 1 -oxopropan-2-yl)phenyl)pyridin-2- yl)-4-((S)-3-fluoropyrrolidin-l-yl)but-2-enamide;

N-(5-(3-(l-((5-cyclopropyl-lH-pyrazol-3-yl)amino)-l-oxopr opan-2-yl)phenyl)pyridin-2- yl)acrylamide;

(E)-N-(5 -(3 -( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)-3 -methyl- 1 -oxobutan-2- yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide;

(E)-N-(5-(3-(l -((5-cyclopropyl-l H-pyrazol-3-yl)amino)-l -oxopropan-2-yl)phenyl)pyridin-2- yl)-4-morpholinobut-2-enamide ;

(E)-N-(5 -(3 -( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)- 1 -oxopropan-2-yl)phenyl)pyridin-2- yl)-4-(pyrrolidin- 1 -yl)but-2-enamide;

(E)-N-(5 -(3 -( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)-3 -methyl- 1 -oxobutan-2- yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide;

(E)-N-(5 -(3 -( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)- 1 -oxopropan-2-yl)phcnyl)pyridin-2- yl)-4-(piperidin- 1 -yl)but-2-enamide;

(E)-N -(3 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)-3 -methyl- 1 -oxobutan-2-yl)-3 -fluoro-

[l,r-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; and

(E)-N-(5 -(3 -( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)- 1 -oxopropan-2-yl)phenyl)pyridin-2- yl)-4-(3-fluoropiperidin- 1 -yl)but-2-enamide.

[0117] In certain preceding embodiments, the compound of formula (I) is selected from:

(E)-N-(5 -(3 -( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)-3 -methyl- 1 -oxobutan-2- yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide;

(E)-N-(5 -(3 -( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)- 1 -oxopropan-2-yl)phenyl)pyridin-2- yl)-4-(pyrrolidin- 1 -yl)but-2-enamide; and

(E)-N-(5 -(3 -( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)- 1 -oxopropan-2-yl)phenyl)pyridin-2- yl)-4-morpholinobut-2-enamide. [0118] In some embodiments, the present methods include administering a compound of formula (I), wherein the compound of formula (I) is (E)-N-(5-(3-(l-((5-cyclopropyl-lH- pyrazol-3-yl)amino)-3-methyl-l-oxobutan-2-yl)phenyl)pyridin- 2-yl)-4-morpholinobut-2- enamide.

[0119] In some embodiments, the present methods include administering a compound of formula (I), wherein the compound of formula (I) is (.S)-(E)-N-(5-(3-(l-((5-cyclopropyl-lH- pyrazol-3-yl)aniino)-3-methyl-l-oxobutan-2-yl)phenyl)pyridin -2-yl)-4-morpholinobut-2- enamide.

[0120] In some embodiments, the present methods include administering a compound of formula (I), wherein the compound of formula (I) is (7?)-(E)-N-(5-(3-(l-((5-cyclopropyl-lH- pyrazol-3-yl)amino)-3-methyl-l-oxobutan-2-yl)phenyl)pyridin- 2-yl)-4-morpholinobut-2- enamide.

[0121] In some embodiments, the present methods include administering a compound of formula (I) in combination with an oral SERD selected from elacestrant, rintodestrant, giredestrant, amcenestrant, camizestrant, imlunestrant, or LSZ-102, or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, the oral SERD is elacestrant or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, the oral SERD is rintodestrant or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, the oral SERD is giredestrant or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the oral SERD is amcenestrant or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the oral SERD is camizestrant or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the oral SERD is imlunestrant or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the oral SERD is LSZ-102 or a pharmaceutically acceptable salt thereof. [0129] In some embodiments, the oral SERD is ZN-c5, D-0502, or SHR9549, or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, compound of formula (I) is compound 44A (“CPD-44A”) of Table 1, which is (S)-(E)-N-(5-(3-(l-((5-cyclopropyl-lH-pyrazol-3-yl)amino)-3- methyl-l- oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide . The structure of compound 44A is shown below:

Compound 44A and crystalline forms thereof are described in PCT Publication No. WO 2022/130304 Al, published June 23, 2022, the entire contents of which are incorporated herein by reference. Processes for preparing Compound 44A are described in PCT Publication NO. WO 2022/229835 Al, published November 3, 2022, the entire contents of which are incorporated herein by reference.

[0131] In some embodiments, compound of formula (I) is a CDK7 inhibitor.

[0132] In some embodiments, the present methods include administering a compound of formula (I) in combination with an oral SERD, wherein the combination therapy provides a synergistic effect.

[0133] In some embodiments, the compound of formula (I) and the oral SERD are administered simultaneously or sequentially.

[0134] In some embodiments, the cancer is breast cancer, prostate cancer, head and neck cancer, squamous cell carcinoma, stomach cancer, ovarian cancer, soft-tissue sarcoma, adenocarcinoma, or lung cancer.

[0135] In some embodiments, the cancer is breast cancer.

[0136] In some embodiments, the cancer is metastatic breast cancer. [0137] In some embodiments, the cancer is ER-positive, HR-positive or HER2 -negative, advanced or metastatic breast cancer.

[0138] In some embodiments, the cancer is ER-positive breast cancer. In some embodiments, the cancer may be characterized by one or more mutations in estrogen receptor 1 (ESRI) that confer estrogen-independent ER activation and resistance to certain therapies such as aromatase inhibitors. Examples of such mutations include ligand binding domain mutations such as D538G, Y537S, Y537N, Y537C, L536H, L536P, L536R, S463P, and E380Q. See, Brett, et al. Breast Cancer Res 23, 85 (2021), which is incorporated herein by reference in its entirety. In some embodiments, the ER-positive breast cancer is characterized by a wild-type ER (e.g., wild-type ESRI).

[0139] In some embodiments, the cancer is HR-positive breast cancer, i.e., the cancer is ER-positive and progesterone receptor (PR)-positive.

[0140] In some embodiments, the cancer is non-small cell lung cancer.

[0141] In some embodiments, the cancer is ER-positive ovarian cancer.

[0142] In some embodiments, the cancer is ER-positive epithelial cancer.

[0143] In some embodiments, the cancer is epithelial ovarian cancer.

[0144] In some embodiments, the cancer is triple negative breast cancer.

[0145] Tn some embodiments, and cancer is metastatic castration-resistant prostate cancer.

[0146] In some embodiments, the present invention provides a pharmaceutical composition comprising an oral SERD, a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0147] In some embodiments, the present invention provides a method of treating breast cancer in a subject, the method comprising: administering to the subject a therapeutically effective amount of ( _< S)-(E)-N-(5-(3-(l-((5-cyclopropyl-lH-pyrazol-3-yl)amin o)-3-methyl-l- oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide or a pharmaceutically acceptable salt thereof in combination with an oral SERD.

[0148] According to some further examples of the preceding embodiment, the breast cancer is ER-positive, HR-positive or HER2 -negative, advanced or metastatic breast cancer. [0149] In some embodiments, the present methods comprise administering a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof. In some embodiments, the therapeutically effective amount of a compound of formula (I) is a total daily dosage of from about 5 mg to about 500 mg. In some embodiments, the therapeutically effective amount of a compound of formula (I) is a total daily dosage of from about 10 mg to about 250 mg. In some embodiments, the total daily dosage is from about 20 mg to about 160 mg. In some embodiments, the total daily dosage is from about 20 mg to about 80 mg. In some embodiments, the total daily dosage is from about 20 mg to about 40 mg. In some embodiments, the total daily dosage is from about 40 mg to about 160 mg. In some embodiments, the total daily dosage is from about 40 mg to about 80 mg. In some embodiments, the total daily dosage is from about 80 mg to about 160 mg. In some embodiments, the total daily dosage is about 20 mg, about 40 mg, about 80 mg, or about 160 mg.

[0150] In some embodiments, the present methods comprise administering a therapeutically effective amount of compound 44A or a pharmaceutically acceptable salt or a stereoisomer thereof. In some embodiments, the therapeutically effective amount of Compound 44A or a pharmaceutically acceptable salt thereof is a total daily dosage of from about 5 mg to about 500 mg. In some embodiments, the total daily dosage of Compound 44A or a pharmaceutically acceptable salt thereof is from about 10 mg to about 250 mg. In some embodiments, the total daily dosage of Compound 44A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 160 mg. In some embodiments, the total daily dosage of Compound 44A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 80 mg. In some embodiments, the total daily dosage of Compound 44A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 40 mg. In some embodiments, the total daily dosage of Compound 44A or a pharmaceutically acceptable salt thereof is from about 40 mg to about 160 mg. In some embodiments, the total daily dosage of Compound 44A or a pharmaceutically acceptable salt thereof is from about 40 mg to about 80 mg. In some embodiments, the total daily dosage of Compound 44A or a pharmaceutically acceptable salt thereof is from about 80 mg to about 160 mg. In some embodiments, the total daily dosage of Compound 44A or a pharmaceutically acceptable salt thereof is about 20 mg, about 40 mg, about 80 mg, or about 160 mg.

[0151] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof (e.g., Compound 44A or a pharmaceutically acceptable salt thereof) is administered orally. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof (e.g., Compound 44A or a pharmaceutically acceptable salt thereof) is administered once daily. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof (e.g., Compound 44A or a pharmaceutically acceptable salt thereof) is administered twice daily. In some embodiments, the total dose of the compound of formula (I) (e.g., Compound 44-A) or a pharmaceutically acceptable salt (e.g., Compound 44-A fumarate) or a stereoisomer thereof is from about 60 mg to about 100 mg, administered in two separate administrations per day, e.g., from about 30 mg to about 50 mg twice daily (BID). In some embodiments, the total dose of the compound or pharmaceutically acceptable salt (e.g., Compound 44-A fumarate) is 80 mg, administered in two separate administrations per day, e.g., 40 mg twice day (BID).

[0152] In some embodiments, the present methods comprise administering a therapeutically effective amount of an oral SERD.

[0153] In some embodiments, the present methods comprise administering a therapeutically effective amount of elacestrant or a pharmaceutically acceptable salt thereof. Elacestrant, compositions thereof, and methods of use thereof, are described in U.S. Patent Nos. 7,612,114; 8,399,520; 10,071,066; 10,385,008; 10,420,734; and 10,745,343, the entire contents of each of which are incorporated herein by reference. In some embodiments, the therapeutically effective amount of elacestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 25 mg to about 500 mg, e.g., about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg. In some embodiments, the therapeutically effective amount of elacestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 100 mg to about 500 mg. In some embodiments, the therapeutically effective amount of elacestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 25 mg to about 250 mg. In some embodiments, the therapeutically effective amount of elacestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 25 mg to about 100 mg. In some embodiments, the therapeutically effective amount of elacestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 50 mg to about 200 mg. In some embodiments, elacestrant or a pharmaceutically acceptable salt thereof is administered once daily. [0154] In some embodiments, the present methods comprise administering a therapeutically effective amount of rintodestrant or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of rintodestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 50 mg to about 1,000 mg, e.g., about 50 mg, about 100 mg, about 200 mg, about 400 mg, about 600 mg, about 800 mg, or about 1,000 mg. In some embodiments, the therapeutically effective amount of rintodestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 200 mg to about 1,000 mg. In some embodiments, the therapeutically effective amount of rintodestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 50 mg to about 500 mg. In some embodiments, the therapeutically effective amount of rintodestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 50 mg to about 200 mg. In some embodiments, the therapeutically effective amount of rintodestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 100 mg to about 300 mg. In some embodiments, rintodestrant or a pharmaceutically acceptable salt thereof is administered once daily.

[0155] In some embodiments, the present methods comprise administering a therapeutically effective amount of giredestrant or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of giredestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 1 mg to about 50 mg, e.g., about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg. In some embodiments, the therapeutically effective amount of giredestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 5 mg to about 50 mg. In some embodiments, the therapeutically effective amount of giredestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 1 mg to about 25 mg. In some embodiments, the therapeutically effective amount of giredestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 1 mg to about 10 mg. In some embodiments, the therapeutically effective amount of giredestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 2 mg to about 20 mg. In some embodiments, giredestrant or a pharmaceutically acceptable salt thereof is administered once daily.

[0156] In some embodiments, the present methods comprise administering a therapeutically effective amount of amcenestrant or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of amcenestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 10 mg to about 400 mg, e.g., about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg. In some embodiments, the therapeutically effective amount of amcenestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 50 mg to about 400 mg. In some embodiments, the therapeutically effective amount of amcenestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 10 mg to about 200 mg. In some embodiments, the therapeutically effective amount of amcenestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 10 mg to about 100 mg. In some embodiments, the therapeutically effective amount of amcenestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 20 mg to about 200 mg. In some embodiments, amcenestrant or a pharmaceutically acceptable salt thereof is administered once daily.

[0157] In some embodiments, the present methods comprise administering a therapeutically effective amount of camizestrant or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of camizestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 2 mg to about 100 mg, e.g., about 2 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, or about 100 mg. In some embodiments, the therapeutically effective amount of camizestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 10 mg to about 100 mg. In some embodiments, the therapeutically effective amount of camizestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 2 mg to about 50 mg. In some embodiments, the therapeutically effective amount of camizestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 2 mg to about 25 mg. In some embodiments, the therapeutically effective amount of camizestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 5 mg to about 50 mg. In some embodiments, camizestrant or a pharmaceutically acceptable salt thereof is administered once daily.

[0158] In some embodiments, the present methods comprise administering a therapeutically effective amount of imlunestrant or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of imlunestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 25 mg to about 500 mg, e.g., about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg. In some embodiments, the therapeutically effective amount of imlunestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 100 mg to about 500 mg. In some embodiments, the therapeutically effective amount of imlunestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 25 mg to about 250 mg. In some embodiments, the therapeutically effective amount of imlunestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 25 mg to about 100 mg. In some embodiments, the therapeutically effective amount of imlunestrant or a pharmaceutically acceptable salt thereof is a total daily dose of from about 50 mg to about 200 mg. In some embodiments, imlunestrant or a pharmaceutically acceptable salt thereof is administered once daily.

[0159] In some embodiments, the present methods comprise administering a therapeutically effective amount of LSZ-102 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of LSZ-102 or a pharmaceutically acceptable salt thereof is a total daily dose of from about 50 mg to about 900 mg, e.g., about 50 mg, about 100 mg, about 200 mg, about 400 mg, about 600 mg, about 800 mg, or about 900 mg. In some embodiments, the therapeutically effective amount of LSZ-102 or a pharmaceutically acceptable salt thereof is a total daily dose of from about 200 mg to about 900 mg. In some embodiments, the therapeutically effective amount of LSZ-102 or a pharmaceutically acceptable salt thereof is a total daily dose of from about 50 mg to about 500 mg. In some embodiments, the therapeutically effective amount of LSZ-102 or a pharmaceutically acceptable salt thereof is a total daily dose of from about 50 mg to about 200 mg. In some embodiments, the therapeutically effective amount of LSZ-102 or a pharmaceutically acceptable salt thereof is a total daily dose of from about 100 mg to about 300 mg. In some embodiments, LSZ-102 or a pharmaceutically acceptable salt thereof is administered once daily.

[0160] In some embodiments, COMPOUND 44A is in the form of a salt or cocrystal of COMPOUND 44A. In some embodiments, COMPOUND 44A is in the form of a salt. In some embodiments, the salt is crystalline. In some embodiments, COMPOUND 44A is in the form of a cocrystal. In some embodiments, COMPOUND 44A is in the form of a fumaric acid salt or cocrystal. In some embodiments, the fumaric acid salt is crystalline. In some embodiments, COMPOUND 44A fumarate is a cocrystal of crystalline Form 1, as described in WO 2022/130304 AL In some embodiments, the molar ratio of COMPOUND A to fumaric acid is 1 : 1. In some embodiments, the COMPOUND 44A fumarate is anhydrous. In some embodiments, the salt or cocrystal comprises greater than or equal to 98 wt% of COMPOUND A fumarate by weight of the salt or cocrystal.

Pharmaceutical compositions

[0161] In some embodiments, the present methods include a pharmaceutical composition comprising one or more of the compounds as disclosed herein, optionally admixed with a pharmaceutically acceptable carrier or diluent.

[0162] The pharmaceutical composition(s) of the present invention can be administered orally, for example in the form of tablets, coated tablets, pills, capsules, granules or elixirs. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermals, in the form of patches, or in other ways, for example in the form of aerosols or nasal sprays. An oral SERD is administered orally and formulated for oral administration.

[0163] The pharmaceutical composition(s) usually contain(s) about 1% to 99%, for example, about 5% to 75%, or from about 10% to about 30% by weight of the compound of formula (I) or pharmaceutically acceptable salts thereof. The amount of the compound of formula (I) or pharmaceutically acceptable salts thereof in the pharmaceutical composition(s) can range from about 1 mg to about 500 mg or from about 2.5 mg to about 250 mg or from about 5 mg to about 50 mg.

[0164] The present invention also provides methods for formulating the disclosed compounds as for pharmaceutical administration.

[0165] The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In some embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an individual, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. [0166] In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen- free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

[0167] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation of pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0168] The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0169] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In some embodiments, a compound may be simply dissolved or suspended in sterile water.

[0170] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0171] In some embodiments, the pharmaceutical composition comprises the active ingredient in an amount of at least about 50% by weight of the composition. In some embodiments, the pharmaceutical composition comprises the active ingredient in an amount of at least about 60% by weight of the composition. In some embodiments, the pharmaceutical composition comprises the active ingredient in an amount of at least about 70% by weight of the composition. In some embodiments, the pharmaceutical composition comprises the active ingredient in an amount of at least about 80% by weight of the composition. In some embodiments, the pharmaceutical composition comprises the active ingredient in an amount of at least about 90% by weight of the composition.

[0172] In some embodiments, the oral pharmaceutical composition comprising the active ingredient of the present invention is a unit dose composition.

[0173] In some embodiments, the active ingredient is a compound of formula (I).

[0174] In some embodiments, the active ingredient is selected from: (E)-N-(5-(3-(l-((5- cyclopropyl- 1 H-pyrazol-3-yl)amino)-3-methyl- 1 -oxobutan-2-yl)phenyl)pyri din-2 -yl)-4- morpholinobut-2-enamide; (E)-N-(5 -(3 -( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)- 1 - oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(pyrrolidin-l-yl)but-2 -enamide; and (E)-N-(5-(3-(l- ((5-cyclopropyl-lH-pyrazol-3-yl)amino)-l-oxopropan-2-yl)phen yl)pyridin-2-yl)-4- morpholinobut-2-enamide.

[0175] In some embodiments, the active ingredient is (E)-N-(5-(3-(l-((5-cyclopropyl-lH- pyrazol-3-yl)amino)-3-methyl-l-oxobutan-2-yl)phenyl)pyridin- 2-yl)-4-morpholinobut-2- enamide.

[0176] In some embodiments, the active ingredient is ( ₁ S)-(E)-N-(5-(3-(l-((5-cyclopropyl- lH-pyrazol-3-yl)amino)-3-methyl-l-oxobutan-2-yl)phenyl)pyrid in-2-yl)-4-morpholinobut-2- enamide.

[0177] In some embodiments, the active ingredient is (7?)-(E)-N-(5-(3-(l-((5-cyclopropyl- lH-pyrazol-3-yl)amino)-3-methyl-l-oxobutan-2-yl)phenyl)pyrid in-2-yl)-4-morpholinobut-2- enamide.

[0178] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0179] Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

[0180] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0181] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0182] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro- encapsulated form, if appropriate, with one or more of the above-described excipients.

[0183] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0184] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0185] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0186] Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0187] Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.

[0188] Alternatively, or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0189] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0190] Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0191] The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0192] Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0193] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0194] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005/0080056, 2005/0059744 and U.S. Pat. No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).

[0195] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[0196] Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0197] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0198] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0199] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0200] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[0201] For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, about 0.1 to about 99.5% (more preferably, about 0.5 to about 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0202] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow-release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0203] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0204] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0205] By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

[0206] In general, a suitable daily dose of a pharmaceutically active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0207] If desired, the effective daily dose of the pharmaceutically active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In some embodiments of the present invention, the pharmaceutically active compound may be administered two or three times daily. In preferred embodiments, the pharmaceutically active compound will be administered once daily.

[0208] The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.

[0209] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. [0210] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0211] The compounds of the present invention may be administered in combination with one or more other drugs (1) to complement and/or enhance therapeutic efficacy of the therapeutic drug effect of the compound of the present invention, (2) to modulate pharmacodynamics, improve absorption improvement, or reduce dosage reduction of the therapeutic compound of the present invention, and/or (3) to reduce or ameliorate the side effects of the therapeutic compound of the present invention. For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. In some embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds. The respective compounds may be administered by the same or different route and the same or different method.

[0212] A concomitant medicine comprising the compounds of the present invention and other drug may be administered as a combination preparation in which both components are contained in a single formulation or administered as separate formulations. The administration by separate formulations includes simultaneous administration and or administration of the formulations separated by some time intervals. In the case of the administration with some time intervals, the compound of the present invention can be administered first, followed by another drug or another drug can be administered first, followed by the compound of the present invention, so long as the two compounds are simultaneously active in the patient at least some of the time during the combination therapy. The administration method of the respective drugs may be administered by the same or different route and the same or different method. [0213] The dosage of the other drug can be properly selected, based on a dosage that has been clinically used, or may be a reduced dosage that is effective when administered in combination with a compound of the present invention. The compounding ratio of the compound of the present invention and the other drug can be properly selected according to age and weight of a subject to be administered, administration method, administration time, disorder to be treated, symptom and combination thereof. For example, the other drug may be used in an amount of about 0.01 to about 100 parts by mass, based on 1 part by mass of the compound of the present invention. The other drug may be a combination of two or more kind of arbitrary drugs in a proper proportion. The other drug that complements and/or enhances the therapeutic efficacy of the compound of the present invention includes not only those that have already been discovered, but those that will be discovered in future, based on the above mechanism.

[0214] In some embodiments, a compound of the invention may be administered with nonchemical methods of cancer treatment. In some embodiments, a compound of the invention may be administered with radiation therapy. In some embodiments, a compound of the invention may be administered with surgery, with thermoablation, with focused ultrasound therapy, with cryotherapy, or with any combination of these.

Methods of treatment

[0215] Disclosed herein are methods for treating cancer that comprise administering a disclosed compound with an oral SERD. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is metastatic breast cancer. In some embodiments, the cancer is ER -positive, HR -positive or HER2-negative, advanced or metastatic breast cancer. In some embodiments, the oral SERD is elacestrant, rintodestrant, giredestrant, amcenestrant, camizestrant, imlunestrant, or LSZ-102, or a pharmaceutically acceptable salt thereof. In some embodiments, the oral SERD is In some embodiments, the oral SERD is ZN-c5, D- 0502, or SHR9549, or a pharmaceutically acceptable salt thereof.

[0216] Tn some embodiments, the present invention provides methods for treating a breast cancer selected from the group consisting of hormone dependent breast cancer and hormone independent breast cancer. In some embodiments, the present invention provides methods wherein the breast cancer is metastatic. In some embodiments, the breast cancer is ER positive. In some embodiments, the breast cancer is HR positive. [0217] Head and neck cancer is a term used to define cancer that develops in the mouth, throat, larynx, nose, salivary glands, oral cancers or other areas of the head and neck. Most of these cancers are squamous cell carcinomas, or cancers that begin in the lining of the mouth, nose and throat. Tobacco use, heavy alcohol use, and infection with human papillomavirus (HPV) increase the risk of head and neck cancers. Eighty- five percent of head and neck cancers are linked to tobacco use, and 75 percent are associated with a combination of tobacco and alcohol use.

[0218] Most (about 90% to 95%) cancers of the stomach are adenocarcinomas. A stomach cancer or gastric cancer almost always is an adenocarcinoma. These cancers develop from the cells that form the innermost lining of the stomach (the mucosa).

[0219] Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Histologically, NSCLC is divided into adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma.

[0220] In some embodiments, the present invention provides methods for treating cancer selected from head and neck cancer, squamous cell carcinoma, stomach cancer, ovarian cancer, prostate cancer, soft-tissue sarcoma, adenocarcinoma, and lung cancer (e.g., non- small-cell lung cancer).

Solid Malignant Tumors

[0221] Sarcomas, carcinomas, melanomas, and glioblastomas are the main types of solid malignant tumors. Sarcomas are tumors in a blood vessel, bone, fat tissue, ligament, lymph vessel, muscle or tendon. Carcinomas are tumors that form in epithelial cells. Epithelial cells are found in the skin, glands and the linings of organs. Melanomas are tumors that develop in the pigment-containing cells known as melanocytes. Glioblastoma is an aggressive cancer that begins in the brain. They can either start from normal brain cells or develop from an existing low-grade astrocytoma. A solid tumor grows in an anatomical site outside the bloodstream (in contrast, for example, to cancers of hematopoietic origin such as leukemias) and requires the formation of small blood vessels and capillaries to supply nutrients, etc. to the growing tumor mass.

[0222] Non-limiting examples of solid malignant tumors include biliary cancer (e.g. , cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma, glioblastomas; medulloblastoma), cervical cancer (e.g., cervical adenocarcinoma), colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC)), kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN)), prostate cancer (e.g., prostate adenocarcinoma), skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma, melanoma, basal cell carcinoma (BCC)) and soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myosarcoma, osteosarcoma).

Additional Malignancies

[0223] In addition to the cancers discussed above, the disclosed methods are useful in the treatment of a wide variety of cancers.

[0224] In some embodiments, the cancer is Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, Anal Cancer, Appendix Cancer, Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain Tumor, Astrocytoma, Brain and Spinal Cord Tumor, Brain Stem Glioma, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Central Nervous System Embryonal Tumors, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous System Cancer, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Chronic Myeloproliferative Disorders, Colon Cancer, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma, Ductal Carcinoma In Situ (DCIS), Embryonal Tumors, Endometrial Cancer, Ependymoblastoma, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, fibrosarcoma, Fibrous Histiocytoma of Bone, Gallbladder Cancer, Gastric Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors (GIST), Germ Cell Tumor, Ovarian Germ Cell Tumor, Gestational Trophoblastic Tumor, Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular Cancer, Histiocytosis, Langerhans Cell Cancer, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors, Kaposi Sarcoma, Kidney Cancer, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, Lip and Oral Cavity Cancer, Liver Cancer, Lobular Carcinoma In Situ (LCIS), Lung Cancer, Lymphoma, AIDS-Related Lymphoma, Macroglobulinemia, Male Breast Cancer, Medulloblastoma, Medulloepithelioma, Melanoma, Merkel Cell Carcinoma, Malignant Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndrome, Myelodysplastic/Myeloproliferative Neoplasm, Chronic Myelogenous Leukemia (CML), Acute Myeloid Leukemia (AML), Myeloma, Multiple Myeloma, Chronic Myeloproliferative Disorder, Nasal Cavity Cancer, Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip Cancer, Oropharyngeal Cancer, Osteosarcoma, Ovarian Cancer, Pancreatic Cancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer, Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumors of Intermediate Differentiation, Pineoblastoma, Pituitary Tumor, Plasma Cell Neoplasm, Pleuropulmonary Blastoma, Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer, Renal Cell Cancer, Clear cell renal cell carcinoma, Renal Pelvis Cancer, Ureter Cancer, Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma, Sezary Syndrome, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, Squamous Cell Carcinoma of the Head and Neck (HNSCC), Stomach Cancer, Supratentorial Primitive Neuroectodermal Tumors, T-Cell Lymphoma, Testicular Cancer, Throat Cancer, Thymoma, Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Triple Negative Breast Cancer (TNBC), Gestational Trophoblastic Tumor, Unknown Primary, Unusual Cancer of Childhood, Urethral Cancer, Uterine Cancer, Uterine Sarcoma, Waldenstrom Macroglobulinemia, or Wilms Tumor. [0225] In some embodiments, the cancer is carcinomas of the breast, liver, lung, colon, kidney, bladder, small cell lung cancer, non-small cell lung cancer, head and neck, thyroid, esophagus, stomach, pancreas, ovary, gall bladder, cervix, prostate, skin, squamous cell carcinoma, hematopoietic tumors of lymphoid lineage, leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, B- cell lymphoma, T- cell lymphoma, hairy cell lymphoma, myeloma, mantle cell lymphoma, Burkett's lymphoma, hematopoietic tumors of myeloid lineage, acute and chronic myelogenous leukemias, myelodysplastic syndrome, promyelocytic leukemia, tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma, tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannomas, seminoma, melanoma, osteosarcoma, teratocarcinoma, keratoacanthoma, xeroderma pigmentosum, thyroid follicular cancer and Kaposi's sarcoma.

[0226] In further embodiments of the invention, the cancer is selected from bladder cancer, breast cancer, esophageal cancer, gastric cancer, head & neck cancer, Kaposi’s sarcoma, lung cancer (including non-small cell lung cancer and small cell lung cancer), melanoma, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, testicular germ cell cancer, thymoma and thymic carcinoma.

[0227] In some embodiments, administering an oral SERD in combination with a compound of formula (I) provides improved efficacy relative to separately administering the compound of formula (I) or the oral SERD.

[0228] In some embodiments, administering an oral SERD in combination with a compound of formula (1) provides a synergistic effect.

[0229] Disclosed herein are methods for treating breast cancer that comprise administering a compound of formula (I) with an oral SERD. Also disclosed herein are methods for treating metastatic breast cancer.

[0230] In some embodiments, administering the oral SERD in combination with a compound of formula (I) provides improved efficacy for treating breast cancer relative to separately administering the compound of formula (I), or the oral SERD. In some embodiments, administering the oral SERD in combination with a compound of formula (I) provides a synergistic effect in treating breast cancer. [0231] In some embodiments, the compound of formula (I) and the oral SERD are administered simultaneously or sequentially. In other embodiments, the oral SERD is administered within about 5 minutes to within about 168 hours prior to or after administration of the compound of formula (I).

[0232] Compounds suitable for the compositions and methods disclosed herein are disclosed in WO2016/193939 Al, published December 8, 2016, entitled “Substituted heterocyclyl derivatives as CDK inhibitors,” which is incorporated by reference in its entirety, and in particular for the compounds disclosed therein as CDK7 inhibitors.

EXAMPLES

Example 1: Synthesis of Compound-44A & 44B:

Step 1 : Synthesis of 2-(3-bromophenyl)-3-methylbutanoic acid

[0233] 2M LDA (698 mL, 1.38 mol) was added to a solution of 2-(3 -bromophenyl) acetic acid (reagent 1, 150 g, 0.69 mol) in THF (700 mL) at -78 °C over a period of 30 min. The reaction mass was stirred for 2 h at -78 °C followed by the dropwise addition of isopropyl bromide (255g, 2.07mol) over a period of 30 min at -78 °C. The reaction mass was stirred at room temperature overnight. The reaction mass was quenched with IN HC1 (pH 2) and the product was extracted with ethyl acetate (500mL x 3). The combined organic layer was washed with water followed by brine, dried and concentrated under reduced pressure to afford the title crude compound which was purified by silica column chromatography with 0- 10% ethyl acetate-hexane to afford the title compound 2 (150g, 83% yield). LCMS: m/z = 254.80 (M-2H)-.

Step 2: Synthesis of tert-butyl 3-(2-(3-bromophenyl)-3-methylbutanamido)-5- cyclopropyl-lH-pyrazole-l-carboxylate

[0234] 2-(3-Bromophenyl)-3-methylbutanoic acid (intermediate 2, 70 g, 0.0.27mol) was dissolved in dry DCM (500 mL) and oxalyl chloride (68 mL, 0.78mol) was added dropwise at 0 °C followed by addition of a catalytic amount of DMF (0.8mL) and reaction mass was maintained at the same temperature for 30 min. The reaction mass was allowed to reach room temperature and stirred for 4 h, solvent was removed via distillation, and excess oxalyl chloride was removed under vacuum. The residue was re-dissolved in DCM (250 mL) and added slowly to a cooled solution of tert-butyl 3-amino-5-cyclopropyl-lH-pyrazole-l- carboxylate (intermediate 3, 49g, 0.218mol) and TEA (55 mL, 0.546 mol) in THF (250 mL) at 0 °C for 30 min. The reaction mixture was stirred at room temperature for 12 h, then the reaction mass was concentrated under reduced pressure. The resulting residue was dissolved in DCM, and washed with a saturated NaHCCh solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude was purified by silica gel column chromatography with 15% ethyl acetate-hexane to afford the title compound 4 (90 g, 71%) LCMS: m/z = 363.80 (M-Boc+2).

Step 3: Synthesis of tert-butyl 5-cyclopropyl-3-(3-methyl-2-(3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)butanamido)-lH-pyrazole-l-carboxyla te

[0235] To a degassed solution of tert-butyl 3-(2-(3-bromophenyl)-3-methylbutanamido)-5- cyclopropyl-lH-pyrazole-1 -carboxylate (intermediate-4, 90 g, 0.193 mol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (62g, 0.25 Imol) in 1,4-dioxane (500 mL) was added potassium acetate (37.80 g, 0.386 mol). The reaction mass was allowed to stir for 10 min with degassing at RT, and PdC12(dppf) DCM complex (12.5 g, 0.015 mol) was added. The reaction mass was heated for 3-4 h at 100 °C. The reaction mixture was cooled to RT and filtered on celite bed, and the filtrate was concentrated to afford a dark brown liquid. The crude material was purified by silica column chromatography by eluting with 20 % ethyl acetate in hexane to afford the title compound 5 (90 g, 86%). LCMS: m/z = 410 (M-Boc+1) ⁺ .

Step 4: Synthesis of (E)-N-(5-(3-(l-((5-cyclopropyl-lH-pyrazol-3-yl)amino)-3-meth yl-l- oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide [0236] A degassed solution of tert-butyl 5-cyclopropyl-3-(3-methyl-2-(3-(4, 4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl)butanamido)- 1 H-pyrazole- 1 -carboxylate 5 (10 g, 0.019 mol) and (E)-N-(5-bromopyridin-2-yl)-4-morpholinobut-2-enamide 6 (7.7 g, 0.023 mol) in 1,4-dioxane (lOOmL) and water (40mL) was prepared, and CS2CO3 (14.5 g, 0.045 mol) was added. The reaction mass was allowed to stir for 10 min with degassing and Pd(PPh3)4 (1-1 g, 0.00095 mol) was added, followed by heating the reaction mass for 4 h at 100 °C in a sealed tube. The reaction mass was cooled and diluted with brine solution. The aqueous layer was separated and re-extracted with ethyl acetate. The combined organic layer was evaporated to dryness and the crude material was purified by silica column chromatography with 10%-l 5% methanol in DCM to afford the desired pure compound 44 (4.5g, 44%). LCMS: m/z = 529.15 (M+H)+; HPLC: 95.17%, rt: 6.34 min.

Step 5: Chiral Separation

[0237] Racemic (E)-N-(5 -(3 -( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)-3 -methyl- 1 - oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide was separated by chiral preparative HPLC (Method: Column: Chiral Pak IA (20mm x 250 mm, 5 micron), Elution: isocratic (50:50), A=ACN, B= MeOH, Flow: 20mL/min ) to afford the pure 44A, i.e., (S)- (E)-N-(5 -(3 -( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)-3 -methyl- 1 -oxobutan-2- yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide and 44B, i.e., (R)-(E)-N-(5-(3-(l-((5- cyclopropyl- 1 H-pyrazol-3-yl)amino)-3-methyl- 1 -oxobutan-2-yl)phenyl)pyridin-2-yl)-4- morpholinobut-2-enamide.

(5)-Isomer (Compound 44A):

[0238] ¹ I INMR (DMSO-d6, 400MHz): 5 12.02 (s, 1H), 10.78 (s, 1H), 10.44 (s, 1H), 8.61 (s, 1H), 8.28 (d, 1H), 8.07-8.05 (m, 1H), 7.68 (s, 1H), 7.57 (d, 1H), 7.41-7.37 (m, 2H), 6.81- 6.78 (m, 1H), 6.49 (d, 1H), 6.13 (s, 1H), 3.61-3.58 (m, 4H), 3.36-3.34 (m, 1H), 3.12 (d, 2H), 2.41-2.32 (m, 5H), 1.82-1.76 (m, 1H), 0.97 (d, 3H), 0.88-0.85 (m, 2H), 0.67 (d, 3H), 0.62- 0.59 (m, 2H); LCMS: m/z = 529.15 (M+H)+; HPLC: 96.72%, rt: 6.39 min; Chiral HPLC: 97.68%, rt: 14.47.

(R)-Isomer (Compound 44B):

[0239] 'HNMR (DMSO-d6, 400MHz): 5 12.02 (s, 1H), 10.78 (s, 1H), 10.44 (s, 1H), 8.61 (s, 1H), 8.28 (d, 1H), 8.07-8.04 (m, 1H), 7.68 (s, 1H), 7.57 (d, 1H), 7.41-7.37 (m, 2H), 6.81- 6.78 (m, 1H), 6.50 (d, 1H), 6.14 (s, 1H), 3.61-3.58 (m, 4H), 3.36-3.34 (m, 1H), 3.12 (d, 2H), 2.40-2.39 (m, 5H), 1.82-1.76 (m, 1H), 0.97 (d, 3H), 0.88-0.85 (m, 2H), 0.67 (d, 3H), 0.62- 0.60 (m, 2H); LCMS: m/z = 529.15 (M+H)+; HPLC: 96.24%, it: 6.39 min; Chiral HPLC: 97.92%, rt: 8.80.

Example 2: Combination Studies of Compound 44A (CPD-44A) and oral SERDs [0240] This example describes the evaluation of the effect of therapeutic test agents in human breast cancer cell lines (MCF7, T47D, and BT474) by Cell Titer Gio Cell Viability Analysis.

[0241] This ex- vivo cell killing assay was conducted in a 384-well plate format (60 wells for test agent, plus 3 wells for vehicle control, and 3 wells for positive control), employing a 4-day incubation, and measuring ICso values with respect to Cell Titer Gio viability endpoints. Test articles in powder form were formulated in 100% DMSO. The Cell Titer Gio assay (Promega Cat# G7571) was conducted according to manufacturer instructions.

[0242] Cell lines received test agents as outlined below. For every cell line being studied, single agents and combinations were prepared in 384-well plates in technical duplicates, along with in-plate positive control and negative control.

Study Design for MCE7

[0243] Each cell group was a 12x8 combination matrix with duplicates per dose-point.

Highest stock concentrations used for this study design were 60 mM for CPD-44A and 2 mM for Amcenestrant, Giredestrant, Camizestrant, and Elacestrant.

Study Design for T47D and BT474

[0244] Each cell group was a 12x8 combination matrix with duplicates per dose-point.

Highest stocks used for this study design were 60 mM for CPD-44A and 2mM for Amcenestrant, Giredestrant, Camizestrant, Elacestrant. [0245] Human cancer cells for every tumor type were seeded in 40 pL of appropriate media in a 384-well plate on Day 0. Therapeutic agents to be tested were added to wells on Day 1 according to the experimental design using a Tecan D300e digital dispenser. 10% DMSO was used as a positive control; media + vehicle (0.2%DMSO) was used as negative control. DMSO was adjusted in all wells corresponding to the highest vehicle control across plates and study designs. Plates were incubated at 37°C with 5% CO2. Media was not changed during the 4-day incubation period with test agents. The highest concentration of DMSO across all plates, cell lines and study designs was 0.2%. On day 5, cell viability was tested using the Cell Titer Gio assay.

[0246] Plates were removed from incubator and equilibrated to room temperature for up to 30 minutes. 20 pL of Cell Titer Gio reagent were added to wells and incubated at room temperature for 10 minutes to stabilize luminescent signal. Luminescence were recorded using a Tecan plate reader.

RESULTS

[0247] Figs. 1 -4 show the matrices for the assay results for the test agents at the tested concentrations in the MCF7 cell line. The assay results in Figs. 1-12 are reported as a viability ratio. Lower ratios indicate lower cell viability at the tested concentrations as compared to negative control.

[0248] Fig. 1 shows the matrix for CPD-44A + amcenestrant in the MCF7 cell line.

[0249] Fig. 2 shows the matrix for CPD-44A + giredestrant in the MCF7 cell line.

[0250] Fig. 3 shows the matrix for CPD-44A + camizestrant in the MCF7 cell line.

[0251] Fig. 4 shows the matrix for CPD-44A + elacestrant in the MCF7 cell line.

[0252] Figs. 5-8 show the matrices for the assay results for the test agents at the tested concentrations in the BT474 cell line.

[0253] Fig. 5 shows the matrix for CPD-44A + amcenestrant in the BT474 cell line.

[0254] Fig. 6 shows the matrix for CPD-44A + giredestrant in the BT474 cell line.

[0255] Fig. 7 shows the matrix for CPD-44A + camizestrant in the BT474 cell line.

[0256] Fig. 8 shows the matrix for CPD-44A + elacestrant in the BT474 cell line. [0257] Figs. 9-12 show the matrices for the assay results for the test agents at the tested concentrations in the T47D cell line.

[0258] Fig. 9 shows the matrix for CPD-44A + amcenestrant in the T47D cell line.

[0259] Fig. 10 shows the matrix for CPD-44A + giredestrant in the T47D cell line.

[0260] Fig. 11 shows the matrix for CPD-44A + camizestrant in the T47D cell line.

[0261] Fig. 12 shows the matrix for CPD-44A + elacestrant in the T47D cell line.

[0262] Synergy scores for different dose combinations of CPD-44A with either amcenestrant, giredestrant, camizestrant, and elacestrant were calculated by the Loewe method using the Synergy Findcr+ web-based FAIR tool (sec, Zheng, ct al. Genomics, Proteomics & Bioinformatics 2022, 20, 587-596; Loewe. Ergebnisse der Physiologie 1928, 27, 47-187.) See, Figures 13-16. Unexpectedly low synergy scores were obtained for higher concentrations of the tested SERDs, indicating that it may be necessary to limit the amount of SERD compound administered to a particular subject in order to elicit a maximum therapeutic effect for the combination of SERD and CDK7 inhibitor.

[0263] Mouse Xenograft Model. Female, 7-8 week-old, NOD/SCID mice were purchased from GemPharmatech Co., and acclimated in the laboratory 1 week before experimentation. The animals were housed in microisolator cages, five per cage, in a 12-h light/dark cycle. The animals received filtered sterilized water and sterile rodent food ad libitum. The animals were observed daily, and clinical signs were noted. Each mouse was inoculated orthotopically at the right mammary fat pad region with MCF7 tumor cells (2 x 10 ⁷ ) in 0.2 ml of PBS mixed with Matrigel (1:1) for tumor development. To support the growth of the estrogen-dependent MCF-7 tumor, a 0.36-mg 17P-estradiol 60-day release pellet (Innovative Research of America, Sarasota, FL) was implanted s.c. on the flank on the same side as the tumor implant one day prior to tumor implantation. The randomization started when the mean tumor size reached approximately 162 mm ³ . All animals were randomly allocated to 9 study groups, 10 mice in each group. Randomization was performed based on “Matched distribution” method (StudyDirector™ software, version 3.1.399.19).

[0264] Animals were treated with CPD-44A orally once daily for a total of 28 days. CPD- 44A is formulated in 0.5% Tween 80 + 0.5% methyl cellulose. Fulvestrant injection solution, purchased from AstraZeneca, was administered s.c. once weekly for the duration of study. Elacestrant, purchased from MedChemExpress, was formulated in 5% DMSO/40%PEG400/5% Tween/50% saline, and administered orally once daily for the duration of study. Compounds were administered by exact body weight, with the administered volume being 1 Opl/ g body weight.

[0265] Tumors were measured and the animals weighed twice weekly. Tumor volume was determined by caliper measurements (mm) and using the formula for an ellipsoid sphere: L x W ² /2 mm3 . As shown in Figure 17, the combination of CPD-44A and elacestrant was found to be more effective in reducing tumor growth than either agent alone.

EXEMPLARY EMBODIMENTS

[0266] Exemplary embodiments according to the present disclosure include, but are not limited to, those recited in the appended claims and the following embodiments.

1. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I): or a pharmaceutically acceptable salt or a stereoisomer thereof, in combination with a therapeutically effective amount of an oral selective estrogen receptor degrader (SERD); wherein, ring A is cycloalkyl, aryl, heteroaryl or heterocyclyl; ring B is aryl, cycloalkyl, heteroaryl, heterocyclyl or absent;

Ri is hydrogen or alkyl;

R2 is hydrogen, alkyl or cycloalkyl;

R3 is hydrogen, alkyl or heteroaryl; alternatively, R2 together with Ri or R3 along with the ring atoms to which they are attached forms a 5- to 7-membered ring;

R4 at each occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro, cyano or haloalkyl;

R ₅ is:

R ₅ ' is hydrogen, halo, alkyl, alkoxy, alkoxyalkyl or -(CH2)i-3-NR _a Rb,

R5" is H or alkyl, and

Ra and Rb are each independently hydrogen, alkyl, alkoxy or alkoxyalkyl, or alternatively, Ra and Rb together with the nitrogen atom to which they are attached form an optionally substituted ring containing 0-2 additional heteroatoms independently selected from N, O or S, wherein the optional substituent is independently one or more halo, alkyl, acyl, hydroxy, cyano, cyanoalkyl, haloalkyl, alkoxy, alkoxyalkyl, -COOH or -COO-alkyl;

Re at each occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro, cyano or haloalkyl;

Li is *-CRcRd-C(O)-, *-NReC(O)- or absent, wherein * is the point of attachment with ring A;

Rc and Rd independently are hydrogen, alkyl or haloalkyl, or alternatively, Rc and Ra together with the carbon to which they are attached form a cycloalkyl ring;

Re is hydrogen or alkyl;

L2 is -C(O)NH- -C(O)O- or absent; m is 0, 1 or 2; p is 0 or 1; and q is 0 to 3.

2. The method of embodiment 1 , wherein the compound is represented by formula (IA): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein: R4 at each occurrence is halo, alkyl, hydroxy or alkoxy; and

R ₅ is: wherein R _a and Rb are each independently hydrogen or alkyl, or alternatively,

R _a and Rb together with the nitrogen atom to which they are attached form the optionally substituted ring, wherein the optional substituent is independently one or more halo, alkyl, hydroxy, haloalkyl or alkoxy.

3. The method of embodiment 1, wherein the compound is represented by formula (IB): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

4. The method of embodiment 1 , wherein the compound is represented by formula (IC): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

5. The method of embodiment 1, wherein the compound is represented by formula (ID): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

6. The method of embodiment 1 , wherein the compound is represented by formula (IE): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein Li is *-CRcRd-C(O)- or *-NReC(O)-; and wherein * is the point of attachment with phenyl ring.

7. The method of embodiment 1, wherein the compound is represented by formula (IF): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein Li is *-CRcRd-C(O)- or *-NReC(O)-; and wherein * is the point of attachment with phenyl ring. 8. The method of embodiment 1, wherein the compound is represented by formula (IG): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

9. The method of any one of embodiments 1 , 2, 4, and 8 wherein ring A is aryl or heteroaryl.

10. The method of any one of embodiments 1, 2, 4, 8, and 9 wherein ring A is aryl.

11. The method of any one of embodiments 1-5, 9, and 10, wherein ring B is cycloalkyl, aryl, heterocycloalkyl or heteroaryl, each of which is monocyclic or bicyclic.

12. The method of any of the embodiments 1-5 and 8-11, wherein R2 is cycloalkyl.

13. The method of any one of embodiments 1 -12, wherein R5 is

14. The method of any one of embodiments 1-13, wherein R5' is -(CH2)I-

3-NRaRh.

15. The method of embodiment 13 or embodiment 14, wherein Ra and Rb together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring having 0-2 additional heteroatoms selected from O, S or N.

16. The method of any one of embodiments 1-15, wherein Li is *-CRcRd- C(O)-; wherein * is the point of attachment with ring A.

17. The method of any one of embodiments 1-3 and 9-16, wherein L2 is absent. 18. The method of embodiment 1, wherein the compound of formula (I) is selected from: or a pharmaceutically acceptable salt or a stereoisomer thereof.

19. The method of embodiment 1, wherein the compound of formula (I) is selected from:

(E)-N-(5 -(3-( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)- 1 -oxopropan-2- yl)phenyl)pyridin-2-yl)-4-((S)-3 -fluoropyrrolidin- 1 -yl)but-2-enamide;

N-(5-(3-(l-((5-cyclopropyl-lH-pyrazol-3-yl)amino)-l-oxopr opan-2- yl)phenyl)pyridin-2-yl)acrylamide;

(E)-N-(5 -(3-( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)-3-methyl- 1 -oxobutan- 2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide; (E)-N-(5 -(3-( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)- 1 -oxopropan-2- yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide;

(E)-N-(5 -(3-( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)- 1 -oxopropan-2- yl)phcnyl)pyridin-2-yl)-4-(pyrrolidin- 1 -yl)but-2-cnamidc;

(E)-N-(5 -(3-( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)-3-methyl- 1 -oxobutan- 2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide;

(E)-N-(5 -(3-( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)- 1 -oxopropan-2- yl)phenyl)pyridin-2-yl)-4-(piperidin- 1 -yl)but-2-enamide; (E)-N-(3'-(l-((5-cyclopropyl-lH-pyrazol-3-yl)amino)-3-methyl -l-oxobutan-2- yl)-3-fluoro-[l,r-biplieiiyl]-4-yl)-4-(diniethylamino)but-2- enamide; and

(E)-N-(5 -(3-( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)- 1 -oxopropan-2- yl)phenyl)pyridin-2-yl)-4-(3 -fluoropiperidin- 1 -yl)but-2-enamide.

20. The method of embodiment 1, wherein the compound of formula (I) is selected from:

(E)-N-(5 -(3-( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)-3-methyl- 1 -oxobutan- 2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide;

(E)-N-(5 -(3-( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)- 1 -oxopropan-2- yl)phenyl)pyridin-2-yl)-4-(pyrrolidin- 1 -yl)but-2-enamide; and

(E)-N -(5 -(3-( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)- 1 -oxopropan-2- yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide.

21. The method of embodiment 1, wherein the compound of formula (I) is (E)-N-(5 -(3 -( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)-3 -methyl- 1 -oxobutan-2- yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide.

22. The method of embodiment 1, wherein the compound of formula (I) is ( ₁ S)-(E)-N-(5-(3-(l-((5-cyclopropyl-lH-pyrazol-3-yl)amin o)-3-methyl-l-oxobutan-2- yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide.

23. The method of embodiment 1, wherein the compound of formula (I) is (R)-(E)-N-(5-(3-(l-((5-cyclopropyl-lH-pyrazol-3-yl)amino)-3- methyl-l-oxobutan-2- yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide.

24. The method of any one of embodiments 1-23, wherein administering an oral SERD in combination with a compound of formula (I) provides improved efficacy relative to separately administering the compound of formula (I) or the oral SERD.

25. The method of any one of embodiments 1 -24, wherein administering the oral SERD in combination with a compound of formula (I) provides a synergistic effect.

26. The method of any one of embodiments 1-25, wherein the compound of formula (I) and the oral SERD are administered simultaneously or sequentially. 27. The method of any one of embodiments 1-26, wherein the cancer is breast cancer, prostate cancer, head and neck cancer, squamous cell carcinoma, stomach cancer, ovarian cancer, soft-tissue sarcoma, adenocarcinoma, or lung cancer.

28. The method of any one of embodiments 1-27, wherein the oral SERD is elacestrant, rintodestrant, giredestrant, amcenestrant, camizestrant, imlunestrant, or LSZ- 102, or a pharmaceutically acceptable salt thereof.

29. The method of embodiment 28, wherein the oral SERD is elacestrant or a pharmaceutically acceptable salt thereof.

30. The method of embodiment 28, wherein the oral SERD is rintodestrant or a pharmaceutically acceptable salt thereof.

31. The method of embodiment 28, wherein the oral SERD is giredestrant or a pharmaceutically acceptable salt thereof.

32. The method of embodiment 28, wherein the oral SERD is amcenestrant or a pharmaceutically acceptable salt thereof.

33. The method of embodiment 28, wherein the oral SERD is camizestrant or a pharmaceutically acceptable salt thereof.

34. The method of embodiment 28, wherein the oral SERD is imlunestrant or a pharmaceutically acceptable salt thereof.

35. The method of embodiment 28, wherein the oral SERD is LSZ-102 or a pharmaceutically acceptable salt thereof.

36. The method of any one of embodiments 1-35, wherein the cancer is breast cancer.

37. The method of embodiment 36, wherein the breast cancer is metastatic breast cancer.

38. The method of embodiment 36, wherein the breast cancer is ERpositive, HR-positive or HER2 -negative, advanced or metastatic breast cancer. 39. The method of embodiment 38, wherein the breast cancer is ERpositive breast cancer.

40. The method of embodiment 38, wherein the breast cancer is HRpositive breast cancer.

41. The method of any one of embodiments 1-35, wherein the cancer is prostate cancer.

42. The method of any one of embodiments 1-35, wherein the cancer is ovarian cancer.

43. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of (5)-(E)-N-(5-(3-(l-((5-cyclopropyl-lH- pyrazol-3-yl)amino)-3-methyl-l-oxobutan-2-yl)phenyl)pyridin- 2-yl)-4-morpholinobut-2- enamide or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of an oral SERD.

44. The method of embodiment 43, wherein the oral SERD is elacestrant, rintodestrant, giredestrant, amcenestrant, camizestrant, imlunestrant, or LSZ-102, or a pharmaceutically acceptable salt thereof.

45. The method of embodiment 43 or 44, wherein the cancer is breast cancer, prostate cancer, head and neck cancer, squamous cell carcinoma, stomach cancer, ovarian cancer, soft-tissue sarcoma, adenocarcinoma, or lung cancer.

46. The method of embodiment 45, wherein the cancer is breast cancer.

47. The method of any one of embodiments 1-47, wherein the compound of formula (I) and the oral SERD are each administered orally.

48. The method of embodiment 47, wherein the compound of formula (I) and the oral SERD are administered in a single composition.

49. The method of embodiment 47, wherein the compound of formula (I) and the oral SERD are administered in separate compositions. 50. The method of any one of embodiments 1-49, wherein the compound of formula (I) is (5)-(E)-N-(5-(3-(l-((5-cyclopropyl-lH-pyrazol-3-yl)amino)-3- methyl-l- oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide fumarate.

51. The method of embodiment 50, wherein the (S)-(E)-N-(5-(3-(l-((5- cyclopropyl- 1 H-pyrazol-3-yl)amino)-3-methyl- 1 -oxobutan-2-yl)phenyl)pyri din-2 -yl)-4- morpholinobut-2-enamide fumarate is crystalline Form 1.

52. The method of any one of embodiments 1-51, wherein the oral SERD is elacestrant.

53. The method of embodiment 52, wherein the elacestrant is administered at a total daily dose of from about 25 to about 250 mg.

54. The method of any one of embodiments 1-51, wherein the oral SERD is giredestrant.

55. The method of embodiment 54, wherein the giredestrant is administered at a total daily dose of from about 1 mg to about 25 mg.

56. The method of any one of embodiments 1-51, wherein the oral SERD is amcenestrant.

57. The method of embodiment 56, wherein the amcenestrant is administered at a total daily dose of from about 10 mg to about 200 mg.

58. The method of any one of embodiments 1-51, wherein the oral SERD is camizestrant.

59. The method of embodiment 58, wherein the camizestrant is administered at a total daily dose of from about 2 mg to about 50 mg.

Other Embodiments

[0267] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the invention. It will be obvious to one of skill in the art that changes and modifications can be practiced within the scope of the appended claims.

Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.