Arylaniline and heteroarylaniline compounds for treatment of skin cancer

Abstract

The present invention provides compounds and pharmaceutical compositions thereof for use in the treatment of skin cancer in a subject in need thereof, where the compounds are any one of formulae (I), (II), (III), (IV) and (V): wherein X1, X2, X3, R1, R2, R2a, R13, R13a, R23, R23a, R23b, R33, R33a, R33b, R43, R43a, R51, R53, R53a, R53b, the bond "a", and the subscript n are as described herein. # imgabs0 #

Description

[0001] This application is a divisional application of the invention patent application with application date of November 20, 2019, application number 201980089588.3, ​​and invention name “Aromatic aniline and heteroaryl aniline compounds for treating skin cancer”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 62 / 769,879, filed on November 20, 2018, the contents of which are incorporated herein by reference. Background of the Invention

[0005] Squamous cell skin cancer (cSCC), also known as cutaneous squamous cell carcinoma (cSCC), is one of the major skin cancers, alongside basal cell carcinoma and melanoma. Sun exposure and immunosuppression are risk factors for cutaneous SCC, with chronic sun exposure being the strongest environmental risk factor.

[0006] The vast majority of SCCs occur on the skin and, like all skin cancers, develop as a result of UV exposure. SCCs typically develop on areas of the body frequently exposed to the sun: the face, ears, neck, hands, or arms. Approximately 12% of men and 7% of women in the United States develop cSCC at some point. While the prognosis is generally good, if distant spread occurs, the five-year survival rate is approximately 34%. SCCs represent approximately 20% of non-melanoma skin cancers, but due to their more visible nature and rapid growth, they account for 90% of all initial head and neck cancers.

[0007] Unfortunately, immunosuppression in solid organ transplant recipients (SOTRs) carries several risks. These risks include an increased prevalence of non-melanoma skin cancer, a leading cause of morbidity after organ transplantation. Among all skin malignancies, cSCC is the predominant type, with a 65- to 250-fold increase in incidence in SOTRs compared to the general population. Among Caucasian SOTRs, cSCCs account for approximately 70% of skin cancers. As of 2017, an estimated 355,000 solid organ transplant recipients lived in the United States. The 3- to 8% mortality rate mentioned above means that within this group, 10,650 to 28,400 patients will die from cSCC.

[0008] Most squamous cell carcinomas are surgically removed. Dermatologists perform routine screening of SOTRs to monitor for the appearance of new actinic keratoses (AKs) and SCCs, which are removed surgically. Screening is primarily based on clinical examination, followed by histological evaluation of suspicious lesions with biopsy, followed by surgical removal with curettage and electrodesiccation, cryosurgery, simple excision, laser, and Mohs surgery. Because skin cancer is the most common form of cancer in transplant patients, cSCCs in transplant patients are much more aggressive and lethal. Even after surgical resection, they have a tendency to recur locally, which means that patients will tend to undergo multiple and repeated surgeries to remove the cSCC.

[0009] When aggressive or highly aggressive cSCC occurs in the head and neck, surgical treatment can have profound functional, cosmetic, and psychosocial consequences, sometimes resulting in the loss of an eye, ear, or nose. This may necessitate major reconstruction and diminish quality of life. Furthermore, quality of life is significantly impacted in patients with advanced cancer, and the costs associated with treatment of advanced cancer are substantial. For patients whose cancer has not progressed to advanced stages, scarring, disfigurement, and the inability to prevent the formation of new cSCCs from repeated surgeries also significantly impact quality of life.

[0010] Photodynamic therapy is an FDA-approved treatment for actinic keratosis (AK) and is also used to treat cSCC. One study demonstrated a complete response rate of 71.4% at a 3-month assessment and 64% at 3-year follow-up for cSCC (n = 30). Advantages include its safe repeatability, the minor side effect of photosensitivity itself, which does not preclude further radiation or surgery, and minimal scarring. Major disadvantages are photosensitivity (up to 6 weeks), pain, lower long-term cure rates than excision, and cost. Topical medications such as imiquimod, 5-fluorouracil, and ingenol mebutate are available for the treatment of AKs, but none are specifically approved for use in immunosuppressed patients. Up to 100% and 97% of patients treated with imiquimod and 5-fluorouracil, respectively, experience at least one adverse event ranging from mild to severe; erythema, pruritus, and pain are common.

[0011] The current standard of care for cSCC includes surgical intervention, including Mohs surgery. Other surgical treatment options exist, such as electrosurgery and cryosurgery, but there is a need for treatment options that minimize scarring. Photodynamic therapy is not FDA-approved for cSCC. These approaches are problematic in the setting of recurrent cSCC, where scarring and disfigurement may become a greater concern.

[0012] The only FDA-approved drug for advanced cSCC is cemiplimab, an anti-PD-1 antibody (Migden, Michael R., New England Journal of Medicine, vol. 379, no. 4, 2018, pp. 341–351). This drug is part of a class of systemic immunotherapies, some of which have been approved for visceral or mucosal SCC. These drugs are not only not suitable for chemoprevention but are also unsuitable for SOTRs due to the role of PD-1 in mediating tolerance and the increased risk of graft rejection.

[0013] The use of retinoids such as acitretin for chemoprevention of cSCC is controversial but potentially promising, but can cause significant side effects, including mucocutaneous dryness, alopecia, musculoskeletal pain, and elevated triglyceride and cholesterol levels, which limit their systemic application.

[0014] Advanced SCC lacks effective chemotherapy or targeted therapies, and there is currently no standard targeted treatment for cSCC. Cutaneous squamous cell carcinoma (CSCC) is the most prone and clinically well-characterized of all human cancers, with a typical progression sequence from a distinct premalignant lesion, actinic keratosis (AK), to squamous cell carcinoma in situ, and finally to invasive carcinoma. Therefore, it is an ideal model for establishing a molecularly targeted cancer chemoprevention paradigm for SCC, potentially addressing a significant unmet medical need for targeted therapies.

[0015] Oral trametinib (2 mg / kg / day) and cobimetinib (10 mg / kg / day) have been shown to effectively reduce skin tumors in a hairless mouse model of UV-driven cSCC using chronic, low-dose, solar-mimicking ultraviolet light. However, oral MEK inhibitors have significant side effects, including decreased left ventricular ejection fraction, pneumonia, renal failure, diarrhea, and rash. See Adelmann, CH et al., Journal of Investigative Dermatology, vol. 136, no. 9, 2016, pp. 1920-1924.

[0016] Finally, the number of SOTRs continues to grow at a rate of 3.6% per year, and as surgical success rates improve, surgeons continue to transplant younger and younger patients. The growing population and prolonged duration of immunosuppressive therapy in this challenging population will continue to increase the incidence of cSCC. Given the significant burden on patients, the high cost of care for advanced cases, and the growing high-risk population, there is a clear need for effective chemopreventive agents to treat cSCC while minimizing the systemic side effects seen with oral MEK inhibitors. Summary of the Invention

[0017] In one aspect, the present invention provides a method for treating or preventing skin cancer. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of Formula (I), (II), (III), (IV) and (V)

[0018]

[0019] or its N-oxide, stereoisomer, mixture of stereoisomers and / or pharmaceutically acceptable salt,

[0020] in:

[0021] X 1 -CR 13b or N; X 2 is a C1-C6 alkyl group; X 3 is S or O;

[0022] Subscript n is an integer from 0 to 2;

[0023] Bond "a" is a single bond or a double bond;

[0024] R 1 For-OR 4 、-NR 5 R 5a 、-N(OR 5b )R 5a or unsubstituted or replaced by one or two R 6 substituted N-linked heterocycloalkyl;

[0025] R 2 is halogen, C1-C6 alkyl, -S-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0026] R 2a is halogen or C1-C6 alkyl;

[0027] R 4 、R 5 and R 5b Each is independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl or R 7 -C(O)-C1-C6 alkyl, wherein each C3-C8 cycloalkyl and heterocycloalkyl group is unsubstituted or substituted with 1-6 R 6replace;

[0028] R 5a is hydrogen or C 1-6 alkyl;

[0029] Each R 6 are independently halogen, hydroxy, oxo, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6-hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl or di-(C1-C6 alkyl)amino-C1-C6 alkyl;

[0030] R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino;

[0031] R 13 、R 13a and R 13b are each independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0032] R 23 、R 23a and R 23b Each is independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C3-C8 cycloalkoxy;

[0033] R 33 、R 33a and R 33b Each is independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C3-C8 cycloalkoxy;

[0034] R 43 Cyano, -C(O)NR 48 R 48a or -C(O)R 46 ;

[0035] R 43a is hydrogen, halogen, C1-C6 alkyl; or

[0036] R 43 and R 43a Together they form -CH2CH2C(O)- or -CH2CH2CH2C(O)-, each of which is unsubstituted or substituted by one or two R 49 replaced;

[0037] R46 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or heterocycloalkyl;

[0038] R 48 and R 48a are each independently hydrogen or C1-C6 alkyl; and

[0039] Each R 49 are independently C1-C6 alkyl, C3-C8 cycloalkyl or C3-C8 cycloalkyl-C1-C6 alkyl;

[0040] R 51 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, R 7 -C(O)-C1-C6 alkyl or -OR 54 , wherein each C3-C8 cycloalkyl and heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 replaced;

[0041] Each R 53 are independently halogen or C1-C6 alkyl;

[0042] R 53a and R 53b are each independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; and

[0043] R 54 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl or R 7 -C(O)-C1-C6 alkyl, wherein each C3-C8 cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 R 6 replaced. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1-4Shown are photographs of mice at baseline, start of treatment, and end of treatment using the protocol described in Example 1 using topical gel formulations containing Compound 2.003 (0.5%, 0.15%, and 0.01% by weight of the formulation, respectively) compared to a topical formulation of vehicle alone.

[0046] Figure 5 Shown are the number of new tumors per mouse from the start to the end of treatment using the protocol described in Example 1 using topical gel formulations containing Compound 2.003 at 0.5%, 0.15% and 0.01% by weight of the formulation, respectively, compared to a topical formulation of vehicle alone.

[0047] Figure 6 Shown are the tumor volumes per mouse at the start and end of treatment using the protocol described in Example 1 using topical gel formulations containing Compound 2.003 (0.5%, 0.15% and 0.01% by weight of the formulation) compared to a topical formulation of vehicle alone.

[0048] Figure 7 and 8 Synthetic Schemes I-1 and I-2 for preparing compounds of formula (Ia) are shown, respectively.

[0049] Figure 9 Synthetic Scheme 1-3 for preparing compounds of formula (Ib) is shown.

[0050] Figure 10-14 Synthesis schemes II-1 to II-5 for preparing the compound of formula (II) are shown respectively.

[0051] Figure 15-16 Synthetic schemes III-1 and III-2 for preparing compounds of formula (IIIa) are shown, respectively.

[0052] Figure 17 Synthetic Scheme IV-1 for preparing compounds of any one of Formulas (IVa), (IVb) and (IVc) is shown.

[0053] Figure 18 Synthetic Scheme IV-2 for preparing compounds of any one of Formulas (IVd-1), (IVd-2), (IVe-1), and (IVe-2) is shown.

[0054] Figure 19 Synthetic Scheme IV-3 for preparing compounds of formula (IVa) is shown.

[0055] Figure 20-21 Synthetic Schemes V-1 and V-2 are shown, respectively, for preparing compounds of formula (Va).

[0056] Figure 22 Synthetic Scheme V-3 for preparing compounds of formula (Vb) is shown. DETAILED DESCRIPTION

[0057] I.General

[0058] Provided herein are methods of using compounds and pharmaceutical compositions containing the compounds to treat skin cancer, particularly cutaneous squamous cell carcinoma (cSCC).

[0059] II. Definitions

[0060] Abbreviations used herein have their conventional meanings in the fields of chemistry and biology.

[0061] Where substituents are designated by their conventional chemical formula (written left to right), they equally include substituents resulting from the structure written right to left, for example, -CH2O- is intended to include -OCH2-.

[0062] "Alkyl" refers to a saturated, aliphatic group having a specified number of carbon atoms (i.e., C1-C6 represents 1 to 6 carbon atoms), which may be straight or branched. Alkyl groups may include any number of carbon atoms, such as C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, C1-C7, C1-C8, C1-C9, C1-C 10 , C2-C3, C2-C4, C2-C5, C2-C6, C3-C4, C3-C5, C3-C6, C4-C5, C4-C6 and C5-C6. For example, C1-C6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl may also refer to an alkyl group having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc.

[0063] "Alkylene" refers to a straight or branched chain saturated aliphatic group having a specified number of carbons (i.e., C1-C6 means 1 to 6 carbons) that links at least two other groups, i.e., divalent hydrocarbon groups. The two moieties linked to the alkylene group can be linked to the same atom or different atoms of the alkylene group. For example, a straight chain alkylene group can be a divalent group -(CH2) n- , wherein n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene.

[0064] "Alkenyl" refers to a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one double bond and having the specified number of carbon atoms (i.e., C2-C6 represents 2 to 6 carbon atoms). Alkenyl groups can include any number of carbon atoms, such as C2, C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C 10 , C3, C3-C4, C3-C5, C3-C6, C4, C4-C5, C4-C5, C5, C5-C6 and C6. The alkenyl group can have any suitable number of double bonds, including but not limited to 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include but are not limited to: vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl.

[0065] "Alkynyl" refers to a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one triple bond and having the specified number of carbon atoms (i.e., C2-C6 represents 2 to 6 carbon atoms). Alkynyl groups can include any number of carbon atoms, such as C2, C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C 10 , C3, C3-C4, C3-C5, C3-C6, C4, C4-C5, C4-C6, C5, C5-C6, and C6. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentenyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl.

[0066] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic, or bridged polycyclic ring assembly containing 3-12 ring atoms or the specified number of atoms. Cycloalkyl may include any number of carbon atoms, such as C3-C6, C4-C6, C5-C6, C3-C8, C4-C8, C5-C8, C6-C8, C3-C9, C3-C 10 、C3-C 11 and C3-C 12. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2] bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups may also be partially unsaturated, having one or more double or triple bonds in the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl (1,3- and 1,4-isomers), cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. When the cycloalkyl group is a saturated monocyclic C3-C8 cycloalkyl group, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0067] "Cycloalkylalkyl" refers to a group having an alkyl moiety and a cycloalkyl moiety, wherein the alkyl moiety connects the cycloalkyl moiety to the point of attachment. The alkyl moiety is as defined above, except that the alkyl moiety is at least divalent (alkylene) to connect to the cycloalkyl moiety and to the point of attachment. The alkyl moiety may include any number of carbons, such as C1-C6, C1-C2, C1-C3, C1-C4, C1-C5, C2-C3, C2-C4, C2-C5, C2-C6, C3-C4, C3-C5, C3-C6, C4-C5, C4-C6, and C5-C6. The cycloalkyl moiety is as defined above. Exemplary cycloalkyl-alkyls include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0068] "Alkoxy" refers to an alkyl group with an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. The alkoxy group can have any suitable number of carbon atoms, for example, C1-C6. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0069] "Hydroxyalkyl" refers to an alkyl group as described above in which at least one hydrogen atom is replaced by a hydroxy group. As for the alkyl group, the hydroxyalkyl group can have any suitable number of carbon atoms, for example, C1-C6. Exemplary hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (wherein the hydroxy group is at the 1- or 2-position), hydroxypropyl (wherein the hydroxy group is at the 1-, 2-, or 3-position), hydroxybutyl (wherein the hydroxy group is at the 1-, 2-, 3-, or 4-position), hydroxypentyl (wherein the hydroxy group is at the 1-, 2-, 3-, 4-, or 5-position), hydroxyhexyl (wherein the hydroxy group is at the 1-, 2-, 3-, 4-, 5-, or 6-position), 1,2-dihydroxyethyl, and the like.

[0070] "Alkoxyalkyl" refers to a group having an alkyl moiety and an alkoxy moiety, wherein the alkyl moiety connects the alkoxy moiety to the point of attachment. The alkyl moiety is as defined above, except that the alkyl moiety is at least divalent (alkylene) to connect to the alkoxy moiety and to the point of attachment. The alkyl component can include any number of carbons, such as C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, C2-C3, C2-C4, C2-C5, C2-C6, C3-C4, C3-C5, C3-C6, C4-C5, C4-C6, and C5-C6. The alkoxy moiety is as defined above. Examples of alkoxy-alkyl groups include, but are not limited to, 2-ethoxy-ethyl and methoxymethyl.

[0071] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0072] "Haloalkyl" refers to an alkyl group as defined above in which some or all of the hydrogen atoms are replaced by halogen atoms. As with alkyl groups, haloalkyl groups can have any suitable number of carbon atoms, such as C1-C6. For example, haloalkyl groups include trifluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, and the like. In some cases, the term "perfluoro" may be used to define a compound or group in which all hydrogen atoms are replaced by fluorine atoms. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0073] As used herein, "amino" refers to -NH2 unless otherwise indicated.

[0074] Unless otherwise indicated, as used herein, "alkylamino" refers to an -NHR group, wherein R is an alkyl group as defined herein, or an N-oxide derivative thereof. In some embodiments, the alkylamino group is a C1-C6-alkyl-amino group. In some embodiments, the C1-C6-alkyl-amino group is a methylamino group, an ethylamino group, an n- or i-propylamino group, an n- or i- or t-butylamino group, or a methylamino-N-oxide group, and the like.

[0075] Unless otherwise indicated, as used herein, "dialkylamino" refers to an NR'R group, wherein R and R' are alkyl as defined herein, or an N-oxide derivative thereof. In some embodiments, the dialkylamino group is a di-C1-C6 alkyl-amino group. In some embodiments, the di-C1-C6 alkyl-amino group is a dimethylamino group, a methylethylamino group, a diethylamino group, or a dimethylamino-N-oxide group, and the like.

[0076] Unless otherwise indicated, as used herein, "aminoalkyl" refers to an alkyl group substituted with one or two NH2. In some embodiments, the aminoalkyl group is amino-C1-C6-alkyl. In some embodiments, the aminoalkyl group is amino-C1-C6 alkyl.

[0077] Unless otherwise indicated, as used herein, "alkylaminoalkyl" refers to an alkyl group substituted with one or two -NH(alkyl) groups. In some embodiments, the alkylaminoalkyl group is C1-C6-alkyl-amino-C1-C6-alkyl.

[0078] Unless otherwise indicated, as used herein, "dialkylaminoalkyl" refers to an alkyl group substituted with one or two -N(alkyl)2 groups. In some embodiments, the dialkylaminoalkyl group is di-C1-C6alkyl-amino-C1-C6alkyl.

[0079] As used herein, unless otherwise indicated, "hydroxyamino" refers to -NHOH.

[0080] Unless otherwise indicated, as used herein, "N-alkylhydroxyamino" refers to a group in which the hydrogen of -NHOH is replaced by an alkyl group as defined herein. In some embodiments, the N-alkylhydroxyamino group is an N-C1-C6 alkyl-hydroxyamino group. In some embodiments, the N-C1-C6 alkyl-hydroxyamino group is an N-methylhydroxyamino group, an N-ethylhydroxyamino group, an N-(n-, iso-propyl)-hydroxyamino group, or an N-(n-, iso-, tert-butyl)hydroxyamino group.

[0081] "Heterocycloalkyl" refers to a saturated ring system having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. The heteroatoms may also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. Heterocycloalkyl may include any number of ring atoms, for example, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms may be included in a heterocycloalkyl, for example, 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. Heterocycloalkyl groups can include, for example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azocanyl, quinuclidinyl, pyrazolidinyl, imidazolidinyl, piperazinyl (1,2-, 1,3-, and 1,4-isomers), oxiranyl, oxetanyl, tetrahydrofuranyl, oxanyl (tetrahydropyranyl), oxepanyl, thioethane, thietanyl, thiolanyl (tetrahydrothiophenyl), thianyl (tetrahydrothiopyranyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, morpholinyl, thiomorpholinyl, dioxanyl, or dithianyl. Heterocycloalkyl can also be fused to an aromatic or non-aromatic ring system to form a member including but not limited to indoline. Heterocycloalkyl can be unsubstituted or substituted. For example, heterocycloalkyl can be substituted by C1-C6 alkyl or oxo (=O) and the like.

[0082] The heterocycloalkyl group may be attached at any position on the ring. For example, aziridinyl can be 1- or 2-aziridinyl, azetidinyl can be 1- or 2-azetidinyl, pyrrolidinyl can be 1-, 2-, or 3-pyrrolidinyl, piperidinyl can be 1-, 2-, 3-, or 4-piperidinyl, pyrazolidinyl can be 1-, 2-, 3-, or 4-pyrazolidinyl, imidazolidinyl can be 1-, 2-, 3-, or 4-imidazolidinyl, piperazinyl can be 1-, 2-, 3-, or 4-piperazinyl, tetrahydrofuranyl can be 1- or 2-tetrahydrofuranyl, oxazolidinyl can be 2-, 3-, 4-, or 5-oxazolidinyl, isoxazolidinyl can be 2-, 3-, 4-, or 5-isoxazolidinyl, thiazolidinyl can be 2-, 3-, 4-, or 5-thiazolidinyl, isothiazolidinyl can be 2-, 3-, 4-, or 5-isothiazolidinyl, and morpholinyl can be 2-, 3-, or 4-morpholinyl.

[0083] "N-linked heterocycloalkyl" or "nitrogen-linked heterocycloalkyl" refers to a heterocycloalkyl group that is attached through the N-position on the ring. For example, an N-linked aziridinyl group is aziridin-1-yl, an N-linked azetidinyl group is azetidin-1-yl, an N-linked pyrrolidinyl group is pyrrolidin-1-yl, an N-linked piperidinyl group is piperidin-1-yl, an N-linked pyrazolidinyl group is pyrazolidin-1-yl or pyrazolidin-2-yl, an N-linked imidazolidinyl group can be imidazolidin-1-yl or imidazolidin-3-yl, an N-linked piperazinyl group is piperazin-1-yl or piperazin-4-yl, an N-linked oxazolidinyl group is oxazolidin-3-yl, an N-linked isoxazolidinyl group is isoxazolidin-2-yl, an N-linked thiazolidinyl group is thiazolidin-3-yl, an N-linked isothiazolidinyl group is isothiazolidin-2-yl, and an N-linked morpholinyl group is 4-morpholinyl.

[0084] When the heterocycloalkyl group contains 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, oxanyl, tetrahydrothiophenyl, thiohexanyl, pyrazolidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl, and dithianyl. The heterocycloalkyl group can also form rings having 5 to 6 ring members and 1 to 2 heteroatoms, and representative members include, but are not limited to, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, and morpholinyl.

[0085] A "protecting group" refers to a compound that renders a functional group inactive to specific reaction conditions, but can be removed in a subsequent synthetic step to restore the functional group to its original state. Such protecting groups are well known to those of ordinary skill in the art and include those disclosed in "Protective Groups in Organic Synthesis," 4th Edition, TW Greene and PGM Wuts, John Wiley & Sons, Inc., New York, 2006, the entire contents of which are incorporated herein by reference.

[0086] "Salt" refers to an acid salt or basic salt of a compound of the present invention. Illustrative examples of pharmaceutically acceptable salts are inorganic acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It should be understood that pharmaceutically acceptable salts are non-toxic. Additional information about suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences (17th edition, Mack Publishing Company, Easton, Pennsylvania, 1985), which is incorporated herein by reference.

[0087] Pharmaceutically acceptable salts of the acidic compounds of the present invention include salts formed with bases, i.e., cationic salts, such as alkali metal and alkaline earth metal salts, e.g., sodium, lithium, potassium, calcium, magnesium, and ammonium salts, such as ammonium, tri-methylammonium, di-ethylammonium and tris-(hydroxymethyl)-methyl-ammonium salts.

[0088] Similarly, acid addition salts, for example of inorganic acids, organic carboxylic acids and organic sulfonic acids, for example hydrochloric acid, methanesulfonic acid, maleic acid, may also provide a basic group (such as pyridyl) which forms part of the structure.

[0089] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents, but for purposes of the present invention, the salts are otherwise equivalent to the parent form of the compound.

[0090] "Isomers" refers to compounds that have the same chemical formula but are distinguishable in structure. Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, and individual isomers are intended to be encompassed within the scope of the present invention.

[0091] A tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one form to another.

[0092] "Solvate" refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0093] "Hydrate" refers to a compound that is complexed with at least one water molecule. "The compounds of the present invention may be complexed with 1-10 water molecules.

[0094] With respect to a composition, "substantially free" or "substantially absent" of a stereoisomer means that the composition comprises at least 85 or 90%, and in some embodiments at least 95%, 98%, 99%, or 100%, by weight of the compound of the specified stereoisomer. In some embodiments, the methods and compounds provided herein are substantially free of stereoisomers.

[0095] With respect to a composition, "isolated" refers to a composition comprising at least 85%, 90%, 95%, 98%, 99% to 100% by weight of a particular compound, with the remainder comprising other chemical forms or stereoisomers.

[0096] As used herein, "composition" refers to a product comprising the specified ingredients in the specified amounts, as well as any product based directly or indirectly on the manufacture of a combination comprising the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0097] A "pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject and its absorption by the subject. Pharmaceutical excipients that can be used in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, and pigments. Those skilled in the art will recognize that other pharmaceutical excipients can be used in the present invention.

[0098] “IC 50 "" refers to the amount, concentration or dose of a particular test compound that achieves a 50% inhibition of a maximum response in an assay measuring that response.

[0099] "Inhibit," "inhibits," and "inhibitor" refer to a compound or method that inhibits a specific effect or function.

[0100] "Administering" refers to administering to a subject orally, as a suppository, topically, parenterally, intravenously, intraperitoneally, intramuscularly, intralesionally, intranasally or subcutaneously, intrathecally, or by implantation of a slow-release device, such as a mini-osmotic pump.

[0101] "Treatment," "therapeutic," and "therapy" refer to any indication of success in treating or ameliorating an injury, pathology, or condition, including any objective or subjective parameter, such as alleviation of symptoms; remission; diminishment or rendering the injury, pathology, or condition more tolerable to the patient; slowing the rate of degeneration or decline; rendering the endpoint of decline less debilitating; or improvement in the patient's physical or mental well-being. Treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0102] In some embodiments, "prophylactic treatment" and "prevention" of cutaneous squamous cell carcinoma (cSCC) refers to reducing the risk of cSCC in a subject who has received a solid organ transplant and is under immunosuppressive drug therapy. In some embodiments, "prophylactic treatment" or "prevention" includes delaying the onset of cSCC resulting from solid organ transplantation and immunosuppressive drug therapy. In some embodiments, "prophylactic treatment" or "prevention" includes slowing the progression of cSCC metastasis or ameliorating one or more symptoms associated with the progression of cSCC.

[0103] "Patient" or "subject" refers to a living organism having or susceptible to a disease or condition that can be treated by administering a pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is a human.

[0104] "Therapeutically effective amount" or "effective amount" refers to an amount of a compound or pharmaceutical composition that can be used to treat or ameliorate an identified disease or condition (such as skin cancer as described herein), or to show a detectable therapeutic or inhibitory effect. The exact amount will depend on the purpose of the treatment and can be determined by one skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (Vol. 13, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th edition, 2003, Gennaro ed., Lippincott, Williams & Wilkins).

[0105] "Topical" refers to applying an appropriate compound (e.g., an active agent) or a composition comprising a compound (e.g., an active agent) to the skin to treat skin cancer. "Subcutaneous" refers to applying an appropriate compound (e.g., an active agent) or a composition comprising a compound (e.g., an active agent) to the layers below the epidermis and dermis. "Intradermal" refers to applying an appropriate compound (e.g., an active agent) or a composition comprising a compound (e.g., an active agent) to the dermis or subcutaneous layer. "Intralesional" refers to injecting an appropriate compound (e.g., an active agent) or a composition comprising a compound (e.g., an active agent) into the lesion site (e.g., squamous cell carcinoma).

[0106] In some embodiments, "topical" refers to applying an appropriate compound (e.g., an active agent) or a composition comprising a compound (e.g., an active agent) to the skin and sufficiently penetrating the epidermis or dermis to treat skin cancer of the epidermis and / or dermis. In some embodiments of topical application, the compound or composition penetrates the epidermis or dermis without significant systemic exposure and with no intention to treat or prevent a disease of another organ system. In some embodiments, "subcutaneous" refers to injecting an appropriate compound (e.g., an active agent) or a composition comprising a compound (e.g., an active agent) into the layer below the epidermis and dermis. In some embodiments, "intradermal" refers to injecting an appropriate compound (e.g., an active agent) or a composition comprising a compound (e.g., an active agent) into the dermis. In some embodiments, "intralesional" refers to injecting a compound (e.g., an active agent) or a combination comprising a compound (e.g., an active agent) directly into a lesion, such as cSCC, to treat skin cancer or lesions.

[0107] The present invention discloses "soft" MEK inhibitors, compositions comprising "soft" MEK inhibitors, and methods for treating and / or ameliorating skin cancer, particularly squamous cell carcinoma (cSCC) (e.g., MEK inhibitor-responsive or MEK-mediated cSCC). For example, the methods described herein provide for local or non-systemic administration, such as topical, subcutaneous, transdermal, intradermal, or intralesional administration of a MEK inhibitor, such as a "soft" MEK inhibitor, such as the "soft" MEK inhibitors described herein, thereby significantly reducing one or more side effects exhibited upon systemic exposure, for example, one or more known side effects exhibited by MEK inhibitors designed for systemic administration.

[0108] In some embodiments, a "soft MEK inhibitor" is a compound that inhibits MEK1 and / or 2 and is characterized by predictable and controllable metabolism / degradation into non-toxic, less biologically active or inactive (i.e., does not inhibit or inhibits MEK1 and / or 2 to a low extent) products after exerting its therapeutic effect in the skin.

[0109] "Hard MEK inhibitors" refer to MEK inhibitors known in the art. In some embodiments, hard MEK inhibitors are designed for oral bioavailability. This is necessary to deliver therapeutically effective levels of MEK inhibitors to surrounding lesions using systemic delivery. Hard MEK inhibitors include, for example, PD0325901; PD184161; SMK-17; AS703026 (Pimasertib, MSC1936369); RO-4987655; Selumetinib (AZD6244, ARRY142886); Binimetinib (MEK162, ARRY-162, ARRY-438162); Refametinib (Refatinib) nib); Cobimetinib (GDC-0973, XL518); GDC-0623; AZD8330 (ARRY-424704); CI-1040 (PD184352); PD198306; PD318088; Trametinib; RO-4987655; GDC-0623; TAK-733; WX-554; CH5126766 (also known as RO5126766); G-573; Arry 300; SHR 7390; MSC2015103B (also known as AS-703988); CS 3006; and LY 2228820 (also known as Ralimetinib).

[0110] Although not wishing to be bound by theory, it is believed that soft MEK inhibitors, for example, "soft" MEK inhibitors as described herein, are more unstable than known "hard" MEK inhibitors. Due to their inherent metabolic instability, for example, for degradation that reaches the body's circulation, "soft" MEK inhibitors, for example, "soft" MEK inhibitors such as those described herein, have skin activity, but have low systemic exposure after local or non-systemic (such as topical, subcutaneous, intradermal or intralesional) administration because they are rapidly degraded when exposed to plasma or blood or liver metabolizing enzymes. Unlike "soft" MEK inhibitors, known MEK inhibitors have been designed for oral bioavailability in the past, which requires good stability in plasma or blood and good stability to liver metabolism necessary for systemic delivery at therapeutically effective or effective levels, and are more likely to produce one or more undesirable side effects and higher toxicity. Therefore, "soft" MEK inhibitors, for example, soft MEK inhibitors such as those described herein, have less systemic toxicity.

[0111] "A," "an," or "one," when used herein as referring to a group of substituents or a "substituent group," means at least one. For example, when a compound is substituted with "an" alkyl or aryl group, the compound is optionally substituted with at least one alkyl group and / or at least one aryl group, wherein each alkyl group and / or aryl group is optionally different. In another example, when a compound is substituted with "a" substituent, the compound is substituted with at least one substituent, wherein each substituent is optionally different.

[0112] III. Methods

[0113] In one aspect, provided herein is a method for treating or preventing skin cancer. The method comprises administering to a subject in need thereof a therapeutically effective amount or an effective amount of a compound selected from the group consisting of Formula (I), (II), (III), (IV), and (V):

[0114]

[0115] or its N-oxide, stereoisomer, mixture of stereoisomers and / or pharmaceutically acceptable salt,

[0116] in:

[0117] X 1 -CR 13b or N; X 2 is a C1-C6 alkyl group; X 3 is S or O;

[0118] Subscript n is an integer from 0 to 2;

[0119] Bond "a" is a single bond or a double bond;

[0120] R 1 For-OR 4 、-NR 5 R 5a 、-N(OR 5b )R 5a or unsubstituted or replaced by one or two R 6 substituted N-linked heterocycloalkyl;

[0121] R 2 is halogen, C1-C6 alkyl, -S-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0122] R 2a Halogen or C 1-6 alkyl;

[0123] R 4 、R 5 and R5b Each is independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl or R 7 -C(O)-C1-C6 alkyl, wherein each C3-C8 cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 R 6 replaced;

[0124] R 5a is hydrogen or C 1-6 alkyl;

[0125] Each R 6 are independently halogen, hydroxy, oxo, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6-hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl or di-(C1-C6 alkyl)amino-C1-C6 alkyl;

[0126] R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino;

[0127] R 13 、R 13a and R 13b are each independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0128] R 23 、R 23a and R 23b Each is independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C3-C8 cycloalkoxy;

[0129] R 33 、R 33a and R 33b Each is independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C3-C8 cycloalkoxy;

[0130] R 43 Cyano, -C(O)NR 48 R 48a or -C(O)R46 ;

[0131] R 43a is hydrogen, halogen, C1-C6 alkyl; or

[0132] R 43 and R 43a Together they form -CH2CH2C(O)- or -CH2CH2CH2C(O)-, each of which is unsubstituted or substituted by one or two R 49 replaced;

[0133] R 46 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or heterocycloalkyl;

[0134] R 48 and R 48a are each independently hydrogen or C1-C6 alkyl; and

[0135] Each R 49 are independently C1-C6 alkyl, C3-C8 cycloalkyl or C3-C8 cycloalkyl-C1-C6 alkyl;

[0136] R 51 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, R 7 -C(O)-C1-C6 alkyl or -OR 54 , wherein each C3-C8 cycloalkyl and heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 replaced;

[0137] Each R 53 are independently halogen or C1-C6 alkyl;

[0138] R 53a and R 53b are each independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; and

[0139] R 54 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl or R7 -C(O)-C1-C6 alkyl, wherein each C3-C8 cycloalkyl and heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 replaced.

[0140] In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount or an effective amount of a compound disclosed herein, such as a compound having any one of Formula (I), (II), (III), (IV), and (V), and compounds in Tables 1-5, including single enantiomers, mixtures of pairs of enantiomers, single diastereomers, mixtures of diastereomers, single stereoisomers, mixtures of stereoisomers, or tautomeric forms thereof; or a pharmaceutically acceptable salt, solvate, prodrug, phosphate salt, or active metabolite thereof.

[0141] In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount or an effective amount of a compound having Formula (I) and a compound in Table 1, including a single enantiomer, a mixture of a pair of enantiomers, a single diastereomer, a mixture of diastereomers, a single stereoisomer, a mixture of stereoisomers, or a tautomeric form thereof; or a pharmaceutically acceptable salt or solvate thereof.

[0142] In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount or an effective amount of a compound of formula (II) and a compound in Table 2, including a single enantiomer, a mixture of a pair of enantiomers, a single diastereomer, a mixture of diastereomers, a single stereoisomer, a mixture of stereoisomers, or a tautomeric form thereof; or a pharmaceutically acceptable salt or solvate thereof.

[0143] In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount or an effective amount of a compound having Formula (III) and a compound in Table 3, including a single enantiomer, a mixture of a pair of enantiomers, a single diastereomer, a mixture of diastereomers, a single stereoisomer, a mixture of stereoisomers, or a tautomeric form thereof; or a pharmaceutically acceptable salt or solvate thereof.

[0144] In some embodiments, the method comprises therapeutically administering to a subject in need thereof a therapeutically effective amount or an effective amount of a compound having Formula (IV) and a compound in Table 4, including a single enantiomer, a mixture of a pair of enantiomers, a single diastereomer, a mixture of diastereomers, a single stereoisomer, a mixture of stereoisomers, or a tautomeric form thereof; or a pharmaceutically acceptable salt or solvate thereof.

[0145] In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount or an effective amount of a compound of Formula (V) and a compound in Table 5, including a single enantiomer, a mixture of a pair of enantiomers, a single diastereomer, a mixture of diastereomers, a single stereoisomer, a mixture of stereoisomers, or a tautomeric form thereof; or a pharmaceutically acceptable salt or solvate thereof.

[0146] In some embodiments, the skin cancer is a MEK-inhibitor responsive or MEK-mediated skin cancer.

[0147] In some embodiments, the skin cancer is cutaneous squamous cell carcinoma (cSCC).

[0148] In some embodiments, the squamous cell carcinoma of the skin is associated with exposure to ultraviolet radiation or immunosuppression in a solid organ transplant recipient. In some embodiments, the squamous cell carcinoma of the skin is associated with immunosuppression in a solid organ transplant recipient.

[0149] In some embodiments, the cutaneous squamous cell carcinoma in a solid organ transplant recipient is a MEK-inhibitor responsive or MEK-mediated cutaneous squamous cell carcinoma.

[0150] In some embodiments, administering comprises contacting the soft MEK inhibitor with the skin, mucous membranes, vagina, penis, throat, vulva, cervix, or anus of the subject by topical or non-systemic administration (e.g., topical, intradermal, or intralesional administration) or by suppository.

[0151] In some embodiments, the subject is treated by reducing the size or total volume of a tumor associated with cutaneous squamous cell carcinoma (cSCC), such as a dermal carcinoma, for example, a tumor, by at least about 15% (e.g., about 15% to about 60%) relative to a reference standard. In some embodiments, the reference standard is the size or total volume of a tumor in an untreated control, e.g., from the same subject or a different subject.

[0152] In the SOTR population, these included patients who currently had SCC, previously had cSCC, or had precancerous lesions including squamous cell carcinoma in situ (also known as Bowen's disease) or actinic keratosis (both of which are known to progress to SCC).

[0153] In some embodiments, provided herein is a method for treating skin squamous cell carcinoma in a solid organ transplant recipient to reduce the progression of skin squamous cell carcinoma (cSCC), wherein the solid organ transplant recipient currently has skin squamous cell carcinoma (cSCC), previously had skin squamous cell carcinoma (cSCC), has a precancerous lesion including squamous cell carcinoma in situ (also known as Bowen's disease), or has actinic keratosis. In some embodiments, provided herein is a method for treating skin squamous cell carcinoma in a solid organ transplant recipient to reduce the progression of skin squamous cell carcinoma (cSCC). In some embodiments, provided herein is a method for treating skin squamous cell carcinoma in a solid organ transplant recipient to reduce the progression of skin squamous cell carcinoma (cSCC), wherein the solid organ transplant recipient previously had skin squamous cell carcinoma (cSCC). In some embodiments, provided herein is a method for treating skin squamous cell carcinoma in a solid organ transplant recipient to reduce the progression of skin squamous cell carcinoma (cSCC), wherein the solid organ transplant recipient has a precancerous lesion including squamous cell carcinoma in situ (also known as Bowen's disease). In some embodiments, provided herein is a method of treating cutaneous squamous cell carcinoma in a solid organ transplant recipient to reduce progression of cutaneous squamous cell carcinoma (cSCC), wherein the solid organ transplant recipient currently has actinic keratosis.

[0154] In some embodiments, provided herein is a method for prophylactically treating or preventing skin squamous cell carcinoma in a solid organ transplant recipient to reduce the risk of tumor progression of skin squamous cell carcinoma (cSCC), wherein the solid organ transplant recipient currently has skin squamous cell carcinoma (cSCC), previously had skin squamous cell carcinoma (cSCC), has a precancerous lesion including squamous cell carcinoma in situ (also known as Bowen's disease), or has actinic keratosis. In some embodiments, provided herein is a method for prophylactically treating or preventing skin squamous cell carcinoma in a solid organ transplant recipient to reduce the risk of tumor progression of skin squamous cell carcinoma (cSCC). In some embodiments, provided herein is a method for prophylactically treating or preventing skin squamous cell carcinoma in a solid organ transplant recipient to reduce the risk of tumor progression of skin squamous cell carcinoma (cSCC), wherein the solid organ transplant recipient previously had skin squamous cell carcinoma (cSCC). In some embodiments, provided herein is a method of prophylactically treating or preventing cutaneous squamous cell carcinoma in a solid organ transplant recipient to reduce the risk of tumor progression to cutaneous squamous cell carcinoma (cSCC), wherein the solid organ transplant recipient has a precancerous lesion including squamous cell carcinoma in situ (also known as Bowen's disease). In some embodiments, provided herein is a method of prophylactically treating or preventing cutaneous squamous cell carcinoma in a solid organ transplant recipient to reduce the risk of tumor progression to cutaneous squamous cell carcinoma (cSCC), wherein the solid organ transplant recipient currently has actinic keratosis.

[0155] In some embodiments, provided herein is a method for prophylactically treating or preventing skin squamous cell carcinoma in a solid organ transplant recipient to delay progression of skin squamous cell carcinoma (cSCC), wherein the solid organ transplant recipient currently has skin squamous cell carcinoma (cSCC), previously had skin squamous cell carcinoma (cSCC), has a precancerous lesion including squamous cell carcinoma in situ (also known as Bowen's disease), or has actinic keratosis. In some embodiments, provided herein is a method for prophylactically treating or preventing skin squamous cell carcinoma in a solid organ transplant recipient to delay progression of skin squamous cell carcinoma (cSCC). In some embodiments, provided herein is a method for prophylactically treating or preventing skin squamous cell carcinoma in a solid organ transplant recipient to delay progression of skin squamous cell carcinoma (cSCC), wherein the solid organ transplant recipient previously had skin squamous cell carcinoma (cSCC). In some embodiments, provided herein is a method of prophylactically treating or preventing cutaneous squamous cell carcinoma in a solid organ transplant recipient to delay progression of cutaneous squamous cell carcinoma (cSCC), wherein the solid organ transplant recipient has cancerous lesions including squamous cell carcinoma in situ (also known as Bowen's disease). In some embodiments, provided herein is a method of prophylactically treating or preventing cutaneous squamous cell carcinoma in a solid organ transplant recipient to delay progression of cutaneous squamous cell carcinoma (cSCC), wherein the solid organ transplant recipient currently has actinic keratosis.

[0156] In some embodiments, provided herein is a method for prophylactically treating or preventing skin squamous cell carcinoma in a solid organ transplant recipient to prevent progression of skin squamous cell carcinoma (cSCC), wherein the solid organ transplant recipient currently has skin squamous cell carcinoma (cSCC), previously had skin squamous cell carcinoma (cSCC), has a precancerous lesion including squamous cell carcinoma in situ (also known as Bowen's disease), or has actinic keratosis. In some embodiments, provided herein is a method for prophylactically treating or preventing skin squamous cell carcinoma in a solid organ transplant recipient to prevent progression of skin squamous cell carcinoma (cSCC). In some embodiments, provided herein is a method for prophylactically treating or preventing skin squamous cell carcinoma in a solid organ transplant recipient to prevent progression of skin squamous cell carcinoma (cSCC), wherein the solid organ transplant recipient previously had skin squamous cell carcinoma (cSCC). In some embodiments, provided herein is a method of prophylactically treating or preventing cutaneous squamous cell carcinoma in a solid organ transplant recipient to prevent progression of cutaneous squamous cell carcinoma (cSCC), wherein the solid organ transplant recipient has a cancerous lesion including squamous cell carcinoma in situ (also known as Bowen's disease). In some embodiments, provided herein is a method of prophylactically treating or preventing cutaneous squamous cell carcinoma in a solid organ transplant recipient to prevent progression of cutaneous squamous cell carcinoma (cSCC), wherein the solid organ transplant recipient currently has actinic keratosis.

[0157] In some embodiments, provided herein is a method for treating skin squamous cell carcinoma in a patient to reduce the progression of skin squamous cell carcinoma (cSCC), wherein the patient has chronic lymphocytic leukemia (CLL), is immunocompromised, and is susceptible to significantly increased cSCC rates. In some embodiments, provided herein is a method for prophylactically treating or preventing skin squamous cell carcinoma in a patient to reduce the risk of tumor progression of skin squamous cell carcinoma (cSCC), wherein the patient has chronic lymphocytic leukemia (CLL), is immunocompromised, and is susceptible to significantly increased cSCC rates. In some embodiments, provided herein is a method for prophylactically treating or preventing skin squamous cell carcinoma in a patient to delay or prevent the progression of skin squamous cell carcinoma (cSCC), wherein the patient has chronic lymphocytic leukemia (CLL), is immunocompromised, and is susceptible to significantly increased cSCC rates.

[0158] In some embodiments, provided herein is a method of treating cutaneous squamous cell carcinoma in a patient to reduce the progression of cSCC, wherein the patient has inoperable cSCC. In some embodiments, provided herein is a method of prophylactically treating or preventing cutaneous squamous cell carcinoma in a patient to reduce the risk of tumor progression of cSCC, wherein the patient has inoperable cSCC. In some embodiments, provided herein is a method of prophylactically treating or preventing cutaneous squamous cell carcinoma in a patient to delay or prevent the progression of cSCC, wherein the patient has inoperable cSCC.

[0159] In some embodiments, provided herein is a method of treating cutaneous squamous cell carcinoma in a patient to reduce the progression of cSCC, wherein the patient previously had a cSCC surgically removed. In some embodiments, provided herein is a method of prophylactically treating or preventing cutaneous squamous cell carcinoma in a patient to reduce the risk of tumor progression of cSCC, wherein the patient previously had a cSCC surgically removed. In some embodiments, provided herein is a method of prophylactically treating or preventing cutaneous squamous cell carcinoma in a patient to delay or prevent the progression of cSCC, wherein the patient previously had a cSCC surgically removed.

[0160] In some or any embodiments, the tumor associated with cutaneous squamous cell carcinoma or skin cancer that is reduced, prophylactically treated, or prevented using the methods described herein is a carcinoma.

[0161] In some embodiments, the disease to be reduced, improved, treated or prevented is skin cancer. In some embodiments, the disease to be reduced, improved, treated or prevented is selected from the group consisting of basal cell carcinoma, squamous cell carcinoma, squamous cell carcinoma in situ (also known as Bowen's disease), actinic keratosis and HPV-associated squamous cell carcinoma. In some embodiments, the disease to be reduced, improved, treated or prevented is a dermal disease associated with squamous cell carcinoma. In some embodiments, the disease to be reduced, improved, treated or prevented is a dermal disease associated with squamous cell carcinoma in solid organ transplant recipients. In some embodiments, the disease to be reduced, improved, treated or prevented is a dermal disease associated with squamous cell carcinoma in patients with chronic lymphocytic leukemia (CLL).

[0162] In some embodiments, the compounds described herein are used to reduce MEK inhibitor-responsive skin cancer or MEK-mediated skin cancer in a subject in need thereof.

[0163] In some embodiments, the compounds described herein are used to improve MEK inhibitor-responsive skin cancer or MEK-mediated skin cancer in a subject in need thereof.

[0164] In some embodiments, the compounds described herein are used to prevent MEK inhibitor-responsive skin cancer or MEK-mediated skin cancer in a subject in need thereof.

[0165] In some embodiments, the compounds described herein are used to treat MEK-inhibitor responsive squamous cell carcinoma or MEK-mediated squamous cell carcinoma in a subject in need thereof.

[0166] In some embodiments, the compounds described herein are used to reduce MEK-inhibitor responsive squamous cell carcinoma or MEK-mediated squamous cell carcinoma in a subject in need thereof.

[0167] In some embodiments, the compounds described herein are used to improve MEK-inhibitor responsive squamous cell carcinoma or MEK-mediated squamous cell carcinoma in a subject in need thereof.

[0168] In some embodiments, the compounds described herein are used to prevent MEK-inhibitor responsive squamous cell carcinoma or MEK-mediated squamous cell carcinoma in a subject in need thereof.

[0169] In some embodiments, the compounds described herein are used to treat cutaneous squamous cell carcinoma in a subject in need thereof.

[0170] In some embodiments, the compounds described herein are used to reduce squamous cell carcinoma of the skin in a subject in need thereof. In some embodiments, the compounds described herein are used to ameliorate squamous cell carcinoma of the skin in a subject in need thereof. In some embodiments, the compounds described herein are used to prevent squamous cell carcinoma of the skin in a subject in need thereof.

[0171] In some embodiments, the subject in need thereof is a human.

[0172] Determination method

[0173] The efficacy of a compound in treating or preventing skin cancer (eg, MEK-inhibitor responsive or MEK-mediated skin cancer) in a subject in need thereof can be determined according to any assay known to those skilled in the art. Exemplary assay methods are provided elsewhere herein.

[0174] IV. Compounds

[0175] The present invention provides a compound for use in a method of treating skin cancer as defined and described herein, wherein the compound is selected from the group consisting of formula (I), (II), (III), (IV) and (V):

[0176]

[0177] or its N-oxide, stereoisomer, mixture of stereoisomers and / or pharmaceutically acceptable salt,

[0178] in:

[0179] X 1 -CR 13b or N; X 2 is a C1-C6 alkyl group; X 3 is S or O;

[0180] Subscript n is an integer from 0 to 2;

[0181] Bond "a" is a single bond or a double bond;

[0182] R 1 For-OR 4 、-NR 5 R 5a 、-N(OR 5b )R 5a or unsubstituted or replaced by one or two R 6 substituted N-linked heterocycloalkyl;

[0183] R 2 is halogen, C1-C6 alkyl, -S-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0184] R 2a Halogen or C 1-6 alkyl;

[0185] R 4 、R 5 and R 5b Each is independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl or R 7 -C(O)-C1-C6 alkyl, wherein each C3-C8 cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 R 6 replaced;

[0186] R 5a is hydrogen or C 1-6 alkyl;

[0187] Each R 6 are independently halogen, hydroxy, oxo, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6-hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl or di-(C1-C6 alkyl)amino-C1-C6 alkyl;

[0188] R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino;

[0189] R 8 is hydroxy, C1-C3 alkyl or C1-C3 alkoxy;

[0190] R 13 、R 13a and R 13b are each independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0191] R 23 、R 23a and R 23b Each is independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C3-C8 cycloalkoxy;

[0192] R 33 、R33a and R 33b Each is independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C3-C8 cycloalkoxy;

[0193] R 43 Cyano, -C(O)NR 48 R 48a or -C(O)R 46 ;

[0194] R 43a is hydrogen, halogen, C1-C6 alkyl; or

[0195] R 43 and R 43a Together they form -CH2CH2C(O)- or -CH2CH2CH2C(O)-, each of which is unsubstituted or substituted by one or two R 49 replaced;

[0196] R 46 is hydrogen, C1-C6 alkyl, -C1-C6 haloalkyl, C3-C8 cycloalkyl or heterocycloalkyl;

[0197] R 48 and R 48a are each independently hydrogen or C1-C6 alkyl; and

[0198] Each R 49 are independently C1-C6 alkyl, C3-C8 cycloalkyl or C3-C8 cycloalkyl-C1-C6 alkyl;

[0199] R 51 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, R 7 -C(O)-C1-C6 alkyl or -OR 54 , wherein each C3-C8 cycloalkyl and heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 replaced;

[0200] Each R 53 are independently halogen or C1-C6 alkyl;

[0201] R 53a and R 53b are each independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; and

[0202] R 54 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl or R 7 -C(O)-C1-C6 alkyl, wherein each C3-C8 cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 R 6 replaced.

[0203] In some embodiments, the cycloalkyl provided in formula (I), (II), (III), (IV) and (V) is a saturated monocyclic C3-C8 cycloalkyl. In some embodiments, the C3-C8 cycloalkyl, alone or as part of a C3-C8 cycloalkyl-C1-C6 alkyl, is cyclopropyl or cyclobutyl. In some embodiments, the C3-C8 cycloalkyl, alone or as part of a C3-C8 cycloalkyl-C1-C6 alkyl, is unsubstituted. In some embodiments, the C3-C8 cycloalkyl, alone or as part of a C3-C8 cycloalkyl-C1-C6 alkyl, is substituted with 1-6 R 6 Replaced, and R 6 As defined and described herein.

[0204] About R 6 , as one or more substituents of the C3-C8 cycloalkyl group, in some embodiments, each R 6 R is independently halogen, hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6-hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl or di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, each R 6 R is independently halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6-hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino or di-(C1-C6 alkyl)amino. 6 are independently halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy or amino. 6 In some embodiments, each R 6 are independently hydroxy or amino.

[0205] In some embodiments, the heterocycloalkyl provided in formula (I), (II), (III), (IV) and (V) is a 3- to 8-membered heterocycloalkyl having 1 to 3 ring heteroatoms selected from N, O and S. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms that are N or O. In some embodiments, the heterocycloalkyl, alone or as part of a heterocycloalkyl-C1-C6 alkyl, is unsubstituted. In some embodiments, the heterocycloalkyl, alone or as part of a heterocycloalkyl-C1-C6 alkyl, is substituted with 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, the N-linked heterocycloalkyl group is replaced by one or two R 6 Replace, and R 6 As defined and described herein.

[0206] About R 6 , as one or more substituents of heterocycloalkyl or N-attached heterocycloalkyl, in some embodiments, each R 6 R is independently halogen, hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6-hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl or di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, each R 6 R is independently halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6-hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino or di-(C1-C6 alkyl)amino. 6 are independently halogen, hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy or amino. 6 In some embodiments, each R 6 In some embodiments, each R 6 are independently hydroxy or amino.

[0207] In some embodiments, the compound useful in the methods of the present invention is a compound of formula (I).

[0208] With respect to Formula (I), in some embodiments, X 1 -CR 13b , the compound is represented by formula (Ia):

[0209]

[0210] Among them, R1 、R 2 、R 2a 、R 13 、R 13a and R 13b As defined in any aspect or embodiment described herein.

[0211] In some embodiments of Formula (Ia), R 13 、R 13a and R 13b Each is independently hydrogen, halogen or C1-C6 alkyl.

[0212] In some embodiments of Formula (Ia), R 13 is hydrogen, halogen or C1-C6 alkyl. 13 In some embodiments, R 13 In some embodiments, R 13 is fluorine, chlorine, bromine or iodine. 13 In some embodiments, R 13 is a C1-C6 alkyl group. 13 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl. 13 It is a methyl group.

[0213] In some embodiments of Formula (Ia), R 13a is hydrogen, halogen or C1-C6 alkyl. 13a In some embodiments, R 13a In some embodiments, R 13a is fluorine, chlorine, bromine or iodine. 13a In some embodiments, R 13a is a C1-C6 alkyl group. 13a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl. 13a It is a methyl group.

[0214] In some embodiments of Formula (Ia), R 13b is hydrogen, halogen or C1-C6 alkyl. 13b In some embodiments, R 13b In some embodiments, R 13b is fluorine, chlorine, bromine or iodine. 13bIn some embodiments, R 13b is a C1-C6 alkyl group. 13b is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl. 13b It is a methyl group.

[0215] In some embodiments of Formula (Ia), R 13 、R 13a and R 13b are all hydrogen. In some embodiments of Formula (Ia), R 13 and R 13a All are hydrogen, R 13b In some embodiments of Formula (Ia), R 13 and R 13a All are hydrogen, R 13b For fluorine.

[0216] Returning to Formula (I), in some embodiments, X 1 is N, and the compound is represented by formula (Ib):

[0217]

[0218] Among them, R 1 、R 2 、R 2a 、R 13 and R 13a As defined in any aspect or embodiment described herein.

[0219] In some embodiments of Formula (Ib), R 13 and R 13a Each is independently hydrogen, halogen or C1-C6 alkyl.

[0220] In some embodiments of Formula (Ib), R 13 is hydrogen, halogen or C1-C6 alkyl. 13 In some embodiments, R 13 In some embodiments, R 13 is fluorine, chlorine, bromine or iodine. 13 In some embodiments, R 13 is a C1-C6 alkyl group. 13 It is a methyl group.

[0221] In some embodiments of Formula (Ib), R 13a is hydrogen, halogen or C1-C6 alkyl. 13aIn some embodiments, R 13a In some embodiments, R 13a is fluorine, chlorine, bromine or iodine. 13a In some embodiments, R 13a is a C1-C6 alkyl group. 13a It is a methyl group.

[0222] In some embodiments of Formula (Ib), R 13 and R 13a Each is independently hydrogen or halogen. In some embodiments, R 13 and R 13a In some embodiments, R 13 and R 13a One of R is hydrogen and the other is halogen. 13 and R 13a One is hydrogen and the other is fluorine.

[0223] With respect to any of Formulas (I), (Ia), and (Ib), in some embodiments, R 1 For-OR 4 、-NR 5 R 5a OR-N(OR 5b )R 5a .

[0224] In some embodiments of any of Formulas (I), (Ia), and (Ib), R 1 For-OR 4 In some embodiments, R 4 In some embodiments, R 4 is a C1-C6 alkyl group. 4 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and R 6 As defined and described herein. In some embodiments, R 4 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and each R 6 In some embodiments, R 4 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 4is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and each R 6 In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl; and each cyclopropyl and cyclobutyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl, and each cyclopropyl and cyclobutyl is unsubstituted or substituted by 1-6 R 6 substituted, and each R 6 In some embodiments, R 4 is C1-C6 hydroxyalkyl. 4 In some embodiments, R 4 In some embodiments, R 4 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 4 In some embodiments, R 4 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and R 6 As defined and described herein. In some embodiments, R 4 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and each R 6 In some embodiments, R 4 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 4 is a heterocycloalkyl-C1-C6 alkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted by 1-6 R 6 Replaced, and each R 6 In some embodiments, R 4In some embodiments, R 4 R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino. 4 R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0225] In some embodiments of any of Formulas (I), (Ia), and (Ib), R 1 Selected from the group consisting of: -OH,

[0226]

[0227] In some embodiments of any of Formulas (I), (Ia), and (Ib), R 1 -NR 5 R 5a In some embodiments, R 5 In some embodiments, R 5 is a C1-C6 alkyl group. 5 is unsubstituted or substituted with 1 to 6 R 6 substituted C3-C8 cycloalkyl, and R 6 As defined and described herein. In some embodiments, R 5 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and each R 6 In some embodiments, R 5 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and each R 6 In some embodiments, R5 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl; and each cyclopropyl and cyclobutyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl, each cyclopropyl and cyclobutyl being unsubstituted or substituted by 1-6 R 6 Replaced, each R 6 In some embodiments, R 5 is C1-C6 hydroxyalkyl. 5 In some embodiments, R 5 In some embodiments, R 5 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 5 In some embodiments, R 5 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and R 6 As defined and described herein. In some embodiments, R 5 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and each R 6 In some embodiments, R 5 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5 is a heterocycloalkyl-C1-C6 alkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with 1-6 R 6 Replaced, and each R 6 In some embodiments, R 5 In some embodiments, R 5 R 7 -C(O)-C1-C6 alkyl; and R 7is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino. 5 R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0228] In some embodiments of any of Formulas (I), (Ia), and (Ib), R 1 -NR 5 R 5a , and R 5 Selected from the group consisting of hydrogen,

[0229]

[0230] In some embodiments of any of Formulas (I), (Ia), and (Ib), R 1 -N(OR 5b )R 5a In some embodiments, R 5b In some embodiments, R 5b is a C1-C6 alkyl group. 5b is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and R 6 As defined and described herein. In some embodiments, R 5b is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and each R 6 In some embodiments, R 5b is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5b is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and each R 6 In some embodiments, R 5b is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl; and each cyclopropyl and cyclobutyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R5b is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl, each cyclopropyl and cyclobutyl being unsubstituted or substituted by 1-6 R 6 substituted, and each R 6 In some embodiments, R 5b is C1-C6 hydroxyalkyl. 5b In some embodiments, R 5b In some embodiments, R 5b is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 5b In some embodiments, R 5b is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and R 6 As defined and described herein. In some embodiments, R 5b is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and each R 6 In some embodiments, R 5b is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5b is a heterocycloalkyl-C1-C6 alkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with 1-6 R 6 Replaced, and each R 6 In some embodiments, R 5b In some embodiments, R 5b R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino. 5b R 7 -C(O)-C1-C6 alkyl; and R7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0231] In some embodiments of any of Formulas (I), (Ia), and (Ib), R 1 -N(OR 5b )R 5a , and-OR 5b Selected from the group consisting of: -OH,

[0232]

[0233] In some embodiments of any of Formulas (I), (Ia), and (Ib), R 5a In some embodiments, R 5a is a C1-C6 alkyl group. 5a In some embodiments, R 5a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. 5a It is a methyl group.

[0234] With respect to any of Formulas (I), (Ia), and (Ib), in some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-linked heterocycloalkyl, wherein R 6 As defined and described herein. In some embodiments, the N-attached heterocycloalkyl is an N-attached azetidinyl, an N-attached pyrrolidinyl, an N-attached isoxazolidinyl, an N-attached piperidinyl, or an N-attached morpholinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached azetidinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached pyrrolidinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached isoxazolidinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached piperidinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached morpholinyl. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 A substituted N-attached azetidinyl group wherein R 6 As defined and described herein. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-linked pyrrolidinyl, wherein R 6 As defined and described herein. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6Substituted N-attached piperidinyl, wherein R 6 As defined and described herein. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-linked isoxazolidinyl, wherein R 6 As defined and described herein. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-attached morpholinyl, wherein R 6 As defined and described herein.

[0235] In any of formulae (I), (Ia) and (Ib), with respect to R 6 , which as one or two substituents of the N-linked heterocycloalkyl group, in some embodiments, each R 6 In some embodiments, each R 6 In some embodiments, each R 6 In some embodiments, each R 6 In some embodiments, one R 6 is a hydroxyl group, and another R 6 It is an amino group.

[0236] In some embodiments of any of Formulas (I), (Ia), and (Ib), R 1 is an N-linked heterocycloalkyl group which is unsubstituted or substituted with hydroxy, oxo or amino. 1 is an N-linked azetidinyl group which is unsubstituted or substituted with hydroxy, oxo or amino. 1 is an N-linked pyrrolidinyl group that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-piperidinyl group which is unsubstituted or substituted with hydroxy, oxo or amino. 1 is an N-linked isoxazolidinyl group which is unsubstituted or substituted with hydroxy, oxo or amino. 1 is an N-linked morpholinyl group which is unsubstituted or substituted by hydroxy, oxo or amino.

[0237] With respect to any of Formulas (I), (Ia), and (Ib), in some embodiments, R 2 is halogen, C1-C6 alkyl, -S-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl. 2 is halogen or C1-C6 alkyl. 2is halogen, -CH3, -SCH3, C2-C3 alkenyl or C2-C3 alkynyl.

[0238] In some embodiments of any of Formulas (I), (Ia), and (Ib), R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 For bromine.

[0239] In some embodiments of any of Formulas (I), (Ia), and (Ib), R 2 is a C1-C6 alkyl group. 2 is a C1-C3 alkyl group. 2 It is a methyl group.

[0240] In some embodiments of any of Formulas (I), (Ia), and (Ib), R 2 In some embodiments, R 2 In some embodiments, R 2 It is -SCH3.

[0241] In some embodiments of any of Formulas (I), (Ia), and (Ib), R 2 is a C3-C8 cycloalkyl group. 2 It is cyclopropyl.

[0242] In some embodiments of any of Formulas (I), (Ia), and (Ib), R 2 In some embodiments, R 2 is C2-C4 alkenyl. In some embodiments, R 2 is vinyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl or butadienyl. 2 For vinyl.

[0243] In some embodiments of any of Formulas (I), (Ia), and (Ib), R 2 is a C2-C6 alkynyl group. 2 is a C2-C3 alkynyl group. 2 In some embodiments, R 2 For ethynyl.

[0244] With respect to any of Formulas (I), (Ia), and (Ib), in some embodiments, R 2a is halogen or C1-C3 alkyl. 2a is halogen or CH3. In some embodiments, R 2a is fluorine or CH3. In some embodiments, R 2a is iodine or CH3. In some embodiments, R 2a is chlorine or CH3. In some embodiments, R 2a It is bromine or CH3.

[0245] In some embodiments of any of Formulas (I), (Ia), and (Ib), R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a For bromine.

[0246] In some embodiments of any of Formulas (I), (Ia), and (Ib), R 2a is a C1-C6 alkyl group. 2a is a C1-C3 alkyl group. 2a For CH3.

[0247] With respect to any of Formulas (I), (Ia), and (Ib), in some embodiments, R 2 and R 2a In some embodiments, R 2 for halogen and R 2a is a C1-C6 alkyl group. 2 is a C1-C6 alkyl group and R 2a In some embodiments, R 2 is -S-C1-C6 alkyl and R 2a In some embodiments, R 2 For -SCH3 and R 2a In some embodiments, R 2 is a C3-C8 cycloalkyl group and R 2a In some embodiments, R 2 is cyclopropyl and R 2a In some embodiments, R 2 is a C2-C6 alkenyl group and R 2a In some embodiments, R 2 is a C2-C6 alkynyl group and R2a In some embodiments, R 2 For ethynyl and R 2a In some embodiments, R 2 and R 2a Each is independently fluorine, chlorine, bromine or iodine. 2 For iodine and R 2a In some embodiments, R 2 for halogen and R 2a is CH3. In some embodiments, R 2 For bromine and R 2a is CH3. In some embodiments, R 2 For iodine and R 2a is CH3. In some embodiments, R 2 For -SCH3 and R 2a In some embodiments, R 2 For ethynyl and R 2a For fluorine.

[0248] In some embodiments, the compound of formula (I) is represented by any one of the following formulae:

[0249]

[0250]

[0251]

[0252] Among them, X 1 、R 2 、R 2a 、R 13 and R 13a As defined in any aspect or embodiment described herein.

[0253] In some embodiments of the above structure having formula (I), X 1 -CR 13b , and R 13b As defined in any aspect or embodiment described herein. In some embodiments of the above structure having formula (I), X 1 is N.

[0254] In some embodiments of the above structure having formula (I), R 2 For iodine and R 2a In some embodiments of the above structure, R 2 For iodine and R 2a In some embodiments of the above structure, R 2 For ethynyl and R2a In some embodiments of the above structure, R 2 For ethynyl and R 2a In some embodiments of the above structure, R 2 For -SCH3 and R 2a In some embodiments of the above structure, R 2 For -SCH3 and R 2a It is a methyl group.

[0255] In some embodiments of the above structure having formula (I), X 1 -CR 13b ; and R 13 、R 13a and R 13b In some embodiments of the above structure having formula (I), X 1 -CR 13b ; R 13 and R 13a are all hydrogen, and R 13b In some embodiments of the above structure having formula (I), X 1 -CR 13b ; R 13 and R 13a are all hydrogen, and R 13b For fluorine.

[0256] In some embodiments of the above structure having formula (I), X 1 It is N; R 13 and R 13a All are hydrogen.

[0257] In some embodiments, the compound used in the method of the present invention is a compound of formula (II).

[0258] Regarding formula (II), in some embodiments, X 2 In some embodiments, X 2 In some embodiments, X 2 is a methyl group, and the compound is represented by formula (IIa):

[0259]

[0260] Among them, R 1 、R 2 、R 2a 、R 23 、R 23a and R 23b As defined in any aspect or embodiment described herein.

[0261] In some embodiments of Formula (II) or (IIa), R 23 、R 23a and R 23b Each is independently hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy.

[0262] In some embodiments of Formula (II) or (IIa), R 23 is hydrogen, halogen or C1-C6 alkyl. 23 In some embodiments, R 23 In some embodiments, R 23 is fluorine, chlorine, bromine or iodine. 23 In some embodiments, R 23 is a C1-C6 alkyl group. 23 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl. 23 It is a methyl group.

[0263] In some embodiments of Formula (II) or (IIa), R 23a is hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy. 23a In some embodiments, R 23a In some embodiments, R 23a is fluorine, chlorine, bromine or iodine. 23a In some embodiments, R 23a is a C1-C6 alkyl group. 23a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl. 23a In some embodiments, R 23a In some embodiments, R 23a is methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy. 23a It is a methoxy group.

[0264] In some embodiments of Formula (II) or (IIa), R 23b is hydrogen, halogen or C1-C6 alkyl. 23b In some embodiments, R 23bIn some embodiments, R 23b is fluorine, chlorine, bromine or iodine. 23b In some embodiments, R 23b is a C1-C6 alkyl group. 23b is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl. 23b It is a methyl group.

[0265] In some embodiments of Formula (II) or (IIa), R 23 、R 23a and R 23b In some embodiments of formula (II) or (IIa), R 23 and R 23b are all hydrogen, and R 23a is halogen, C1-C6 alkyl or C1-C6 alkoxy. In some embodiments of formula (II) or (IIa), R 23 and R 23b are all hydrogen, and R 23a is fluoro, methyl or methoxy.

[0266] With respect to any of Formula (II) or (IIa), in some embodiments, R 1 For-OR 4 、-NR 5 R 5a OR-N(OR 5b )R 5a .

[0267] In some embodiments of Formula (II) or (IIa), R 1 For-OR 4 In some embodiments, R 4 In some embodiments, R 4 is a C1-C6 alkyl group. 4 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and R 6 As defined and described herein. In some embodiments, R 4 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and each R 6 In some embodiments, R 4 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replace, and R6 As defined and described herein. In some embodiments, R 4 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and each R 6 In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl; and each cyclopropyl and cyclobutyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl, each cyclopropyl and cyclobutyl being unsubstituted or substituted by 1-6 R 6 Replaced, each R 6 In some embodiments, R 4 is C1-C6 hydroxyalkyl. 4 In some embodiments, R 4 In some embodiments, R 4 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 4 In some embodiments, R 4 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and R 6 As defined and described herein. In some embodiments, R 4 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and each R 6 In some embodiments, R 4 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 4 is a heterocycloalkyl-C1-C6 alkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with 1-6 R 6 Replace, and each R 6 In some embodiments, R 4In some embodiments, R 4 R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino. 4 R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0268] In some embodiments of Formula (II) or (IIa), R 1 Selected from the group consisting of: -OH,

[0269]

[0270] In some embodiments of Formula (II) or (IIa), R 1 -NR 5 R 5a In some embodiments, R 5 In some embodiments, R 5 is a C1-C6 alkyl group. 5 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and R 6 As defined and described herein. In some embodiments, R 5 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and each R 6 In some embodiments, R 5 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replace, and R 6 As defined and described herein. In some embodiments, R 5 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replace, and each R 6 In some embodiments, R 5is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl; and each cyclopropyl and cyclobutyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl, each cyclopropyl and cyclobutyl being unsubstituted or substituted by 1-6 R 6 substituted, and each R 6 In some embodiments, R 5 is C1-C6 hydroxyalkyl. 5 In some embodiments, R 5 In some embodiments, R 5 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 5 In some embodiments, R 5 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and R 6 As defined and described herein. In some embodiments, R 5 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and each R 6 In some embodiments, R 5 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5 is a heterocycloalkyl-C1-C6 alkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with 1-6 R 6 Replace, and each R 6 In some embodiments, R 5 In some embodiments, R 5 R 7 -C(O)-C1-C6 alkyl; and R 7is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino. 5 R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0271] In some embodiments of Formula (II) or (IIa), R 5 Selected from the group consisting of hydrogen,

[0272]

[0273] In some embodiments of Formula (II) or (IIa), R 1 -N(OR 5b )R 5a In some embodiments, R 5b In some embodiments, R 5b is a C1-C6 alkyl group. 5b is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and R 6 As defined and described herein. In some embodiments, R 5b is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and each R 6 In some embodiments, R 5b is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5b is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replace, and each R 6 In some embodiments, R 5b is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl; and each cyclopropyl and cyclobutyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5b is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl, each cyclopropyl and cyclobutyl being unsubstituted or substituted by 1-6 R6 substituted, and each R 6 In some embodiments, R 5b is C1-C6 hydroxyalkyl. 5b In some embodiments, R 5b In some embodiments, R 5b is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 5b In some embodiments, R 5b is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and R 6 As defined and described herein. In some embodiments, R 5b is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and each R 6 In some embodiments, R 5b is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5b is a heterocycloalkyl-C1-C6 alkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with 1-6 R 6 Replaced, and each R 6 In some embodiments, R 5b In some embodiments, R 5b R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino. 5b R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0274] In some embodiments of Formula (II) or (IIa), R 1 -N(OR 5b )R 5a , and -OR 5b Selected from the group consisting of: -OH,

[0275]

[0276] In some embodiments of Formula (II) or (IIa), R 5a In some embodiments, R 5a is a C1-C6 alkyl group. 5a In some embodiments, R 5a It can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. 5a It is a methyl group.

[0277] With respect to Formula (II) or (IIa), in some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-linked heterocycloalkyl, wherein R 6 As defined and described herein. In some embodiments, the N-attached heterocycloalkyl is an N-attached azetidinyl, an N-attached pyrrolidinyl, an N-attached isoxazolidinyl, an N-attached piperidinyl, or an N-attached morpholinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached azetidinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached pyrrolidinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached isoxazolidinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached piperidinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached morpholinyl. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 A substituted N-attached azetidinyl group wherein R 6 As defined and described herein. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-linked pyrrolidinyl, wherein R 6 As defined and described herein. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-attached piperidinyl, wherein R 6 As defined and described herein. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6Substituted N-linked isoxazolidinyl, wherein R 6 As defined and described herein. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-attached morpholinyl, wherein R 6 As defined and described herein.

[0278] In formula (II) or (IIa), with respect to R 6 , which as one or two substituents of the N-linked heterocycloalkyl group, in some embodiments, each R 6 In some embodiments, each R 6 In some embodiments, each R 6 In some embodiments, each R 6 In some embodiments, one R 6 is a hydroxyl group, and another R 6 It is an amino group.

[0279] In some embodiments of Formula (II) or (IIa), R 1 is an N-linked heterocycloalkyl group which is unsubstituted or substituted with hydroxy, oxo or amino. 1 is an N-linked azetidinyl group which is unsubstituted or substituted with hydroxy, oxo or amino. 1 is an N-linked pyrrolidinyl group that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-piperidinyl group which is unsubstituted or substituted with hydroxy, oxo or amino. 1 is an N-linked isoxazolidinyl group which is unsubstituted or substituted with hydroxy, oxo or amino. 1 is an N-linked morpholinyl group which is unsubstituted or substituted by hydroxy, oxo or amino.

[0280] With respect to Formula (II) or (IIa), in some embodiments, R 2 is halogen, C1-C6 alkyl, -S-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl. 2 is halogen or C1-C6 alkyl. 2 is halogen, -CH3, -SCH3, C2-C3 alkenyl or C2-C3 alkynyl.

[0281] In some embodiments of Formula (II) or (IIa), R 2 In some embodiments, R2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 For bromine.

[0282] In some embodiments of Formula (II) or (IIa), R 2 is a C1-C6 alkyl group. 2 is a C1-C3 alkyl group. 2 It is a methyl group.

[0283] In some embodiments of Formula (II) or (IIa), R 2 In some embodiments, R 2 In some embodiments, R 2 It is -SCH3.

[0284] In some embodiments of Formula (II) or (IIa), R 2 is a C3-C8 cycloalkyl group. 2 It is cyclopropyl.

[0285] In some embodiments of Formula (II) or (IIa), R 2 In some embodiments, R 2 is C2-C4 alkenyl. In some embodiments, R 2 is vinyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl or butadienyl. 2 For vinyl.

[0286] In some embodiments of Formula (II) or (IIa), R 2 is a C2-C6 alkynyl group. 2 is a C2-C3 alkynyl group. 2 In some embodiments, R 2 For ethynyl.

[0287] With respect to Formula (II) or (IIa), in some embodiments, R 2a is halogen or C1-C3 alkyl. 2a is halogen or CH3. In some embodiments, R 2a is fluorine or CH3. In some embodiments, R 2a is iodine or CH3. In some embodiments, R 2ais chlorine or CH3. In some embodiments, R 2a It is bromine or CH3.

[0288] In some embodiments of Formula (II) or (IIa), R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a For bromine.

[0289] In some embodiments of Formula (II) or (IIa), R 2a is a C1-C6 alkyl group. 2a is a C1-C3 alkyl group. 2a For CH3.

[0290] With respect to Formula (II) or (IIa), in some embodiments, R 2 and R 2a In some embodiments, R 2 for halogen and R 2a is a C1-C6 alkyl group. 2 is a C1-C6 alkyl group and R 2a In some embodiments, R 2 is -S-C1-C6 alkyl and R 2a In some embodiments, R 2 For -SCH3 and R 2a In some embodiments, R 2 is a C3-C8 cycloalkyl group and R 2a In some embodiments, R 2 is cyclopropyl and R 2a In some embodiments, R 2 is a C2-C6 alkenyl group and R 2a In some embodiments, R 2 is a C2-C6 alkynyl group and R 2a In some embodiments, R 2 For ethynyl and R 2a In some embodiments, R 2 and R 2a Each is independently fluorine, chlorine, bromine or iodine. 2 For iodine and R 2a In some embodiments, R 2 for halogen and R 2ais CH3. In some embodiments, R 2 For bromine and R 2a is CH3. In some embodiments, R 2 For iodine and R 2a is CH3. In some embodiments, R 2 For -SCH3 and R 2a In some embodiments, R 2 For ethynyl and R 2a For fluorine.

[0291] In some embodiments, the compound of formula (II) or (IIa) is represented by any one of the following formulae:

[0292]

[0293]

[0294] Among them, R 2 、R 2a 、R 23 、R 23a and R 23b As defined in any aspect or embodiment described herein.

[0295] In some embodiments of the above structures having formula (II) or (IIa), R 2 For iodine and R 2a In some embodiments of the above structure, R 2 For iodine and R 2a In some embodiments of the above structure, R 2 For ethynyl and R 2a In some embodiments of the above structure, R 2 For ethynyl and R 2a In some embodiments of the above structure, R 2 For -SCH3 and R 2a In some embodiments of the above structure, R 2 For -SCH3 and R 2a It is a methyl group.

[0296] In some embodiments of the above structures having formula (II) or (IIa), R 23 、R 23a and R 23b In some embodiments of the above structure, R 23 and R 23b are all hydrogen, and R 23a In some embodiments of the above structure, R 23 and R 23bare all hydrogen, and R 23a It is a methoxy group.

[0297] In some embodiments, the compound used in the method of the present invention is a compound of formula (III).

[0298] Regarding formula (III), in some embodiments, X 3 is S, and the compound is represented by formula (IIIa):

[0299]

[0300] Among them, R 2 、R 2a 、R 33 、R 33a and R 33b As defined in any aspect or embodiment described herein.

[0301] In some embodiments of Formula (III), X 3 is O, and the compound is represented by formula (IIIb):

[0302]

[0303] Among them, R 2 、R 2a 、R 33 、R 33 3 a and R 33b As defined in any aspect or embodiment described herein.

[0304] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 33 、R 33a and R 33b Each is independently hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy.

[0305] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 33 is hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy. 33 In some embodiments, R 33 In some embodiments, R 33 is fluorine, chlorine, bromine or iodine. 33 In some embodiments, R 33 is a C1-C6 alkyl group. 33is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl. 33 In some embodiments, R 33 In some embodiments, R 33 is methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy. 33 It is a methoxy group.

[0306] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 33a is hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy. 33a In some embodiments, R 33a In some embodiments, R 33a is fluorine, chlorine, bromine or iodine. 33a In some embodiments, R 33a is a C1-C6 alkyl group. 33a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl. 33a In some embodiments, R 33a In some embodiments, R 33a is methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy. 33a It is a methoxy group.

[0307] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 33b is hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy. 33b In some embodiments, R 33b In some embodiments, R 33b is fluorine, chlorine, bromine or iodine. 33b In some embodiments, R 33b is a C1-C6 alkyl group. 33b is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl. 33bIn some embodiments, R 33b In some embodiments, R 33b is methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy. 33b It is a methoxy group.

[0308] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 33 、R 33a and R 33b In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 33a and R 33b are all hydrogen, and R 33 is halogen, C1-C6 alkyl or C1-C6 alkoxy. In some embodiments of any one of formula (III), (IIIa) and (IIIb), R 33 and R 33b are all hydrogen, and R 33a is fluoro, methyl or methoxy. In some embodiments of any one of formula (III), (IIIa) and (IIIb), R 33 and R 33a are all hydrogen, and R 33b is halogen, C1-C6 alkyl or C1-C6 alkoxy. In some embodiments of any one of formula (III), (IIIa) and (IIIb), R 33a and R 33b are all hydrogen, and R 33 is fluoro, methyl or methoxy. In some embodiments of any one of formula (III), (IIIa) and (IIIb), R 33 and R 33b are all hydrogen, and R 33a is fluoro, methyl or methoxy. In some embodiments of any one of formula (III), (IIIa) and (IIIb), R 33 and R 33a are all hydrogen, and R 33b is fluoro, methyl or methoxy.

[0309] With respect to any of Formulas (III), (IIIa), and (IIIb), in some embodiments, R 1 For-OR 4 、-NR 5 R 5a OR-N(OR 5b )R 5a .

[0310] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 1 For-OR 4 In some embodiments, R 4 In some embodiments, R 4 is a C1-C6 alkyl group. 4 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and R 6 As defined and described herein. In some embodiments, R 4 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and each R 6 In some embodiments, R 4 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 4 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replace, and each R 6 In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl; and each cyclopropyl and cyclobutyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl, each cyclopropyl and cyclobutyl being unsubstituted or substituted by 1-6 R 6 substituted, and each R 6 In some embodiments, R 4 is C1-C6 hydroxyalkyl. 4 In some embodiments, R 4 In some embodiments, R 4 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 4 In some embodiments, R 4is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and R 6 As defined and described herein. In some embodiments, R 4 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and each R 6 In some embodiments, R 4 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 4 is a heterocycloalkyl-C1-C6 alkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with 1-6 R 6 Replace, and each R 6 In some embodiments, R 4 In some embodiments, R 4 R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino. 4 R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0311] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 1 Select the following group: -OH,

[0312]

[0313] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R1 is -NR 5 R 5a In some embodiments, R 5 In some embodiments, R 5 is a C1-C6 alkyl group. 5 is unsubstituted or substituted with 1 to 6 R6 substituted C3-C8 cycloalkyl, and R 6 As defined and described herein. In some embodiments, R 5 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and each R 6 In some embodiments, R 5 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replace, and each R 6 In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl; and each cyclopropyl and cyclobutyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl, each cyclopropyl and cyclobutyl being unsubstituted or substituted by 1-6 R 6 substituted, and each R 6 In some embodiments, R 5 is C1-C6 hydroxyalkyl. 5 In some embodiments, R 5 In some embodiments, R 5 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 5 In some embodiments, R 5 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and R 6 As defined and described herein. In some embodiments, R 5 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and each R 6 In some embodiments, R 5is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5 is a heterocycloalkyl-C1-C6 alkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with 1-6 R 6 Replace, and each R 6 In some embodiments, R 5 In some embodiments, R 5 R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino. 5 R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0314] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 5 Select the following group: Hydrogen,

[0315]

[0316] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R1 is -N(OR 5b )R 5a In some embodiments, R 5b In some embodiments, R 5b is a C1-C6 alkyl group. 5b is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and R 6 As defined and described herein. In some embodiments, R 5b is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and each R 6 In some embodiments, R 5bis C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5b is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and each R 6 In some embodiments, R 5b is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl; each cyclopropyl and cyclobutyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5b is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl, each of cyclopropyl and cyclobutyl is unsubstituted or substituted with 1-6 R 6 Replace, each R 6 In some embodiments, R 5b is C1-C6 hydroxyalkyl. 5b In some embodiments, R 5b In some embodiments, R 5b is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 5b In some embodiments, R 5b is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and R 6 As defined and described herein. In some embodiments, R 5b is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and each R 6 In some embodiments, R 5b is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5b is a heterocycloalkyl-C1-C6 alkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted by 1-6 R 6 Replaced, and each R 6In some embodiments, R 5b In some embodiments, R 5b R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino. 5b R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0317] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 1 -N(OR 5b )R 5a , and -OR 5b Selected from the group consisting of: -OH,

[0318]

[0319] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 5a In some embodiments, R 5a is a C1-C6 alkyl group. 5a In some embodiments, R 5a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. 5a It is a methyl group.

[0320] With respect to any of Formulas (III), (IIIa), and (IIIb), in some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-linked heterocycloalkyl, wherein R 6As defined and described herein. In some embodiments, the N-attached heterocycloalkyl is an N-attached azetidinyl, an N-attached pyrrolidinyl, an N-attached isoxazolidinyl, an N-attached piperidinyl, or an N-attached morpholinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached azetidinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached pyrrolidinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached isoxazolidinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached piperidinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached morpholinyl. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 A substituted N-attached azetidinyl group wherein R 6 As defined and described herein. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-linked pyrrolidinyl, wherein R 6 As defined and described herein. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-attached piperidinyl, wherein R 6 As defined and described herein. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-linked isoxazolidinyl, wherein R 6 As defined and described herein. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-attached morpholinyl, wherein R 6 As defined and described herein.

[0321] In any of formulae (III), (IIIa) and (IIIb), with respect to R 6 As one or two substituents of an N-linked heterocycloalkyl group, in some embodiments, each R 6 In some embodiments, each R 6 In some embodiments, each R 6 In some embodiments, each R 6 In some embodiments, one R 6 is a hydroxyl group, and another R 6 It is an amino group.

[0322] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 1is an N-linked heterocycloalkyl group which is unsubstituted or substituted with hydroxy, oxo or amino. 1 is an N-azetidinyl group which is unsubstituted or substituted with hydroxy, oxo or amino. 1 is an N-linked pyrrolidinyl group that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-piperidinyl group which is unsubstituted or substituted with hydroxy, oxo or amino. 1 is an N-linked isoxazolidinyl group which is unsubstituted or substituted with hydroxy, oxo or amino. 1 is an N-linked morpholinyl group which is unsubstituted or substituted by hydroxy, oxo or amino.

[0323] With respect to any of Formulas (III), (IIIa), and (IIIb), in some embodiments, R 2 is halogen, C1-C6 alkyl, -S-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl. 2 is halogen or C1-C6 alkyl. 2 is halogen, -CH3, -SCH3, C2-C3 alkenyl or C2-C3 alkynyl.

[0324] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 For bromine.

[0325] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 2 is a C1-C6 alkyl group. 2 is a C1-C3 alkyl group. 2 It is a methyl group.

[0326] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 2 In some embodiments, R 2 In some embodiments, R 2 It is -SCH3.

[0327] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 2 is a C3-C8 cycloalkyl group. 2 It is cyclopropyl.

[0328] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 2 In some embodiments, R 2 is C2-C4 alkenyl. In some embodiments, R 2 is vinyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl or butadienyl. 2 For vinyl.

[0329] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 2 is a C2-C6 alkynyl group. 2 is a C2-C3 alkynyl group. 2 In some embodiments, R 2 For ethynyl.

[0330] With respect to any of Formulas (III), (IIIa), and (IIIb), in some embodiments, R 2a is halogen or C1-C3 alkyl. 2a is halogen or CH3. In some embodiments, R 2a is fluorine or CH3. In some embodiments, R 2a is iodine or CH3. In some embodiments, R 2a is chlorine or CH3. In some embodiments, R 2a It is bromine or CH3.

[0331] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a For bromine.

[0332] In some embodiments of any of Formulas (III), (IIIa), and (IIIb), R 2a is a C1-C6 alkyl group. 2ais a C1-C3 alkyl group. 2a For CH3.

[0333] With respect to any of Formulas (III), (IIIa), and (IIIb), in some embodiments, R 2 and R 2a In some embodiments, R 2 for halogen and R 2a is a C1-C6 alkyl group. 2 is a C1-C6 alkyl group and R 2a In some embodiments, R 2 is -S-C1-C6 alkyl and R 2a In some embodiments, R 2 For -SCH3 and R 2a In some embodiments, R 2 is a C3-C8 cycloalkyl group and R 2a In some embodiments, R 2 is cyclopropyl and R 2a In some embodiments, R 2 is a C2-C6 alkenyl group and R 2a In some embodiments, R 2 is a C2-C6 alkynyl group and R 2a In some embodiments, R 2 For ethynyl and R 2a In some embodiments, R 2 and R 2a Each is independently fluorine, chlorine, bromine or iodine. 2 For iodine and R 2a In some embodiments, R 2 for halogen and R 2a In some embodiments, R 2 For bromine and R 2a In some embodiments, R 2 For iodine and R 2a In some embodiments, R 2 For -SCH3 and R 2a In some embodiments, R 2 For ethynyl and R 2a For fluorine.

[0334] In some embodiments, the compound of formula (III) is represented by any one of the following formulae:

[0335]

[0336]

[0337] Among them, X 3 、R 2 、R 2a 、R 33 、R 33a and R 33b As defined in any aspect or embodiment described herein.

[0338] In some embodiments of the above structures having any one of Formulas (III), (IIIa), and (IIIb), R 2 is iodine, and R 2a In some embodiments of the above structure, R 2 For iodine and R 2a In some embodiments of the above structure, R 2 For ethynyl and R 2a In some embodiments of the above structure, R 2 For ethynyl and R 2a In some embodiments of the above structure, R 2 For -SCH3 and R 2a In some embodiments of the above structure, R 2 For -SCH3 and R 2a It is a methyl group.

[0339] In some embodiments of the above structures having any one of Formulas (III), (IIIa), and (IIIb), R 33 、R 33a and R 33b In some embodiments of the above structure, R 33 and R 33b are all hydrogen, and R 33a In some embodiments of the above structure, R 33 and R 33b are all hydrogen, and R 33a In some embodiments of the above structure, R 33 and R 33b are all hydrogen, and R 33a In some embodiments of the above structure, R 33 and R 33a Both hydrogen and R 33b In some embodiments of the above structure, R 33 and R 33a Both hydrogen and R 33b In some embodiments of the above structure, R33a and R 33b Both hydrogen and R 33 It is a methyl group.

[0340] In some embodiments, the compound useful in the methods of the present invention is a compound of formula (IV).

[0341] Regarding Formula (IV), in some embodiments, R 43 Cyano, -C(O)NR 48 R 48a or -C(O)R 46 , and R 43a is hydrogen, halogen or C1-C6 alkyl. 43a In some embodiments, R 43a In some embodiments, R 43a is fluorine, chlorine, bromine or iodine. 43a In some embodiments, R 43a is a C1-C6 alkyl group. 43a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl. 43a It is a methyl group.

[0342] In some embodiments of Formula (IV), R 43 is a cyano group, and the compound is represented by formula (IVa):

[0343]

[0344] Among them, R 1 、R 2 、R 2a and R 43a As defined in any aspect or embodiment described herein.

[0345] In some embodiments of Formula (IVa), R 43a is hydrogen, halogen or C1-C6 alkyl. 43a is hydrogen, halogen or methyl. 43a It is a methyl group.

[0346] Regarding Formula (IV), in some embodiments, R 43 -C(O)NR 48 R 48a , the compound is represented by formula (IVb):

[0347]

[0348] Among them, R 1 、R 2 、R 2a 、R 43a 、R 48 and R 48a As defined in any aspect or embodiment described herein.

[0349] In some embodiments of Formula (IVb), R 43a is hydrogen, halogen or C1-C6 alkyl. 43a is hydrogen, halogen or methyl. 43a It is a methyl group.

[0350] In some embodiments of Formula (IVb), R 48 and R 48a Each is independently hydrogen or C1-C6 alkyl. 48 and R 48a In some embodiments, R 48 and R 48a Each is independently C1-C6 alkyl. In some embodiments, R 48 and R 48a One of them is hydrogen and the other is C1-C6 alkyl.

[0351] In some embodiments of Formula (IV), R 43 is -C(O)NH2, and R 43a It is a methyl group.

[0352] Regarding Formula (IV), in some embodiments, R 43 -C(O)R 46 , the compound is represented by formula (IVc):

[0353]

[0354] Among them, R 1 、R 2 、R 2a 、R 43a and R 43 As defined in any aspect or embodiment described herein.

[0355] In some embodiments of Formula (IVc), R 43a is hydrogen, halogen or C1-C6 alkyl. 43a is hydrogen, halogen or methyl. 43a It is a methyl group.

[0356] In some embodiments of Formula (IVc), R46 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. 46 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl, wherein the haloalkyl is an alkyl substituted by 1, 2 or 3 fluorine groups.

[0357] In some embodiments of Formula (IVc), R 46 In some embodiments of formula (IVc), R 46 is a C1-C6 alkyl group. 46 is a C1-C4 alkyl group. 6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0358] In some embodiments of Formula (IVc), R 46 is a C1-C6 haloalkyl group, wherein the haloalkyl group is an alkyl group substituted with 1, 2 or 3 fluorine groups. 46 is a C1-C4 haloalkyl group, wherein the C1-C4 haloalkyl group is a C1-C4 alkyl group substituted with 1, 2 or 3 fluorine groups. 46 is trifluoromethyl, fluoromethyl or 2,2,2-trifluoroethyl.

[0359] In some embodiments of Formula (IVc), R 46 is a C3-C8 cycloalkyl or heterocycloalkyl group. 46 is a C3-C8 cycloalkyl group. 46 In some embodiments, R 6 In some embodiments, R 46 is a 3-8 membered heterocycloalkyl group having 1-3 N, O or S heteroatoms. 46 is a 3-6 membered heterocycloalkyl group having 1-2 N or O heteroatoms. 46 is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, isoxazolidinyl or morpholinyl.

[0360] Returning to Formula (IV), in some embodiments, R 43 and R 43a Together form -CH2CH2C(O)- or -CH2CH2CH2C(O)-, each of which is unsubstituted or substituted by one or two R 49 In some embodiments, R 43 and R 43aTogether they form -CH2CH2C(O)- or -CH2CH2CH2C(O)-.

[0361] In some embodiments of formula (IV), the compound is represented by formula (IVd-1) or (IVd-2):

[0362]

[0363] Among them, R 1 、R 2 、R 2a and R 49 As defined in any aspect or embodiment described herein.

[0364] In some embodiments of formula (IV), the compound is represented by formula (IVe-1) or (IVe-2):

[0365]

[0366] Among them, R 1 、R 2 、R 2a and R 49 As defined in any aspect or embodiment described herein.

[0367] In some embodiments of any of Formulas (IVd-1), (IVd-2), (IVe-1), and (IVe-2), each R 49 are independently C1-C6 alkyl. In some embodiments of formula (IVd-1), (IVd-2), (IVe-1) or (IVe-2), R 49 Does not exist.

[0368] With respect to any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), in some embodiments, R 1 For-OR 4 、-NR 5 R 5a OR-N(OR 5b )R 5a .

[0369] In some embodiments of any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 1 For-OR 4 In some embodiments, R 4 In some embodiments, R 4is a C1-C6 alkyl group. 4 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and R 6 As defined and described herein. In some embodiments, R 4 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and each R 6 In some embodiments, R 4 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 4 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replace, and each R 6 In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl; and each cyclopropyl and cyclobutyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl, each cyclopropyl and cyclobutyl being unsubstituted or substituted by 1-6 R 6 substituted, and each R 6 In some embodiments, R 4 is C1-C6 hydroxyalkyl. 4 In some embodiments, R 4 In some embodiments, R 4 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 4 In some embodiments, R 4 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and R 6 As defined and described herein. In some embodiments, R 4 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and each R 6In some embodiments, R 4 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 4 is a heterocycloalkyl-C1-C6 alkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with 1-6 R 6 Replace, and each R 6 In some embodiments, R 4 In some embodiments, R 4 R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino. 4 R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0370] In some embodiments of any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 1 Selected from the group consisting of: -OH,

[0371]

[0372] In some embodiments of any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 1 -NR 5 R 5a In some embodiments, R 5 In some embodiments, R 5 is a C1-C6 alkyl group. 5 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and R 6As defined and described herein. In some embodiments, R 5 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and each R 6 In some embodiments, R 5 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replace, and R 6 As defined and described herein. In some embodiments, R 5 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and each R 6 In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl; and each cyclopropyl and cyclobutyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl, each cyclopropyl and cyclobutyl being unsubstituted or substituted by 1-6 R 6 Replaced, each R 6 In some embodiments, R 5 is C1-C6 hydroxyalkyl. 5 In some embodiments, R 5 In some embodiments, R 5 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 5 In some embodiments, R 5 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and R 6 As defined and described herein. In some embodiments, R 5 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and each R 6 In some embodiments, R 5 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl is unsubstituted or substituted by 1-6 R 6Replaced, and R 6 As defined and described herein. In some embodiments, R 5 is a heterocycloalkyl-C1-C6 alkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with 1-6 R 6 Replace, and each R 6 In some embodiments, R 5 In some embodiments, R 5 R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino. 5 R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0373] In some embodiments of any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 1 -NR 5 R 5a , and R 5 Selected from the group consisting of hydrogen,

[0374]

[0375]

[0376] In some embodiments of any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 1 -N(OR 5b )R 5a In some embodiments, R 5b In some embodiments, R 5b is a C1-C6 alkyl group. 5b is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and R 6As defined and described herein. In some embodiments, R 5b is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and each R 6 In some embodiments, R 5b is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replace, and R 6 As defined and described herein. In some embodiments, R 5b is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and each R 6 In some embodiments, R 5b is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl; and each cyclopropyl and cyclobutyl is unsubstituted or replaced by 1-6 R 6 Replace, and R 6 As defined and described herein. In some embodiments, R 5b is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl, each cyclopropyl and cyclobutyl being unsubstituted or substituted by 1-6 R 6 Replace, each R 6 In some embodiments, R 5b is C1-C6 hydroxyalkyl. 5b In some embodiments, R 5b In some embodiments, R 5b is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 5b In some embodiments, R 5b is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and R 6 As defined and described herein. In some embodiments, R 5b is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and each R 6 In some embodiments, R 5b is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R6 As defined and described herein. In some embodiments, R 5b is a heterocycloalkyl-C1-C6 alkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with 1-6 R 6 Replace, and each R 6 In some embodiments, R 5b In some embodiments, R 5b R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino. 5b R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0377] In some embodiments of any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 1 -N(OR 5b )R 5a , and-OR 5b Selected from the group consisting of: -OH,

[0378]

[0379]

[0380] In some embodiments of any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 5a In some embodiments, R 5a is a C1-C6 alkyl group. 5a In some embodiments, R 5a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. 5a It is a methyl group.

[0381] With respect to any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), in some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-linked heterocycloalkyl, wherein R 6 As defined and described herein. In some embodiments, the N-attached heterocycloalkyl is an N-attached azetidinyl, an N-attached pyrrolidinyl, an N-attached isoxazolidinyl, an N-attached piperidinyl, or an N-attached morpholinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached azetidinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached pyrrolidinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached isoxazolidinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached piperidinyl. In some embodiments, the N-attached heterocycloalkyl is an N-attached morpholinyl. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 A substituted N-attached azetidinyl group wherein R 6 As defined and described herein. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-linked pyrrolidinyl, wherein R 6 As defined and described herein. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-attached piperidinyl, wherein R 6 As defined and described herein. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-linked isoxazolidinyl, wherein R 6 As defined and described herein. In some embodiments, R 1 is unsubstituted or replaced by one or two R 6 Substituted N-attached morpholinyl, wherein R 6 As defined and described herein.

[0382] In any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1) and (IVe-2), with respect to R 6 , which as one or two substituents of the N-linked heterocycloalkyl group, in some embodiments, each R 6 In some embodiments, each R 6In some embodiments, each R 6 In some embodiments, each R 6 In some embodiments, one R 6 is a hydroxyl group, and another R 6 It is an amino group.

[0383] In some embodiments of any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 1 is an N-linked heterocycloalkyl group which is unsubstituted or substituted with hydroxy, oxo or amino. 1 is an N-linked azetidinyl group which is unsubstituted or substituted with hydroxy, oxo or amino. 1 is an N-linked pyrrolidinyl group that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-piperidinyl group which is unsubstituted or substituted with hydroxy, oxo or amino. 1 is an N-linked isoxazolidinyl group which is unsubstituted or substituted with hydroxy, oxo or amino. 1 is an N-linked morpholinyl group which is unsubstituted or substituted by hydroxy, oxo or amino.

[0384] With respect to any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), in some embodiments, R 2 is halogen, C1-C6 alkyl, -S-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl. 2 is halogen or C1-C6 alkyl. 2 R 2 Halogen, -CH 3 , -SCH3, C2-C3 alkenyl or C2-C3 alkynyl.

[0385] In some embodiments of any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 For bromine.

[0386] In some embodiments of any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 2 is a C1-C6 alkyl group. 2 is a C1-C3 alkyl group. 2 It is a methyl group.

[0387] In some embodiments of any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 2 In some embodiments, R 2 In some embodiments, R 2 It is -SCH3.

[0388] In some embodiments of any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 2 is a C3-C8 cycloalkyl group. 2 It is cyclopropyl.

[0389] In some embodiments of any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 2 In some embodiments, R 2 is C2-C4 alkenyl. In some embodiments, R 2 is vinyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl or butadienyl. 2 For vinyl.

[0390] In some embodiments of any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 2 is a C2-C6 alkynyl group. 2 is a C2-C3 alkynyl group. 2 In some embodiments, R 2 For ethynyl.

[0391] With respect to any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), in some embodiments, R 2a is halogen or C1-C3 alkyl. 2a is halogen or CH3. In some embodiments, R 2a is fluorine or CH3. In some embodiments, R 2a is iodine or CH3. In some embodiments, R 2a is chlorine or CH3. In some embodiments, R 2a It is bromine or CH3.

[0392] In some embodiments of any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a For bromine.

[0393] In some embodiments of any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 2a is a C1-C6 alkyl group. 2a is a C1-C3 alkyl group. 2a For CH3.

[0394] With respect to any of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), in some embodiments, R 2 and R 2a In some embodiments, R 2 for halogen and R 2a is a C1-C6 alkyl group. 2 is a C1-C6 alkyl group and R 2a In some embodiments, R 2 is -S-C1-C6 alkyl and R 2a In some embodiments, R 2 For -SCH3 and R 2a In some embodiments, R 2is a C3-C8 cycloalkyl group and R 2a In some embodiments, R 2 is cyclopropyl and R 2a In some embodiments, R 2 is a C2-C6 alkenyl group and R 2a In some embodiments, R 2 is a C2-C6 alkynyl group and R 2a In some embodiments, R 2 For ethynyl and R 2a In some embodiments, R 2 and R 2a Each is independently fluorine, chlorine, bromine or iodine. 2 For iodine and R 2a In some embodiments, R 2 for halogen and R 2a is CH3. In some embodiments, R 2 For bromine and R 2a is CH3. In some embodiments, R 2 For iodine and R 2a is CH3. In some embodiments, R 2 For -SCH3 and R 2a In some embodiments, R 2 For ethynyl and R 2a For fluorine.

[0395] In some embodiments, the compound of formula (IV) is represented by any one of the following formulae:

[0396]

[0397]

[0398] Among them, R 2 、R 2a 、R 43 and R 43a As defined in any aspect or embodiment described herein.

[0399] In some embodiments of the above structure having formula (I), R 2 For iodine and R 2a In some embodiments of the above structure, R 2 For iodine and R 2a In some embodiments of the above structure, R 2 For ethynyl and R 2a In some embodiments of the above structure, R 2 For ethynyl and R2a In some embodiments of the above structure, R 2 For -SCH3 and R 2a In some embodiments of the above structure, R 2 For -SCH3 and R 2a It is a methyl group.

[0400] In some embodiments of the above structure having formula (IV), R 43 Cyano, -C(O)NR 48 R 48a or -C(O)R 46 , and R 43a is a C1-C6 alkyl group. In some embodiments of the above structure, R 43 For cyano and R 43a In some embodiments of the above structure, R 43 -C(O)NR 48 R 48a ; R 48 and R 48a All are hydrogen; R 43a In some embodiments of the above structure, R 43 -C(O)R 46 ; R 46 is a C1-C4 alkyl group; R 43a is a C1-C4 alkyl group. In some embodiments of the above structure, R 43 -C(O)R 46 ; R 46 is a C1-C4 alkyl group; R 43a In some embodiments of the above structure, R 43 and R 43a Together they form -CH2CH2C(O)- or

[0401] -CH2CH2CH2C(O)-.

[0402] In some embodiments, the compound useful in the methods of the present invention is a compound of formula (V).

[0403] With respect to Formula (V), in some embodiments, bond "a" is a double bond, and the compound is represented by Formula (Va):

[0404]

[0405] Among them, subscripts n, R 2 、R 2a 、R 51 、R 53 、R 53a and R 53bAs defined in any aspect or embodiment described herein.

[0406] In some embodiments of Formula (V), bond "a" is a single bond, and the compound is represented by Formula (Vb):

[0407]

[0408] Among them, subscripts n, R 2 、R 2a 、R 51 、R 53 、R 53a and R 53b As defined in any aspect or embodiment described herein.

[0409] In some embodiments of any of Formulas (V), (Va), and (Vb), R 53 Each is independently halogen or C1-C3 alkyl. 53 Each R is independently fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl or isopropyl. 53 It is a methyl group.

[0410] In some embodiments of any one of formulae (V), (Va), and (Vb), subscript n is 0 or 1. In some embodiments, subscript n is 0, and the compound is represented by formula (Va-1) or (Vb-1):

[0411]

[0412] Among them, R 2 、R 2a 、R 51 、R 53a and R 53b As defined in any aspect or embodiment described herein.

[0413] With respect to any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), R 53a and R 53b Each is independently hydrogen, halogen or C1-C6 alkyl.

[0414] In some embodiments of any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), R 53a is hydrogen, halogen or C1-C6 alkyl. 53a In some embodiments, R 53a In some embodiments, R 53a is fluorine, chlorine, bromine or iodine.53a In some embodiments, R 53a is a C1-C6 alkyl group. 53a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl. 53a It is a methyl group.

[0415] In some embodiments of any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), R 53b is hydrogen, halogen or C1-C6 alkyl. 53b In some embodiments, R 53b In some embodiments, R 53b is fluorine, chlorine, bromine or iodine. 53b In some embodiments, R 53b is a C1-C6 alkyl group. 53b It can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl. In some embodiments, R 53b It is a methyl group.

[0416] In some embodiments of any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), R 53a and R 53b In some embodiments, R 53a For hydrogen and R 53b In some embodiments, R 53a For hydrogen and R 53b For fluorine.

[0417] With reference to any one of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), in some embodiments, R 51 is a C1-C6 alkyl group. 5 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and R 6 As defined and described herein. In some embodiments, R 51 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and each R 6 In some embodiments, R 51 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6Replaced, and R 6 As defined and described herein. In some embodiments, R 51 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and each R 6 In some embodiments, R 51 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl; and each cyclopropyl and cyclobutyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 51 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl, each cyclopropyl and cyclobutyl being unsubstituted or substituted by 1-6 R 6 Replaced, each R 6 In some embodiments, R 51 is C1-C6 hydroxyalkyl. 51 In some embodiments, R 51 In some embodiments, R 51 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 51 In some embodiments, R 51 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and R 6 As defined and described herein. In some embodiments, R 51 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and each R 6 In some embodiments, R 5 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 51 is a heterocycloalkyl-C1-C6 alkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with 1-6 R 6 Replace, and each R 6 In some embodiments, R 51In some embodiments, R 51 R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino. 51 R 7 -C(O)-C1-C6 alkyl; R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0418] In some embodiments of any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), R 51 Selected from the group consisting of hydrogen,

[0419]

[0420] In some embodiments of any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), R 51 OR 54 In some embodiments, R 54 In some embodiments, R 54 is a C1-C6 alkyl group. 54 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and R 6 As defined and described herein. In some embodiments, R 54 is unsubstituted or substituted with 1-6 R 6 substituted C3-C8 cycloalkyl, and each R 6 In some embodiments, R 54 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 54 is C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and each R 6 In some embodiments, R 54is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl; and each cyclopropyl and cyclobutyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl or cyclobutyl-C1-C6 alkyl, each cyclopropyl and cyclobutyl being unsubstituted or substituted by 1-6 R 6 Replaced, each R 6 In some embodiments, R 54 is C1-C6 hydroxyalkyl. 54 In some embodiments, R 54 In some embodiments, R 54 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 54 In some embodiments, R 54 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and R 6 As defined and described herein. In some embodiments, R 54 is unsubstituted or substituted with 1-6 R 6 substituted heterocycloalkyl, and each R 6 In some embodiments, R 54 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 As defined and described herein. In some embodiments, R 54 is a heterocycloalkyl-C1-C6 alkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with 1-6 R 6 Replace, and each R 6 In some embodiments, R 54 In some embodiments, R 54 R 7 -C(O)-C1-C6 alkyl; and R 7is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino. 54 R 7 -C(O)-C1-C6 alkyl; and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0421] In some embodiments of any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), R 51 Selected from the group consisting of: -OH,

[0422]

[0423] With respect to any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), in some embodiments, R 2 is halogen, C1-C6 alkyl, -S-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl. 2 is halogen or C1-C6 alkyl. 2 is halogen, -SCH3, C2-C3 alkenyl or C2-C3 alkynyl.

[0424] In some embodiments of any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 For bromine.

[0425] In some embodiments of any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), R 2 is a C1-C6 alkyl group. 2 is a C1-C3 alkyl group. 2 It is a methyl group.

[0426] In some embodiments of any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), R 2 In some embodiments, R 2 In some embodiments, R 2 It is -SCH3.

[0427] In some embodiments of any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), R 2 is a C3-C8 cycloalkyl group. 2 It is cyclopropyl.

[0428] In some embodiments of any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), R 2 In some embodiments, R 2 is C2-C4 alkenyl. In some embodiments, R 2 is vinyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl or butadienyl. 2 For vinyl.

[0429] In some embodiments of any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), R 2 is a C2-C6 alkynyl group. 2 is a C2-C3 alkynyl group. 2 In some embodiments, R 2 For ethynyl.

[0430] With respect to any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), in some embodiments, R 2a is halogen or C1-C3 alkyl. 2a is halogen or CH3. In some embodiments, R 2a is fluorine or CH3. In some embodiments, R 2a is iodine or CH3. In some embodiments, R 2a is chlorine or CH3. In some embodiments, R 2a It is bromine or CH3.

[0431] In some embodiments of any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a For bromine.

[0432] In some embodiments of any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), R 2a is a C1-C6 alkyl group. 2a is a C1-C3 alkyl group. 2a For CH3.

[0433] With respect to any of Formulas (V), (Va), (Vb), (Va-1), and (Vb-1), in some embodiments, R 2 and R 2a In some embodiments, R 2 for halogen and R 2a is a C1-C6 alkyl group. 2 is a C1-C6 alkyl group and R 2a In some embodiments, R 2 is -S-C1-C6 alkyl and R 2a In some embodiments, R 2 For -SCH3 and R 2a In some embodiments, R 2 is a C3-C8 cycloalkyl group and R 2a In some embodiments, R 2 is cyclopropyl and R 2a In some embodiments, R 2 is a C2-C6 alkenyl group and R 2a In some embodiments, R 2 is a C2-C6 alkynyl group and R 2a In some embodiments, R 2 For ethynyl and R 2a In some embodiments, R 2 and R 2a Each is independently fluorine, chlorine, bromine or iodine. 2 For iodine and R 2a In some embodiments, R 2 for halogen and R 2a is CH3. In some embodiments, R 2 For bromine and R 2a is CH3. In some embodiments, R 2 For iodine and R 2a is CH3. In some embodiments, R 2 For -SCH3 and R 2a In some embodiments, R 2 For ethynyl and R 2aIn some embodiments, the compound of formula (V) is represented by any one of the following formulae:

[0434]

[0435]

[0436] Among them, the key "a", R 2 、R 2a 、R 53a and R 53b As defined in any aspect or embodiment described herein.

[0437] In some embodiments of the above structure having formula (V), bond "a" is a double bond. In some embodiments of the above structure having formula (V), bond "a" is a single bond.

[0438] In some embodiments of the above structure having Formula (V), R 2 For iodine and R 2a In some embodiments of the above structure, R 2 For iodine and R 2a In some embodiments of the above structure, R 2 For ethynyl and R 2a In some embodiments of the above structure, R 2 For ethynyl and R 2a In some embodiments of the above structure, R 2 For -SCH3 and R 2a In some embodiments of the above structure, R 2 For -SCH3 and R 2a It is a methyl group.

[0439] In some embodiments of the above structure having Formula (V), R 53a and R 53b In some embodiments of the above structure, R 53a For hydrogen and R 53b In some embodiments of the above structure, R 53a For hydrogen and R 53b For fluorine.

[0440] Tables 1-5 list exemplary compounds having any of Formula (I), (II), (III), (IV), and (V).

[0441] Table 1: Compounds of formula (I)

[0442]

[0443]

[0444]

[0445]

[0446]

[0447] Table 2: Compounds of formula (II)

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454] Table 3: Compounds of formula (II)

[0455]

[0456]

[0457]

[0458] Table 4: Compounds of formula (IV)

[0459]

[0460]

[0461]

[0462]

[0463] Table 5: Compounds of formula (V)

[0464]

[0465]

[0466] The compounds of the present invention may exist in the form of salts. The present invention includes such salts. Examples of applicable salt forms include: hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof, including racemic mixtures, succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art. Also included are base addition salts such as sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts may be obtained by contacting the neutral forms of these compounds with a sufficient amount of the desired acid, which may be solvent-free or in a suitable inert atmosphere. The invention relates to a kind of aqueous solution of the present invention, wherein the aqueous solution of the present invention is ...

[0467] Other salts include acid salts or basic salts of the compound for the method of the present invention. Illustrative examples of pharmaceutically acceptable salts include inorganic acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts and quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It should be understood that pharmaceutically acceptable salts are nontoxic. Other information about suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences (17th edition, Mack Publishing Company, Easton, Pennsylvania, 1985), which is incorporated herein by reference.

[0468] Pharmaceutically acceptable salts include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents present on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of these compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino acid salts, magnesium salts, or the like. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral forms of these compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginine, and organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups, allowing the compounds to be converted into base or acid addition salts.

[0469] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0470] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are included within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous forms. Generally, all physical forms are equivalent for the purposes contemplated by the present invention and are intended to be within the scope of the present invention.

[0471] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)- or, as for amino acids, (D)- or (L)-, and individual isomers are within the scope of the present invention. The compounds of the present invention do not include compounds known in the art that are too unstable to synthesize and / or separate. The present invention is intended to include racemic and optically pure forms of the compounds. Optically active (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0472] Isomers include compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ in the structural arrangement or configuration of the atoms.

[0473] It will be apparent to those skilled in the art that certain compounds of the present invention may exist as tautomers, and all such tautomeric forms of the compounds are within the scope of the present invention. A tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0474] Unless otherwise indicated, structures depicted herein are also meant to include all stereochemical forms of the structures; i.e., R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

[0475] Unless otherwise indicated, the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute these compounds. For example, the compounds of the present invention may be labeled with radioactive or stable isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), fluorine-18( 18 F), nitrogen-15 ( 15 N), oxygen-17 ( 17 O), oxygen-18 ( 18 O), carbon-13 ( 13 C) or carbon-14 ( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0476] In addition to salt forms, the present invention provides compounds that exist in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted into the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when the prodrug is placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, the prodrug will slowly convert into the compounds of the present invention.

[0477] The compounds of this application are designed for topical, subcutaneous, intradermal or intralesional application, resulting in inhibition of MEK activity in the dermis and epidermis (or within the birthmark) to treat birthmarks. After treating the birthmark, in some embodiments, the compound is designed to be metabolically unstable so as to limit the systemic toxicity after topical, subcutaneous, transdermal, intradermal, or intralesional application by limiting the amount of time the compound remains in the peripheral circulation. The application provides a solution for treating birthmarks with a compound that exhibits the ability to penetrate the skin and inhibit ERK phosphokinase.

[0478] V. Composition

[0479] The present invention provides a pharmaceutical composition comprising a compound having any one of formulae (I) to (V) and a pharmaceutically acceptable carrier for use in a method of treating skin cancer, as defined and described herein.

[0480] The compounds provided herein can be formulated into pharmaceutical compositions using methods available in the art and disclosed herein. Any compound disclosed herein can be provided in an appropriate pharmaceutical composition and administered by an appropriate route of administration.

[0481] Administration of the compounds described herein to a subject can be local or non-systemic, e.g., topical, subcutaneous, intradermal, or intralesional. In some embodiments, the compound can be administered by topical administration. In some embodiments, the compound can be administered by intradermal administration. In some embodiments, the compound can be administered by intralesional administration (e.g., by intralesional injection).

[0482] The methods provided herein include administering to a patient in need thereof a pharmaceutical composition containing at least one compound as described herein, including a compound of any one of Formulae (I) to (V) (if appropriate in salt form), alone or in combination with one or more compatible and pharmaceutically acceptable carriers (e.g., diluents or adjuvants), or in combination with another agent for treating skin cancer (e.g., MEK inhibitor-responsive or MEK-mediated skin cancer).

[0483] In some embodiments, the second agent can be formulated or packaged together with the compound provided herein. Of course, the second agent will be formulated with the compound provided herein only when, according to the judgment of one skilled in the art, such a co-formulation should not interfere with the activity or administration method of either formulation. In some embodiments, the compound provided herein and the second agent are formulated separately. For the convenience of practitioners in this field, they can be packaged together or individually packaged.

[0484] In clinical practice, the active agents provided herein can be administered by any conventional route, particularly topical, subcutaneous, intradermal, or intralesional administration. In some embodiments, the compounds provided herein are administered topically. In some embodiments, the compounds provided herein are administered subcutaneously. In some embodiments, the compounds provided herein are administered intradermally. In some embodiments, the compounds provided herein are administered intralesional.

[0485] As the composition of topical application, paste, lotion, tincture, emulsion, spray, ointment, cream or gel can be used.In alternative embodiments, topical administration can be realized with the patch form comprising activating agent, wherein the patch contacts the affected area on the skin.In a further embodiment, topical administration can be realized with the form of a liquid lotion, wherein the liquid lotion is dried on the skin after being applied to the affected area.In some such embodiments, the composition can include a skin penetrant so that the activating agent penetrates the epidermis and is delivered transdermally.In a further embodiment, the composition is formulated for intradermal injection.In an alternative embodiment, the composition is formulated for intralesional injection.

[0486] As the composition of topical application, paste, lotion, tincture, emulsion, spray, ointment, cream or gel can be used. In these compositions, active product is mixed with one or more inert excipients, and the excipient includes: water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil and its mixture. Topical composition (for example, gel, cream, ointment, lotion) can include pharmaceutically acceptable polymer. Cream and ointment can include paraffin base. For the active agent of transdermal delivery, topical composition can further include skin penetration enhancer (for example, DMSO, pyrrolidone). Skin emollient (for example glycerol, cocoa butter) can be present in the composition comprising the compound with any one of formula (I) to (V) described herein.

[0487] The composition that is used for local, subcutaneous, intradermal or focus administration can be emulsion or sterile solution.As solvent or solvent, propylene glycol, polyethylene glycol, vegetable oil, particularly olive oil, or injectable organic ester can be used, in some embodiments, ethyl oleate.These compositions can also contain auxiliary agent, particularly wetting agent, isotonic agent, emulsifying agent, dispersant and stabilizing agent.In some embodiments, sterilization can be carried out by several modes, uses bacterial filter, by radiation or by heating.They can also be prepared with the form of sterile solid composition, and described sterile solid composition can be dissolved in sterile water or any other injectable sterile medium when using.

[0488] Compositions for rectal administration are suppositories or rectal capsules containing, in addition to the active ingredient, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

[0489] The composition can also be in the form of an aerosol that can be sprayed on the affected area. For use in the form of a liquid aerosol, the composition can be a stable sterile solution or a solid composition that is dissolved in unheated sterile water, saline or any other pharmaceutically acceptable carrier at the time of use. For use in the form of a dry aerosol intended for direct inhalation, the active ingredient is finely divided and combined with a water-soluble solid (in some embodiments, dextran, mannitol or lactose) diluent or carrier.

[0490] In some embodiments, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein comprise an effective amount, one or more preventive or therapeutic agents (e.g., compounds provided herein or other preventive or therapeutic agents) of a preventive or therapeutically effective amount, and typical one or more pharmaceutically acceptable carriers or excipients. In a specific embodiment and in this context, the term "pharmaceutically acceptable" refers to a pharmaceutical composition approved by a regulatory agency of a federal or state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, more specifically for humans. The term "carrier" includes diluents, adjuvants (e.g., Freund's adjuvant (complete and incomplete)), excipients, or administration vehicles. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including oils of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. When the pharmaceutical composition is administered intravenously, water can be used as a carrier. Saline solutions, as well as aqueous glucose solutions and glycerol solutions can also be used as liquid carriers, particularly for injection solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy, 22nd ed. (September 15, 2012).

[0491] Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and in some embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerine, propylene glycol, water, ethanol etc. Whether specific excipients are suitable for being incorporated into pharmaceutical compositions or dosage forms depends on multiple factors well known in the art, includes but is not limited to the specific active ingredient in the mode and dosage form of the object being administered to the dosage form. If desired, compositions or single unit dosage form can also contain a small amount of wetting agent or emulsifying agent, or pH buffer.

[0492] The lactose-free compositions provided herein can include excipients known in the art and, in some embodiments, listed in the United States Pharmacopoeia (USP 36-NF 31S2). Typically, the lactose-free compositions include an active ingredient, a binder / filler, and a pharmaceutically acceptable amount of a lubricant. Exemplary lactose-free dosage forms include an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0493] Also encompassed herein are anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, as water can promote the degradation of certain compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical field as a method for simulating long-term storage to determine properties such as the shelf life or stability of a formulation over time. See, for example, Jens T. Carstensen, Pharmaceutical Stability: Principles and Practice, 2nd ed., Marcel Dekker, New York, 1995, pp. 379-80. In fact, water and heat accelerate the decomposition of certain compounds. Therefore, the effect of water on formulations is very important because moisture and / or humidity are commonly encountered during the manufacture, handling, packaging, storage, shipment, and use of formulations.

[0494] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine can be anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected.

[0495] Anhydrous pharmaceutical compositions should be prepared and stored to maintain their anhydrous nature. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water so that they can be included in suitable formulation packages. In some embodiments, suitable packaging includes, but is not limited to, hermetically sealed foils, plastics, unit dose containers (such as bottles), blister packs, and strip packs.

[0496] Also provided are pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate at which the active ingredient decomposes. Such compounds, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0497] The pharmaceutical composition can be a solution, a suspension, an emulsion, a gel, a cream, an ointment or an aerosol formulation. In some embodiments, the composition is immersed in a suitable matrix to form a patch. In some embodiments, the composition is a sustained release formulation. Preparation should be adapted to mode of administration (such as topical administration, subcutaneous administration, intradermal administration or intralesional administration). In some embodiments, pharmaceutical composition or independent unit dosage form are sterile, and are administered to object in a suitable form, in some embodiments, animal subject (such as mammalian subject), in certain embodiments, is people.

[0498] A pharmaceutical composition is formulated to be compatible with its intended route of administration. In some embodiments, the route of administration includes but is not limited to parenteral administration, such as intradermal, subcutaneous, intramuscular, inhalation, intranasal, intrasynovial, rectal, local, intralesional and mucosal administration. In some embodiments, the route of administration is subcutaneous administration, intradermal administration, topical administration or intralesional administration. In some embodiments, the route of administration is non-systemic administration. In a specific embodiment, the composition is formulated as a pharmaceutical composition suitable for subcutaneous or topical administration to people according to a conventional method. In some embodiments, the pharmaceutical composition is formulated as for intradermal or intralesional administration to people according to a conventional method. Typically, the composition for injection (such as, intradermal or subcutaneous injection) is a solution, emulsion, suspension in a sterile isotonic aqueous buffer. If necessary, the composition may also include a solubilizing agent and a local anesthetic (such as lidocaine) to relieve pain at the injection site.

[0499] In some embodiments, dosage forms include, but are not limited to, ointments; poultices; pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays, inhalers, or skin sprays); gels; liquid dosage forms suitable for administration to the skin of a subject, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and lotions; liquid dosage forms suitable for administration to the mucosal membranes of a subject, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral (e.g., subcutaneous or intradermal) administration to a subject; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject.

[0500] The composition, shape and type of the dosage forms provided herein generally vary according to their use. In some embodiments, the dosage form for the initial treatment of skin cancer (such as MEK inhibitor responsiveness or MEK-mediated skin cancer) can contain a larger amount of one or more active ingredients contained therein than the dosage form for maintaining the treatment of the same disease or disease. Similarly, compared with the topical form for treating the same disease or disease, the parenteral (intradermal) dosage form can contain a smaller amount of one or more active ingredients contained therein. These and other ways of the specific dosage forms encompassed herein are different from each other, which are apparent to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0501] Typically, the components of the composition are supplied separately or mixed together in unit dosage form, and in some embodiments, are provided as a lyophilized powder or anhydrous concentrate dried in a hermetically sealed container (such as an ampoule or sachet) indicating the active dose. When the composition is to be administered by infusion, it can be dispensed with an infusion bottle filled with sterile pharmaceutical grade water or saline. In the case of a composition to be administered by injection, an ampoule of sterile water for injection or normal saline can be provided so that the components can be mixed before administration.

[0502] Typical dosage forms include a compound provided herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in the range of about 0.1 mg to about 1000 mg per day, administered in a single dose once daily in the morning, or in divided doses taken throughout the day with food. Specific dosage forms can have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500, or 1000 mg of active compound.

[0503] In some cases, compositions described herein include lubricants. The lubricants that can be used for pharmaceutical compositions and dosage forms include but are not limited to calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (such as peanut oil, cottonseed oil, sunflower seed oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and their mixture. In some embodiments, other lubricants include micropowder (syloid) silica gel (AEROSIL 200, manufactured by WR Grace, Baltimore, Maryland), the solidified aerosol of synthetic silica (sold by Degussa, Plano, Texas), CAB O SIL (the pyrolytic silica product sold by Cabot, Boston, Massachusetts), and their mixture. If all used, lubricants are usually used with an amount of about 1% by weight less than the pharmaceutical composition or dosage form they incorporate.

[0504] Delayed-release dosage form

[0505] Active ingredients, such as the compounds provided herein, can be administered by controlled release means or delivery devices known to those of ordinary skill in the art. In some embodiments, but not limited to those described in the following U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891 ,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500; each of which is incorporated herein by reference in its entirety. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients, and in some embodiments, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof are used to provide a desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein and can be used in, for example, a bandage or patch. Thus, included herein are individual unit dosage forms suitable for skin administration, such as, but not limited to, gels, ointments, patches, creams, lesion dressings, and the like, suitable for controlled release.

[0506] All controlled-release pharmaceutical products have a common goal, namely to improve drug therapy relative to their corresponding non-controlled-release drugs. Ideally, the use of an optimally designed controlled-release formulation in medical treatment is characterized by using a minimum of raw materials to cure or control a disease or condition in the shortest possible time. The advantages of controlled-release formulations include prolonged drug activity, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to influence the time of onset of action or other characteristics, such as blood levels of the drug, and thus can affect the occurrence of one or more side (e.g., adverse) effects.

[0507] Most controlled-release formulations are designed to initially release a certain amount of drug (active ingredient) to quickly produce the desired therapeutic effect, and gradually and continuously release additional amounts of drug to maintain this level of therapeutic or preventive effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled release of the active ingredient can be stimulated by various physiological factors, including but not limited to pH, temperature, enzymes, water, or other physiological factors or compounds related to skin cancer.

[0508] In some embodiments, the drug can be administered using a transdermal patch, liposomes, or other modes of administration. In some embodiments, a polymeric material can be used. In some embodiments, a controlled release system can be placed in the patient at an appropriate location determined by one skilled in the art, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, Vol. 2, pp. 115-138 (1984)). Other controlled release systems are described in Langer's review (Science 249: 1527-1533 (1990)). The active ingredient can be dispersed in a solid matrix such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of acrylic acid and methacrylate, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate, which are not The active ingredient is then diffused through the outer polymer membrane in a release rate-controlling step. The percentage of active ingredient in such parenteral (e.g., subcutaneous) compositions is highly dependent on their properties and the needs of the patient.

[0509] Parenteral (intramuscular, subcutaneous, intralesional, intradermal) dosage forms

[0510] In some embodiments, parenteral dosage forms are provided. In some embodiments, parenteral dosage forms can be administered to a subject by various routes, including but not limited to subcutaneous, intramuscular and intradermal. In some embodiments, parenteral dosage forms can be administered to a subject by various routes, including but not limited to subcutaneous, intramuscular, intradermal or intralesional. Because their administration usually bypasses the subject's natural defenses against pollutants, parenteral dosage forms are typically sterile or can be disinfected before being administered to a subject. In some embodiments, parenteral dosage forms include but are not limited to, solutions for injection, dry products that can be dissolved or suspended in a pharmaceutically acceptable injection carrier, suspensions for injection and emulsions.

[0511] Suitable carriers that can be used to provide parenteral dosage forms are well known to those skilled in the art. In some embodiments, suitable carriers include, but are not limited to, Water for Injection USP; aqueous carriers such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible carriers such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous carriers such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0512] Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into parenteral dosage forms.

[0513] Topical and mucosal dosage forms

[0514] Topical and mucosal dosage forms are also provided. Transdermal, topical and mucosal dosage forms include, but are not limited to, pastes, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012); and Introduction to Pharmaceutical Dosage Forms, 4th edition, Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating oral mucosal tissue can be formulated as mouthwashes or oral gels. In addition, transdermal dosage forms include "reservoir-type" or "matrix-type" patches, which can be applied to the skin and worn for a specific period of time to allow the desired amount of active ingredient to penetrate.

[0515] The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle involved in carrying or transporting any subject composition or its components, 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 subject composition and its components and not harmful to the patient. Suitable carriers (such as excipients and diluents) and other materials that can be used to provide transdermal, topical, and, in some embodiments, mucosal dosage forms encompassed herein are well known to those skilled in the pharmaceutical arts and depend on the specific tissue to which a given pharmaceutical composition or dosage form is to be applied. With this fact in mind, typical carriers include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3 diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form non-toxic and pharmaceutically acceptable lotions, tinctures, creams, emulsions, gels, or ointments. In some embodiments, the materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) astragalus powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, etc. Oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical formulations. If desired, moisturizers or humectants can also be added to the pharmaceutical compositions and dosage forms. Examples of such additional ingredients are well known in the art. See, for example, Remington: The Science and Practice of Pharmacy, 22nd ed. (September 15, 2012).

[0516] Depending on the specific tissue to be treated, additional components may be used before, in combination with, or after treatment with the provided active ingredient. In some embodiments, a penetration enhancer can be used to assist in delivering the active ingredient to the tissue. Suitable penetration enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl alcohol, and tetrahydrofuran methanol; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethylformamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (Polysorbate 80) and Span 60 (Sorbitol Monostearate).

[0517] The pH value of pharmaceutical composition or dosage form can also be regulated, or the pH value of the tissue that pharmaceutical composition or dosage form are applied to, to improve the sending of one or more active components.Similarly, the polarity of solvent carrier, its ionic strength or tension (tonicity) can be regulated to improve sending. Compounds such as stearate can also be added to pharmaceutical composition or dosage form, to advantageously change the hydrophilicity or lipophilicity of one or more active components, thereby improve sending. In this respect, stearate can be used as lipid carrier, emulsifying agent or surfactant of preparation and as sending enhancing or penetration enhancer. Different salts, hydrates or solvates of active component can be used to further regulate the character of resulting composition.

[0518] Dosage and unit dosage form

[0519] In human therapy, the physician will determine what he deems most appropriate posology, depending on whether the treatment is prophylactic or therapeutic, and based on the age, weight, stage of the condition or disease, and other specific factors unique to the subject being treated. In some embodiments, the dosage is about 1 to about 1000 mg per day for an adult, or about 5 to about 250 mg per day for an adult, or about 10 to 50 mg per day. In some embodiments, the dosage is about 5 to about 400 mg per adult per day, or 25 to 200 mg per day. In some embodiments, dosage rates of about 50 to about 500 mg per day are also contemplated.

[0520] In other aspects, there is provided a method for treating skin cancer (such as MEK inhibitor responsiveness or MEK-mediated skin cancer) in a subject by administering a therapeutically effective amount or an effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof to a subject in need thereof. The amount of the compound or composition with treatment or effectiveness in treating skin cancer or one or more symptoms thereof will vary with the nature and severity of the disease or illness and the route of administration of the active ingredient. Frequency and dosage will also vary according to the specific factors of each subject, depending on the severity of a particular therapy (such as a therapeutic agent or preventive agent), illness, disease or condition, route of administration, and age, health, body weight, reaction, and previous medical history of the subject. The effective dose can be inferred from a dose-response curve derived from an in vitro or animal model test system.

[0521] In some embodiments, exemplary dosages of the compositions include milligram or microgram amounts of active compound per kilogram of subject or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 micrograms per kilogram to about 10 milligrams per kilogram). For the compositions provided herein, in some embodiments, the dosage administered to a subject is 0.140 mg / kg to 3 mg / kg of the subject's body weight, based on the weight of the active compound. In some embodiments, the dose administered to a subject is between 0.20 mg / kg and 2.00 mg / kg, between 0.30 mg / kg and 1.50 mg / kg, between 1 mg / kg and 100 mg / kg, between 5 mg / kg and 50 mg / kg, between 10 mg / kg and 50 mg / kg, between 20 mg / kg and 50 mg / kg, between 15 mg / kg and 40 mg / kg, between 15 mg / kg and 35 mg / kg, between 15 mg / kg and 30 mg / kg, between 25 mg / kg and 35 mg / kg, between 10 mg / kg and 30 mg / kg, between 10 mg / kg and 20 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, or about 50 mg / kg of the subject's body weight.

[0522] In some embodiments, the recommended daily dose range of the compositions provided herein for the diseases or conditions described herein is in the range of about 0.1 mg to about 1000 mg per day, given as a single dose once daily or in divided doses throughout the day. In some embodiments, the daily dose is administered twice daily in equally divided doses. In some embodiments, the daily dose range should be about 10 mg to about 200 mg per day, in some embodiments, about 10 mg to about 150 mg per day, and in other embodiments, about 25 mg to about 100 mg per day. In some cases, it may be necessary to use a dosage of the active ingredient outside the range disclosed herein, which will be apparent to those of ordinary skill in the art. In addition, it should be noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate treatment in conjunction with patient response.

[0523] Different therapeutically effective amounts or effective amounts may be applicable to different diseases and conditions, as readily known to those of ordinary skill in the art. Similarly, amounts sufficient to prevent, control, treat or improve such conditions, but not sufficient to cause or reduce the adverse effects associated with the compositions provided herein, are also included in the dosage amounts and dosage frequency tables described herein. In addition, when multiple doses of the compositions provided herein are administered to a subject, not all doses need to be the same. In some embodiments, the dose administered to a subject can be increased to improve the preventive or therapeutic effect of the composition, or can be reduced to reduce one or more side effects that a particular subject is experiencing.

[0524] In some embodiments, the dosage of a composition provided herein administered to prevent, treat, manage, or ameliorate a disorder or one or more symptoms thereof in a subject is 0.1 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg, or 15 mg / kg or more of the subject's body weight, based on the weight of the active compound. In some embodiments, the dosage of the compositions or compositions provided herein for administration to prevent, treat, manage, or ameliorate a disease or one or more symptoms thereof in a subject is a unit dose of 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.

[0525] In some embodiments, treatment or prevention can be started with one or more loading doses of a compound or composition provided herein, followed by one or more maintenance doses. In such embodiments, the loading dose can be, for example, about 60 to about 400 mg per day or about 100 to about 200 mg per day for 1 day to 5 weeks. The loading dose can be followed by one or more maintenance doses. In some embodiments, each maintenance dose is independently about 10 mg to about 200 mg per day, about 25 mg and about 150 mg per day, or about 25 and about 80 mg per day. The maintenance dose can be administered daily, either as a single dose or as divided doses.

[0526] In some embodiments, provided herein is the dosage of compound or composition and can be used to realize the steady-state concentration of active ingredient in the patient's blood or serum.Steady-state concentration can be measured according to the available technology of technical personnel or can be determined based on the patient's physical characteristics (such as height, weight and age).In some embodiments, provided herein is a sufficient amount of compound or composition, to realize the steady-state concentration of about 300 to about 4000ng / mL, about 400 to about 1600ng / mL or about 600 to about 1200ng / mL in the patient's blood or serum.In some embodiments, loading dose can be used to obtain the steady-state blood or serum concentration of about 1200 to about 8000ng / mL or about 2000 to about 4000ng / mL in 1 to 5 days.In some embodiments, maintenance dose can be used to obtain the steady-state concentration of about 300 to about 4000ng / mL, about 400 to about 1600ng / mL or about 600 to about 1200ng / mL in the patient's blood or serum.

[0527] In some embodiments, the same composition can be administered repeatedly, and the administrations can be separated by at least 6 hours, 12 hours, 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In some embodiments, the same prophylactic or therapeutic agent can be administered repeatedly, and the administrations can be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0528] In some aspects, provided herein is a unit dose comprising a compound or a pharmaceutically acceptable salt thereof in a suitable form for administration. These forms are described in detail herein. In some embodiments, the unit dose comprises 1 to 1000 mg, 5 to 250 mg, or 10 to 50 mg of active ingredient. In a specific embodiment, the unit dose comprises about 1, 5, 10, 25, 50, 100, 125, 250, 500, or 1000 mg of active ingredient. Such unit doses can be prepared according to techniques familiar to those skilled in the art.

[0529] The dosage can vary within a range depending on the dosage form employed and the route of administration utilized. For any compound, the therapeutically effective dose or amount can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a certain level in skin with skin cancer (such as cSCC described herein), including IC values ​​determined in cell culture. 50 (i.e., the concentration of the test compound that achieves half-maximal inhibition of symptoms.) This information can be used to more accurately determine useful doses in humans. Additionally, levels in plasma can be measured, for example, by high performance liquid chromatography, to determine systemic exposure.

[0530] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, size of the lesion, number of lesions, general health, sex, diet, time of administration, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of a soft MEK inhibitor (such as a soft MEK inhibitor described herein) in the composition will also depend on the specific soft MEK inhibitor in the composition.

[0531] In some embodiments, the topical, subcutaneous, intradermal, or intralesional dose is about 0.01 μg / cm 2 , about 0.05μg / cm 2 , about 0.1μg / cm 2 , about 0.15μg / cm 2 , about 0.2μg / cm 2 , about 0.3μg / cm 2 , about 0.4μg / cm 2 , about 0.5μg / cm 2 , about 0.6μg / cm 2 , about 0.7μg / cm 2 , about 0.8μg / cm 2 , or about 0.9 μg / cm 2 ; or at about 0.01-0.03 μg / cm 2 , about 0.03-0.05μg / cm 2, about 0.05-0.1μg / cm 2 , about 0.1-0.3μg / cm 2 , about 0.3-0.5μg / cm 2 , about 0.5-0.8μg / cm 2 , about 0.8-1.0μg / cm 2 , about 1-10 μg / cm 2 , about 10-20 μg / cm 2 , about 20-30μg / cm 2 , about 30-40 μg / cm 2 , about 40-50 μg / cm 2 , about 50-60μg / cm 2 , about 60-70 μg / cm 2 , about 70-80 μg / cm 2 , about 80-90 μg / cm 2 , about 90-100 μg / cm 2 , about 100-125μg / cm 2 , about 125-150μg / cm 2 , about 150-175μg / cm 2 , about 175-200 μg / cm 2 , about 200-250μg / cm 2 , about 250-300 μg / cm 2 , about 300-350μg / cm 2 , about 350-400 μg / cm 2 , about 400-450μg / cm 2 , about 450-500μg / cm 2 , about 500-550μg / cm 2 , about 550-600 μg / cm 2 , about 600-650μg / cm 2 , about 650-700 μg / cm 2 , about 700-750μg / cm 2 , about 750-800μg / cm 2 , about 800-850μg / cm 2 , about 850-900 μg / cm 2 , about 900-950μg / cm 2 or about 950-1000 μg / cm 2 within the range.

[0532] In some embodiments, the topical, subcutaneous, intradermal, or intralesional dose is about 0.5-1.0 mg / cm2 1.0-1.5mg / cm 2 , 1.5-2.0mg / cm 2 2.5-2.5mg / cm 2 3.0-3.5mg / cm 2 3.5-5.0mg / cm 2 5.0-7.5mg / cm 2 7.5-10mg / cm 2 , 1-10mg / cm 2 , about 10-20mg / cm 2 , about 20-30mg / cm 2 , about 30-40mg / cm 2 , about 40-50mg / cm 2 , about 50-60mg / cm 2 , about 60-70mg / cm 2 , about 70-80mg / cm 2 , about 80-90mg / cm 2 , about 90-100mg / cm 2 , about 100-125mg / cm 2 , about 125-150mg / cm 2 , about 150-175mg / cm 2 , about 175-200mg / cm 2 , about 200-250mg / cm 2 , about 250-300mg / cm 2 , about 300-350mg / cm 2 , about 350-400mg / cm 2 , about 400-450mg / cm 2 , about 450-500mg / cm 2 , about 500-550mg / cm 2 , about 550-600mg / cm 2 , about 600-650mg / cm 2 , about 650-700mg / cm 2 , about 700-750mg / cm 2 , about 750-800mg / cm 2 , about 800-850mg / cm 2 , about 850-900mg / cm 2 , about 900-950mg / cm 2 or about 950-1000mg / cm 2 within the range.

[0533] VI. Kit

[0534] Also provided is a kit for treating or preventing a method for treating or preventing skin cancer (such as MEK-inhibitor responsiveness or MEK-mediated skin cancer) of a subject in need. The kit may include provided herein a compound or composition, a second reagent or composition, and instructions for providing information on the usage of treating skin cancer (such as MEK-inhibitor responsiveness or MEK-mediated skin cancer) to a medical service staff. Instructions may be provided in printed form, or in the form of an electronic medium such as a floppy disk, CD or DVD, or in the form of a website address that can obtain such instructions. The unit dose of the compound or composition or the second reagent or composition provided herein may include such a dosage, i.e., when administered to a subject, the therapeutically effective plasma level of the compound or composition may be maintained in the subject for at least 1 day. In some embodiments, the compound or composition may be used as a sterile aqueous pharmaceutical composition or a dry powder (such as, lyophilized) composition.

[0535] In some embodiments, suitable packaging is provided. As used herein, "packaging" includes a solid matrix or material that is generally used in a system and can accommodate, within fixed limits, a compound provided herein and / or a second reagent that is suitable for administration. These materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic foil laminated envelopes, etc. If electron beam sterilization technology is used, the packaging should have a sufficiently low density to allow the contents to be sterilized.

[0536] VII. Combination Therapy

[0537] In some embodiments, the compounds and compositions provided herein can be used in a method of treating skin cancer (such as MEK inhibitor-responsive or MEK-mediated skin cancer) in a subject in need thereof, the method comprising further administering a second agent that is effective for treating skin cancer. The second agent can be any agent known to those skilled in the art to be effective for treating skin conditions or diseases, including agents currently approved by the U.S. Food and Drug Administration or other similar agencies in countries outside the United States.

[0538] In some embodiments, the compounds provided herein are administered in combination with one second agent. In further embodiments, the compounds provided herein are administered in combination with two second agents. In still further embodiments, the compounds provided herein are administered in combination with two or more second agents.

[0539] In some embodiments, the method includes administering (e.g., topically, subcutaneously, intradermally, or intralesionally) to a subject in need thereof an amount of a compound effective to treat skin cancer (e.g., MEK inhibitor-responsive or MEK-mediated skin cancer) in a subject in need thereof, in combination with a second agent effective to treat or prevent skin cancer (e.g., MEK inhibitor-responsive or MEK-mediated skin cancer) in a subject in need thereof. The compound can be any compound described herein, and the second agent can be any second agent described in the art or herein. In some embodiments, the compound is in the form of a pharmaceutical composition or dosage form, as described elsewhere herein.

[0540] As used herein, the term "combination" includes the use of more than one therapy (such as one or more preventive and / or therapeutic agents). The term "combination" is used without limiting the order in which treatment (such as preventive and / or therapeutic agents) is given to the object suffering from the disease. The first therapy (such as preventive or therapeutic agents such as provided herein compound) can be used to administer the second medicament (such as a preventive or therapeutic agent) to the object suffering from the disease before (such as 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks ago), while administering the second medicament or after administering the second medicament (such as 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks later).

[0541] As used herein, the term "synergistic" includes a combination of a compound provided herein and another therapy (such as a preventive or therapeutic agent) that has been or is being used to prevent, control, or treat a disease, which is more effective than the combined effects of these therapies. The synergistic effect of a combination therapy (such as a combination of a preventive or therapeutic agent) allows the use of one or more therapies at lower doses and / or less frequent administration of the therapy to a subject suffering from a condition. The use of a lower dose of therapy (such as a preventive or therapeutic agent) and / or less frequent administration of the therapy reduces the toxicity associated with administering the therapy to the subject without reducing the efficacy of the therapy in preventing or treating the disease. In addition, a synergistic effect can result in improved efficacy of the agent in preventing or treating a condition. Finally, a synergistic therapy (such as a combination of preventive or therapeutic agents) can avoid or reduce one or more adverse or undesirable side effects associated with the use of any one therapy alone.

[0542] The active compounds provided herein can be combined or administered in alternation with another therapeutic agent, particularly to effectively treat skin cancer (e.g., MEK inhibitor-responsive or MEK-mediated skin cancer) in subjects in need thereof. In combination therapy, effective doses of two or more agents are administered together, while in alternating or sequential step therapy, effective doses of each agent are administered continuously or sequentially. The dose administered depends on the absorption, inactivation, and excretion rates of the drug and other factors known to those skilled in the art. It should be noted that dosage values ​​will also vary with the severity of the skin cancer to be alleviated. It should be further understood that for any particular subject, the specific dosage regimen and schedule should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition.

[0543] In some embodiments, provided herein is a dosage of a second agent used in a combination therapy. In some embodiments, the dosage used in the combination therapy provided herein is lower than the dosage that has been or is currently used to treat MEK inhibitor responsiveness or MEK-mediated skin disorders. The recommended dosage of the second agent can be obtained from the knowledge of those skilled in the art. For those second agents approved for clinical use, the recommended dosage is, for example, in Hardman et al., eds., 1996, Goodman & Gilman The Pharmacological Basis Of Therapeutics, 9th edition, Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57th edition, 2003, Medical Economics Co., Inc., Montvale, New Jersey; which are incorporated herein by reference in their entirety.

[0544] The present disclosure provides a combination therapy by administering a MEK inhibitor, such as a soft MEK inhibitor, herein together with one or more additional agents. In some embodiments, the one or more additional agents are selected from:

[0545] Medications for acne (such as tretinoin (Accutane), azelaic acid, benzoyl peroxide, salicylic acid);

[0546] Analgesics (e.g., acetaminophen, capsaicin), for example Cox2 inhibitors such as celecoxib);

[0547] Anesthetics (such as benzocaine, benzocaine / menthol, dibucaine, diperodon, lidocaine, lidocaine / prilocaine, and pramoxine);

[0548] Anti-infective drugs (such as crotamiton);

[0549] Antipruritic drugs (eg, ammonium lactate, benzocaine, ascomycin macrolides such as pimecrolimus);

[0550] Antipruritic drugs / 5HT3 receptor antagonists (such as ondansetron);

[0551] Antibiotics (such as clindamycin, doxycycline, erythromycin, tetracycline);

[0552] Antiemetics with anti-parasympathetic nervous system physiological effects (such as diphenhydramine);

[0553] Antifibrotic drugs (such as collagenase, pirfenidone);

[0554] Antihistamines (such as triprolidine Fexofenadine ( D-12, -24), Astepro / Astelin nasal spray (Azalastine) Hydroxyzine hydrochloride Diphenhydramine hydrochloride Brompheniramine ( Cold and allergy elixirs), (Cetirizine), (Chlor- )(Chlorpheniramine), Descoratadine( D-12, D-24), loratadine ( D-12, D-24 and ), Dimenhydrinate Diphenhydramine ( allergy, ), doxylamine ( Strengthen nighttime cold medicine), cyproheptadine Promethazine Acrivastine Clemastine Doxylamine Levoceterizine

[0556] Mast cell stabilizers (eg, β2-adrenergic agonists, cromolyn, cromolyn sodium, Ketotifen, methylxanthines, omalizumab, pemirolast, quercetin, ketotifen );

[0557] Anti-inflammatory drugs (such as NSAIDs (such as aspirin, choline and magnesium salicylate, diclofenac potassium) Diclofenac sodium ( XR), diclofenac sodium and misoprostol Diflunisal Etodolac ( XL), Fenoprofen Calcium Flurbiprofen Ibuprofen ( IB, ), indomethacin ( SR), ketoprofen ( KT, ), magnesium salicylate (Arthrita, Choose Doan'pill, Magan, Mobidin, Mobogesic, meclofenamic acid sodium Mefenamic acid (Mefenamic acid ), Meloxicam Nabumetone naproxen Naproxen sodium Oxaprozin Piroxicam Rofecoxib Salsalate (Amigesic, Anaflex 750, Disalcid, Marthritic, Mono-Gesic, Salflex, Salsitab), sodium salicylate, sulindac Tolmetin sodium Valdecoxib );

[0558] Receptor tyrosine kinase inhibitors (such as sunitinib);

[0559] Alkylating agents (eg, dacarbazine, carboplatin);

[0560] CDK4 / 6 inhibitors (such as LEE011);

[0561] PKC inhibitors (such as AEB071);

[0562] MAPK inhibitors (such as RAS inhibitors / farnesyl transferase inhibitors (such as Tipifarnib)), Raf kinase inhibitors (such as sorafenib (BAY43-9006, Nexavar), Vemurafenib, Dabrafenib, LGX818, TAK-632, MLN2480, PLX-4720), ERK inhibitors (such as SCH772984, VTX11e);

[0563] BRAF inhibitors (such as vemurafenib, dabrafenib);

[0564] PI3K inhibitors (such as LY294002);

[0565] AKT inhibitors (such as MK 2206);

[0566] PI3K / AKT inhibitors (such as buparlisib and cixutumumab);

[0567] mTOR inhibitors (eg, topical rapamycin, RAD001 (everolimus / rapamycin), temsirolimus, sirolimus);

[0568] Tyrosine kinase inhibitors (such as imatinib Cabozantinib (tyrosine kinase c-Met and VEGFR2 inhibitor), nilotinib

[0569] VEGF inhibitors (such as ranibizumab cediranib);

[0570] Immune response modifiers (eg, topical imiquimod, interferon, PEG interferon);

[0571] Calcium channel blockers (such as Avocil (Mederma) / 15% verapamil, vitamin D alone, doxycycline injection);

[0572] Statins (such as lovastatin, methotrexate, vinblastine, pregabalin, temozolomide, PLX3397);

[0573] HDAC inhibitors (such as AR-42);

[0574] HSP-90 inhibitors (such as glatiramer (Ganetespib));

[0575] Retinoids (such as adapalene, isotretinoin, tazarotene, tretinoin);

[0576] Steroids (e.g., alclometasone, amcinonide, betamethasone, betamethasone dipropionate, augmented betamethasone dipropionate, budesonide, clobetasol propionate, cortisone, desonide, dexamethasone, diflorasone diacetate, fluocinoloneacetonide, fluocinonide, flurandrenolide, fluticasone propionate, halobetasol propionate, propionate), Halocinonide, hydrocortisone, hydrocortisone butyrate, hydrocortisone valerate, methylprednisolone, mometasone, mometasone furoate, prednicarbate, prednisolone, prednisone, triamcinolone acetonide);

[0577] Topical calcineurin inhibitors (such as pimecrolimus (Elidel) Cream 1%, Novartis, tacrolimus (Protopic ointment, Astellas; and

[0578] Non-drug interventions (such as photodynamic therapy (Levulan Kerastick topical application + phototherapy), electrodessication (ED), YAG laser).

[0579] In various embodiments, the therapy (e.g., a compound as provided herein and a second agent) is administered at least 5 minutes apart, at least 30 minutes apart, at least 1 hour apart, about 1 hour apart, about 1 hour apart, about 2 hours apart, about 3 hours apart, about 3 hours apart, about 4 hours apart, about 4 hours apart, about 5 hours apart, about 5 hours apart, about 6 hours apart, about 7 hours apart, about 8 hours apart, about 9 hours apart, about 9 hours apart, about 10 hours apart, about 10 hours apart, about 11 hours apart, about 11 hours apart, about 12 hours apart, about 12 hours apart, 18 hours apart, 24 hours apart, 36 hours apart, 36 hours apart, 48 hours apart, 52 hours apart, 52 hours apart, 60 hours apart, 72 hours apart, 84 hours apart, 84 hours apart, 96 hours apart, or 6 hours apart. In various embodiments, the therapy is administered no more than 24 hours apart or no more than 48 hours apart. In some embodiments, two or more therapies are administered in the same patient visit.In some embodiments, a compound provided herein and a second agent are administered simultaneously.

[0580] In some embodiments, the compound provided herein and the second agent are administered about 2 to 4 days apart, about 4 to 6 days apart, about 1 week apart, about 1 to 2 weeks apart, or more than 2 weeks apart.

[0581] In some embodiments, the same agent can be administered repeatedly, and the administrations can be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In some embodiments, the same agent can be administered repeatedly, and the administrations can be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0582] In some embodiments, provided herein is a compound and a second agent administered to a patient in sequence and at intervals, and in some embodiments, administered to a mammal, such as a human, so that provided herein is a compound that can act with other agents to provide an increased benefit than when administered in other ways. In some embodiments, the second active agent can be administered simultaneously or in any order, sequentially at different times in a timely manner; however, if not administered simultaneously, they should be administered close enough in time to provide the desired treatment or preventive effect. In some embodiments, provided herein is a compound and a second active agent that exert their effects at overlapping times. Each second active agent can be administered separately in any appropriate form and by any appropriate route. In some embodiments, provided herein is a compound administered before, simultaneously with, or after the administration of the second active agent.

[0583] In some embodiments, provided herein are compounds and a second agent administered in cycles to the patient. Cycling therapy comprises administering a first agent (such as a first preventive or therapeutic agent) for a period of time, followed by administering a second agent and / or a third agent (such as a second and / or third preventive or therapeutic agent) for a period of time and repeating the administration of this sequence. Cycling therapy can reduce the development of resistance to one or more therapies, avoid or reduce one or more side effects of a therapy, and / or improve the efficacy of treatment.

[0584] In some embodiments, provided herein is a compound and a second active agent with a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days, or about once a week. A cycle can include administering a compound and a second agent provided herein in an infusion of about 90 minutes per cycle, about 1 hour per cycle, or about 45 minutes per cycle. Each cycle can include a pause of at least 1 week, a pause of at least 2 weeks, or a pause of at least 3 weeks. The number of cycles administered is about 1 to about 12 cycles, more typically about 2 to about 10 cycles, and more typically about 2 to about 8 cycles.

[0585] In some embodiments, the patient receives different courses of treatment simultaneously, i.e., a second agent is administered separately at a separate dose within a certain time interval so that the compound provided herein can act together with the second active agent. In some embodiments, a component can be administered once a week in combination with other components that can be administered once every two weeks or every three weeks. In other words, even if not administered at the same time or on the same day, the administration is carried out simultaneously.

[0586] The second agent can act additively or synergistically with the compound provided herein. In some embodiments, the compound provided herein is administered simultaneously with one or more second agents in the same pharmaceutical composition. In some embodiments, the compound provided herein is administered simultaneously with one or more second agents in a separate pharmaceutical composition. In some embodiments, the compound provided herein is administered before or after the use of the second agent. It is also contemplated that the compound provided herein and the second agent are administered by the same or different routes of administration (such as oral and parenteral). In some embodiments, when the compound provided herein is administered simultaneously with a second agent that potentially produces one or more adverse side effects including but not limited to toxicity, the second active agent can advantageously be administered at a dose lower than the threshold value that causes adverse side effects.

[0587] VIII. Examples

[0588] General synthetic method

[0589] The compounds provided herein can be prepared, isolated, and obtained by any method apparent to those skilled in the art. The compounds provided herein can be prepared according to the exemplary preparation schemes provided below. The reaction conditions, steps, and reactants not provided in the exemplary preparation schemes are apparent to those skilled in the art and are known. As used herein, the symbols and conventions used in these processes, schemes, and embodiments, regardless of whether specific abbreviations are specifically defined, are consistent with the symbols and conventions used in contemporary scientific literature (e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry). Specifically, but not limited to, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimole); μM (micromolar); Hz (hertz); MHz (megahertz); mmol (millimole); hr or hrs (hours); min (minutes); MS (mass spectrometry); ESI (electrospray ionization); TLC (thin layer chromatography); HPLC (high performance liquid chromatography); THF (tetrahydrofuran); CDCl3 (deuterated chloroform); AcOH (acetic acid); DCM (dichloromethane); DMSO (dimethyl sulfoxide); DMSO-d6 (deuterated dimethyl sulfoxide); EtOAc (ethyl acetate); MeOH (methanol); Tces (2,2,2-trichloroethoxysulfonyl); -Si(tert-Bu)(Ph)2 and -Si t BuPh2 (tert-butyl-diphenylsilyl); and BOC (tert-butyloxycarbonyl).

[0590] For all of the following examples, standard processing and purification methods known to those skilled in the art can be used. Unless otherwise stated, all temperatures are expressed in degrees Celsius. Unless otherwise stated, all reactions are carried out at room temperature. The synthetic methods shown herein are intended to illustrate applicable chemical substances by using specific examples and do not represent the scope of this disclosure.

[0591] Compound of formula (I)

[0592] The compound of formula (Ia) can be prepared according to Figure 7 The preparation method of Scheme I-1 is shown, wherein R 1 For-OR 4 、-NR 5 R 5a 、-N(OR 5b )R 5a , or unsubstituted or replaced by one or two R 6 Substituted N-linked heterocycloalkyl; X 1 、R 2 、R 2a 、R 13 、R 13a 、R4 、R 5 、R 5a 、R 5b and R 6 As defined in any aspect, embodiment, or claim described herein. In some embodiments, R 13 and R 13a All are hydrogen.

[0593] Starting from a commercially available or conventionally available acid of formula (I-101) and a commercially available or conventionally available aniline of formula (I-102), compounds of formula (I-103) can be prepared by methods readily apparent to those skilled in the art. The acid-containing compound of formula (I-103) can be activated with a variety of reagents readily apparent to those skilled in the art to produce a compound having a suitable leaving group attached to the carbonyl of the C(O)OH acid group, such as an acyl chloride produced by reacting (I-103) with thionyl chloride or an active ester produced by reacting (I-103) with a reagent such as EDCI or HOBT. The acyl chloride or active ester can then be reacted with an aniline of formula R 4 OH, HNR 5 R 5a 、HN(OR 5b )R 5a 、R a -H compound (wherein R a is unsubstituted or replaced by one or two R 6 substituted N-linked heterocycloalkyl) or a suitably protected form thereof to produce a compound of formula (Ia).

[0594] The compound of formula (Ia) can be prepared according to Figure 8 The preparation method of Scheme I-2 is shown, wherein R 1 For-OR 4 、-NR 5 R 5a 、-N(OR 5b )R 5a , or unsubstituted or replaced by one or two R 6 Substituted N-linked heterocycloalkyl; R 2 is iodine; R 13b is fluorine; R 2a 、R 13 、R 13a 、R 4 、R 5 、R 5a 、R 5b and R 6 As defined in any aspect, embodiment, or claim described herein. In some embodiments, R 13 and R 13a All are hydrogen.

[0595] Starting from a commercially available or conventionally available acid of formula (I-104) and a commercially available or conventionally available aniline of formula (I-105), a compound of formula (I-106) can be prepared by methods readily apparent to those skilled in the art. The compound of formula (I-106) is then treated with Zn(CN) in the presence of a catalyst such as Pd(PPh3)4. The compound of formula (I-108) is prepared by treating (I-107) with iodine or, alternatively, with iodine monochloride in the presence of silver trifluoroacetate. The acid-containing compound of formula (I-108) can be activated with a variety of reagents readily apparent to those skilled in the art to produce a compound having a suitable leaving group attached to the carbonyl of the C(O)OH acid group, such as an acyl chloride produced by reacting (I-108) with thionyl chloride or an active ester produced by reacting (I-108) with a reagent such as EDCI or HOBT. The acyl chloride or active ester can then be reacted with an iodine-containing compound of formula R 4 OH, HNR 5 R 5a 、HN(OR 5b )R 5a R a -H compound (wherein R a is unsubstituted or replaced by one or two R 6 substituted N-linked heterocycloalkyl) or a suitable protected form thereof to produce a compound of formula (Ia), wherein R 2 For iodine, R 13b For fluorine.

[0596] The compound of formula (Ib) can be prepared according to Figure 9 The preparation method of Scheme I-3 is shown, wherein R 1 For-OR 4 、-NR 5 R 5a 、-N(OR 5b )R 5a , or unsubstituted or replaced by one or two R 6 Substituted N-linked heterocycloalkyl; R 2 is iodine; R 3b is fluorine; R 2a 、R 13 、R 13a 、R 4 、R 5 、R 5a 、R 5b and R 6 As defined in any aspect, embodiment, or claim described herein. In some embodiments, R 13 and R 13a In some embodiments, R 3 is hydrogen, R 13a For fluorine.

[0597] Starting from commercially available or conventionally available acids of formula (I-109) and commercially available or conventionally available anilines of formula (I-105), compounds of formula (I-110) can be prepared by methods apparent to those skilled in the art. Alternatively, the compound of formula (I-110) can be converted into a methyl ester of formula (I-111) by methods known in the art. The compound of formula (I-110) or (I-111) is then treated with Zn(CN) in the presence of a catalyst such as Pd(PPh3)4. The compound of formula (I-110) or (I-111) is treated with iodine in the presence of silver trifluoroacetate or alternatively with iodine monochloride to produce a compound of formula (I-114) or (I-115). In the case of the compound of formula (I-115), the methyl ester is then hydrolyzed to the corresponding acid. The acid-containing compound of formula (I-114) can be activated with a variety of reagents readily apparent to those skilled in the art to produce a compound having a suitable leaving group attached to the carbonyl group of the C(O)OH acid group, such as an acid chloride produced by reacting (I-114) with thionyl chloride or an active ester produced by reacting (I-114) with a reagent such as EDCI or HOBT. The acid chloride or active ester can then be reacted with a compound of formula R 4 OH, HNR 5 R 5a 、HN(OR 5b )R 5a 、R a -H compound (wherein R a is unsubstituted or replaced by one or two R 6 substituted N-linked heterocycloalkyl) or a suitably protected form thereof to produce a compound of formula (Ib).

[0598] Compound of formula (II)

[0599] The compounds of formula (II) can be prepared according to the following methods: Figure 10-14 Scheme II-1 shown,

[0600] II-2, II-3, II-4 and II-5 were prepared as in Scheme II-1,

[0601] As shown in II-2, II-3, II-4 and II-5, R 1 For-OR 4 、-NR 5 R 5a 、-N(OR 5b )R 5a , or unsubstituted or replaced by one or two R 6 Substituted N-linked heterocycloalkyl; X 2 、R 2 、R 2a 、R 23 、R 23a、R 23b 、R 4 、R 5 、R 5a 、R 5b and R 6 As defined in any aspect, embodiment, or claim described herein. In some embodiments, X 2 In some embodiments, X 2 is methyl; R 23 and R 23b are both hydrogen; and R 23a In some embodiments, X 2 is methyl, and R 23 、R 23a and R 23b All are hydrogen.

[0602] The compound of formula (II) can be prepared according to Figure 10 The preparation of Scheme II-1 shown in FIG. 1 starts from the commercially available intermediate (II-101). The compound of formula (II-102) is prepared by reacting the intermediate (II-101) with X 2 -LG alkylation, wherein LG is a suitable leaving group. The compound of formula (II-103) can be prepared by methods obvious to those skilled in the art and converted to a compound of formula (II-104) by iodination. The compound of formula (II-104) is then reacted with aniline in the presence of a Pd catalyst to obtain a compound of formula (II-105). In the presence of silver trifluoroacetate, the compound of formula (II-106) is prepared by treating (II-106) with iodine or treating (I-107) with iodine monochloride. The acid-containing compound of formula (II-106) can be activated with a variety of reagents obvious to those skilled in the art to produce a compound with a suitable leaving group attached to the carbonyl group of the C(O)OH acid group, such as an acyl chloride generated by reacting (II-106) with thionyl chloride. The acyl chloride can then be reacted with a compound of formula R 4 OH, HNR 5 R 5a 、HN(OR 5b )R 5a 、R a -H compound (wherein R a is unsubstituted or replaced by one or two R 6 substituted N-linked heterocycloalkyl) or its appropriate protected form to produce a compound of formula (II), wherein R 2 For iodine.

[0603] The compound of formula (II) can be prepared according to Figure 11The preparation of Scheme II-2 shown in FIG. 1 starts from a commercially available or readily available intermediate of formula (II-107). The compound of formula (II-108) is prepared by reacting intermediate (II-107) with X 2 -LG alkylation, wherein LG is a suitable leaving group. The compound of formula (II-109) can be prepared by a chlorination method obvious to those skilled in the art. The compound of formula (II-109) is then reacted with aniline to obtain a compound of formula (II-110), which is further converted into an acid of formula (II-111). The acid-containing compound of formula (II-111) can be activated with a variety of reagents obvious to those skilled in the art to produce a compound with a suitable leaving group attached to the carbonyl group of the C(O)OH acid group, such as the acid chloride generated by the reaction of (II-111) with thionyl chloride. The acid chloride can then be reacted with a thionyl chloride of formula R 4 OH, HNR 5 R 5a 、HN(OR 5b )R 5a 、R a -H compound (wherein R a is unsubstituted or replaced by one or two R 6 substituted N-linked heterocycloalkyl) or a suitably protected form thereof to produce a compound of formula (II).

[0604] The compound of formula (II) can be prepared according to Figure 12 The preparation of Scheme II-3 shown in FIG. 1 starts from a commercially available or readily available intermediate of formula (II-107). The compound of formula (II-108) is prepared by reacting intermediate (II-107) with X 2 -LG alkylation, wherein LG is a suitable leaving group. The compound of formula (II-112) can be prepared by methods obvious to those skilled in the art by hydrolyzing the nitrile group to an acid, protecting the acid group, and chlorinating. The compound of formula (II-112) is then reacted with aniline to obtain a compound of formula (II-113), which is further hydrolyzed to an acid of formula (II-114). The acid-containing compound of formula (II-114) can be activated with a variety of reagents obvious to those skilled in the art to produce a compound with a suitable leaving group attached to the carbonyl group of the C(O)OH acid group, such as the acid chloride generated by reacting (II-114) with thionyl chloride. Alternatively, the compound of formula (II-113) can be directly converted to an acid chloride or activated ester according to the methods described in Schemes II-4 or II-5. The acid chloride or activated ester can then be reacted with a mixture of the compounds of formula R 4 OH, HNR 5 R 5a 、HN(OR 5b )R 5a 、R a -H compound (wherein R ais unsubstituted or replaced by one or two R 6 substituted N-linked heterocycloalkyl) or a suitably protected form thereof to produce a compound of formula (II).

[0605] The compound of formula (II) can be prepared according to Figure 13 The preparation shown in Scheme II-4 begins with a commercially available or readily available intermediate of formula (II-115). Intermediate (II-116), prepared by N-alkylation of the pyrrole nitrogen of (II-115), is readily converted to the trifluoromethylketone intermediate (II-117), hydrolyzed to the corresponding acid (II-118), and converted to the tert-butyl ester (II-119) by esterification using methods readily apparent to those skilled in the art. Chlorination of intermediate (II-119) at the 2-position is achieved by treating (II-119) with a base such as LDA, followed by treatment with a chlorinating agent such as perchloroethane to provide the chlorinated intermediate (II-120). In the presence of a base, the chlorine of the intermediate (II-120) is replaced with an appropriate aniline to give the intermediate (II-121), which can be easily converted to the corresponding acid chloride (II-122) by treatment with thionyl chloride with or without the addition of 4N HCl in dioxane (J. Org. Chem., 2017, 82 (6), pp 3245-3251). Alternatively, the intermediate (II-122) can be converted to an activated ester by treatment with an alcohol such as pentafluorophenol. The acid chloride or activated ester can then be reacted with a compound of formula R 4 OH, HNR 5 R 5a 、HN(OR 5b )R 5a 、R a -H compound (wherein R a is unsubstituted or replaced by one or two R 6 substituted N-linked heterocycloalkyl) or a suitably protected form thereof to produce a compound of formula (II).

[0606] In addition, the compound of formula (II) can be prepared by Figure 14 The synthetic route shown in Scheme II-5 is shown. The nitrile (II-108) prepared by N-alkylation on the pyrrole nitrogen of (II-107) can be hydrolyzed to the corresponding acid and esterified to the tert-butyl ester (II-120). Then, following the sequence of Scheme II-4, the compound of formula (II) can be prepared.

[0607] Compound of formula (III)

[0608] The compound of formula (IIIa) can be prepared according to the following methods: Figure 15-16 As shown in Scheme III-1 or III-2, R 1 For-OR4 、-NR 5 R 5a 、-N(OR 5b )R 5a , or unsubstituted or replaced by one or two R 6 Substituted N-linked heterocycloalkyl; R 2 、R 2a 、R 33 、R 33a 、R 33b 、R 4 、R 5 、R 5a 、R 5b and R 6 As defined in any aspect, embodiment, or claim described herein. In some embodiments, R 33a and R 33b are both hydrogen; and R 33 In some embodiments, R 33 and R 33b are both hydrogen; and R 33a In some embodiments, R 33 and R 33a All are hydrogen, R 33b In some embodiments, X 2 is methyl, and R 33 、R 33a and R 33b All are hydrogen.

[0609] The compound of formula (IIIa) can be prepared according to Figure 15 Prepared as shown in Scheme III-1. Starting from commercially available or conventionally available substituted isothiocyanate phenyl esters (III-101) and intermediates (III-102), intermediates (III-103) can be prepared by methods obvious to those skilled in the art. In a suitable solvent (such as dichloromethane or dioxane), intermediate (III-103) can be hydrolyzed by contact with a suitable acid (such as hydrochloric acid or trifluoroacetic acid) to obtain intermediate (III-104). The acid intermediate (III-104) can be activated with a variety of reagents obvious to those skilled in the art to generate a compound containing a suitable leaving group attached to the carbonyl group, such as an acyl chloride generated by reacting (III-104) with thionyl chloride or an active ester generated by reacting (III-104) with a reagent such as EDCI or HOBT. The acyl chloride or active ester can then be reacted with a compound of formula R 4 OH, HNR 5 R 5a 、HN(OR 5b )R 5a 、R a-H compound (wherein R a is unsubstituted or replaced by one or two R 6 substituted N-linked heterocycloalkyl) or a suitably protected form thereof to produce a compound of formula (IIIa).

[0610] Alternatively, compounds of formula (IIIa) wherein R2 is a C2-C6 alkynyl group may be prepared according to the following method: Figure 16 Scheme III-2 shown is prepared from a compound of formula (IIIa) wherein R2 is initially iodine (i.e., formula III-105). Reaction conditions similar to those described in Journal of Medical Chemistry 2007, 50, 5090-5102 can be employed to provide conversion of an aromatic iodine group to an alkyne. Intermediate (IIIa-107) can be converted to a compound of formula (IIIa) using the methods described herein and in Scheme III-1 above.

[0611] Compounds of formula (IV)

[0612] The compounds of formula (IVa), (IVb) and (IVc) can be prepared according to the following methods: Figure 17 The preparation method is shown in Scheme IV-1, wherein R 1 For-OR 4 、-NR 5 R 5a 、-N(OR 5b )R 5a , or unsubstituted or replaced by one or two R 6 substituted N-linked heterocycloalkyl;

[0613] R 2 、R 2a 、R 43a 、R 4 、R 5 、R 5a 、R 5b 、R 6 、R 46 、R 48 and R 48a As defined in any aspect, embodiment or claim described herein.

[0614] Starting from commercially available or conventionally available aniline of formula (IV-101) and thiophosgene, intermediate (IV-102) can be prepared by methods obvious to those skilled in the art. In the presence of a base and a solvent, intermediate (IV-102) can be easily condensed with an intermediate of formula (IV-103) and then treated with an intermediate of formula (IV-104) to obtain an intermediate of formula (IV-105). Intermediate (IV-105) is then hydrolyzed by contacting it with a suitable base (such as LiOH) in a suitable solvent (such as THF and / or ethanol and / or water) to obtain intermediate (IV-106). The acid intermediate (IV-106) can be activated with a variety of reagents obvious to those skilled in the art to produce a compound containing a suitable leaving group attached to the carbonyl group, such as an acyl chloride produced by reacting intermediate (IV-106) with thionyl chloride or an active ester produced by reacting (IV-106) with a reagent such as EDCI or HOBT. The acyl chloride or active ester can then be reacted with a thionyl chloride of formula R 4 OH, HNR 5 R 5a 、HN(OR 5b )R 5a 、R a -H compound (wherein R a is unsubstituted or replaced by one or two R 6 substituted N-linked heterocycloalkyl) or a suitable protected form thereof to produce a compound of any one of Formulas (IVa), (IVb) and (IVc), wherein R 43 Cyano, -C(O)NR 48 R 48a or -C(O)R 46 .

[0615] where R 3a and R 3 Compounds of formula (IV) that together form -CH2CH2C(O)- or -CH2CH2CH2C(O)-, such as compounds of formula (IVe-1), can be prepared using the methods described in WO2008 / 020206 or by Figure 18 As shown in Scheme IV-2, R 1 For-OR 4 、-NR 5 R 5a 、-N(OR 5b )R 5a , or unsubstituted or replaced by one or two R 6 Substituted N-linked heterocycloalkyl; R 2a 、R 4 、R 5 、R 5a 、R 5b and R 6As defined in any aspect, embodiment, or claim described herein. In some embodiments, R 2a For fluorine.

[0616] Starting from a commercially available or conventionally available compound of formula (IV-108) and a commercially available or conventionally available aniline of formula (IV-109), a compound of formula (IV-110) can be prepared by methods obvious to those skilled in the art. In the presence of silver trifluoroacetate, (IV-110) is treated with iodine or, alternatively, with iodine monochloride to prepare a compound of formula (IV-111). The compound of formula (IV-111) is then subjected to ester hydrolysis to produce an acid-containing compound of formula (IV-112). The acid group of the compound of formula (IV-112) can be activated with a variety of reagents obvious to those skilled in the art to produce a compound containing a suitable leaving group attached to the carbonyl group of the C(O)OH acid group, such as an acyl chloride produced by reacting (IV-112) with thionyl chloride or an active ester produced by reacting (IV-112) with a reagent such as EDCI or HOBT. The acyl chloride or active ester can then be reacted with an amine of formula R 4 OH, HNR 5 R 5a 、HN(OR 5b )R 5a 、R a -H compound (wherein R a is unsubstituted or replaced by one or two R 6 substituted N-linked heterocycloalkyl) or its appropriate protected form to produce a compound of formula (IVe-1), wherein R 2 is iodine. Similarly, where R 2 Compounds of any of formulae (IVd-1), (IVd-2) and (IVe-2) that are iodo can be prepared according to Scheme IV-2 starting from the corresponding starting materials.

[0617] The compound of formula (IVa) can be prepared according to Figure 19 The preparation method of Scheme IV-3 is shown, wherein R 1 For-OR 4 、-NR 5 R 5a 、-N(OR 5b )R 5a , or unsubstituted or replaced by one or two R 6 Substituted N-linked heterocycloalkyl; R 2a 、R 43a 、R 4 、R 5 、R 5a 、R 5b and R 6As defined in any aspect, embodiment, or claim described herein. In some embodiments, R 2a In some embodiments, R 43a It is a methyl group.

[0618] Starting from commercially available or conventionally available compounds of formula (IV-113), compounds of formula (IV-115) can be prepared by methods known in the art. Starting from compounds of formula (IV-115) and commercially available or conventionally available aniline of formula (IV-109), compounds of formula (IV-116) can be prepared by methods obvious to those skilled in the art. In the presence of silver trifluoroacetate, (IV-116) is treated with iodine or optionally with iodine monochloride to prepare compounds of formula (IV-117). Compounds of formula (IV-117) are then subjected to ester hydrolysis to obtain acidic compounds of formula (IV-118). The acid group of compounds of formula (IV-118) can be activated with a variety of reagents obvious to those skilled in the art to produce compounds containing a suitable leaving group connected to the carbonyl group of the C(O)OH acid group, such as an acyl chloride produced by reacting (IV-118) with thionyl chloride or an active ester generated by reacting (IV-118) with a reagent such as EDCI or HOBT. Then the acyl chloride or active ester can be reacted with the formula R 4 OH, HNR 5 R 5a 、HN(OR 5b )R 5a 、R a -H compound (wherein R a is unsubstituted or replaced by one or two R 6 substituted N-linked heterocycloalkyl) or a suitable protected form thereof to produce a compound of formula (IVa), wherein R 2 For iodine.

[0619] Compound of formula (V)

[0620] The compound of formula (Ia) can be prepared according to Figure 20 The preparation method of Scheme V-1 is shown, wherein the subscript n is 0; R 51 Not for-OR 54 , but including -OH; R 51 、R 2 、R 2a 、R 53a and R 53b As defined in any aspect, embodiment, or claim described herein. In some embodiments, R 53a and R 53b All are hydrogen.

[0621] Starting from commercially available or conventionally available pyridine of formula (V-101), and commercially available methyl chloroformate, compound of formula (V-102) can be prepared by methods obvious to those skilled in the art. Then, in the presence of Cs2CO3 and a catalyst (e.g., PdXPhos G2), compound of formula (V-102) is reacted with compound of formula (V-103), wherein compound of formula (V-103) is prepared by pinacol borane and ethyl vinyl ether. Under acidic conditions, compound of formula (V-104) is cyclized to obtain intermediate of formula (V-105). Various commercially available or conventionally available R 51 Amines or protected amines containing NH2 can react with intermediates of formula (V-105) to provide compounds of formula (V-106). Compounds of formula (Va) can be prepared by coupling compounds of formula (V-106) with commercially available or conventionally available anilines, followed by optional deprotection, by methods readily apparent to those skilled in the art. In some embodiments of compounds of formula (Va), wherein R 51 After further activation of the -C(O)OH group by methods known in the art, these compounds are converted into compounds of formula (Va), wherein R 51 R 7 C(O)-C1-C6 alkyl.

[0622] The compound of formula (Va) can be prepared according to Figure 21 The preparation method of Scheme V-2 is shown, wherein the subscript n is 0; R 51 For-OR 54 ; R 2 、R 2a 、R 53a 、R 53b and R 54 As defined in any aspect, embodiment, or claim described herein. In some embodiments, R 53a and R 53b All are hydrogen.

[0623] As shown in Scheme V-1, starting from the common intermediate of formula (V-104), various commercially available or conventionally available R 54 ONH2 hydroxylamine or protected hydroxylamine can react with the compound of formula (V-104) to obtain the compound of formula (V-107). Under alkaline conditions, the compound of formula (V-107) is cyclized to obtain the compound of formula (V-108) (note R 51 Any ester groups in are also hydrolyzed to the corresponding acid). Compounds of formula (Va) can be prepared by coupling compounds of formula (V-108) with commercially available or conventionally available aniline, followed by optional deprotection, by methods readily apparent to those skilled in the art. In some embodiments of compounds of formula (Va), wherein R 51 For-OR54 , R 54 After further activation of the C(O)OH group by methods known in the art, these compounds are converted into compounds of formula (Ia), wherein R 51 For-OR 54 , R 54 R 7 C(O)-C1-C6 alkyl. In some embodiments, when R 51 When is -OH, the corresponding compound of formula (Va) is prepared according to Scheme V-1.

[0624] The compound of formula (Vb) can be prepared according to Figure 22 The preparation method of Scheme V-3 is shown, wherein the subscript n is 0; R 51 、R 2 、R 2a 、R 53a and R 53b As defined in any aspect, embodiment, or claim described herein. In some embodiments, R 53a and R 53b All are hydrogen.

[0625] As shown in Scheme V-1, starting from a common intermediate of formula (V-104), various commercially available or conventionally available R 51 Amine, hydroxylamine, protected amine or protected hydroxylamine of NH2 can react with the compound of formula (V-104) to obtain the compound of formula (V-109). Under a reducing agent (such as NaCNBH3), the compound of formula (V-109) is reduced and cyclized to obtain the compound of formula (V-110) (note R 51 The ester group in the formula (Va) is also hydrolyzed to the corresponding acid). The compound of formula (Va) can be prepared by a method obvious to those skilled in the art by coupling a compound of formula (V-110) with a commercially available or conventionally available aniline, followed by optional deprotection. In some embodiments of the compound of formula (Va), wherein R 51 is HOC(O)-C1-C6 alkyl or -OR 54 , R 54 After further activation of the C(O)OH group by methods known in the art, these compounds are converted into compounds of formula (Ia), wherein R 51 R 7 C(O)-C1-C6 alkyl or -OR 54 , R 54 R 7 C(O)-C1-C6 alkyl.

[0626] The compounds in Tables 1-5 can be prepared using the exemplary preparative schemes provided herein and methods known to those of ordinary skill in the art.

[0627] Example 1: UV irradiation hairless mouse skin squamous cell carcinoma model

[0628] Mouse model: UV irradiated hairless mouse skin squamous cell carcinoma model was used according to the method described in Adelmann, CH et al., Journal of Investigative Dermatology, vol. 136, no. 9, 2016, pp. 1920-1924, the entire contents of which are incorporated herein by reference for all purposes.

[0629] Study Methods: A gel formulation comprising 0.01%, 0.15% and 0.5% (based on the weight of the base formulation) of Compound 2.003 was used in this study.

[0630] for Figures 1 to 6 Based on the data provided in

[0015] , a topical gel formulation of compound 2.003 or a topical formulation containing only the vehicle was applied to skin squamous cell carcinoma of ultraviolet-irradiated hairless mice for a period of time (e.g., approximately a 20-30 day course of treatment). The composition of gel formulation A (i.e., FA) is shown below.

[0631]

[0632] Data from the first 12 mice to complete the study showed that over the 30-day treatment period, mice treated with the topical vehicle (placebo) developed significantly more tumors than mice treated with all concentrations of Compound 2.003.

[0633] Figure 1-4 Shown are photographs of mice at baseline, start of treatment, and end of treatment using a topical gel formulation containing Compound 2.003 at concentrations of 0.5%, 0.15%, and 0.01% by weight of the formulation, compared to a topical formulation of vehicle alone.

[0634] Figure 5 Shown are the number of new tumors per mouse from the start to the end of treatment using topical gel formulations containing Compound 2.003 at 0.5%, 0.15%, and 0.01% by weight of the formulation, respectively, compared to a topical formulation of vehicle alone.

[0635] Figure 6 Shown are the tumor volumes per mouse at the end of treatment using topical gel formulations containing Compound 2.003 (0.5%, 0.15%, and 0.01% by weight of the formulation, respectively) compared to a topical formulation of vehicle alone.

[0636] Figure 5-6 Compound 2.003 was shown to completely inhibit tumor induction and reduce the size of existing tumors. Importantly, none of the mice lost weight, indicating that topical administration of 2.003 does not appear to cause the toxicities associated with "hard" MEK inhibitors.

[0637] Example 2: Human cSCC Explant Protocol

[0638] MEK inhibitors inhibit the RAS / MAPK pathway in human explant models of normal skin and squamous cell carcinoma (cSCC) In vitro studies of the effects

[0639] Study objectives: In vitro studies of RAS / MAPK pathway inhibition exposure in normal skin and squamous cell carcinoma (cSCC) human explant models.

[0640] Research Methods Six biopsies of normal skin and SCC were used for in vitro explant analysis using discarded surgical specimens from Solano Dermatology Associates (obtained under Western IRB approval). These biopsies were collected in DMEM / F-12 (Thermo Fisher Scientific, Cat#11320033) supplemented with 1× B27 supplement (Thermo Fisher Scientific, Cat#17504044), 2.5 μg / ml amphotericin B (Thermo Fisher Scientific, Cat#15290018), and 50 units / ml penicillin-50 μg / ml streptomycin (Thermo Fisher Scientific, Cat#15070063) and incubated in the same medium for subsequent processing. Specimens were cut into 3 mm × 3 mm fragments containing the epidermis and underlying dermis. Subcutaneous fat was trimmed. Tissue sections were submerged in culture medium in 384-well plates, with the epidermis exposed to air. 5 μL of a topical formulation containing 0.01, 0.15, or 0.5% (w / v) of the test compound (in a FA gel formulation) was added to the exposed epidermal surface of the explant. After incubation for 4 hours at 37°C and 5% CO2, half of the specimens were quickly frozen in liquid nitrogen for Western Blot analysis of phosphorylated ERK, total ERK, and phosphorylated MEK levels, and liquid chromatography mass spectrometry (LCMS) for analysis of the test compound concentration. The other half of the specimens were fixed in 10% formalin for 24 hours and then transferred to 70% ethanol for immunohistochemistry. For partially submerged tissue, 2.5 μL of the gel formulation was topically applied to the partially submerged tissue. After incubation for 4 hours at 37°C and 5% CO2, the tissue was harvested in the same manner as described above.

[0641] Liquid chromatography tandem mass spectrometry (LC-MS / MS) analysis;Skin samples were weighed and added to 1 volume of Bullet Beads (Next Advance, Cat#SSB14B) and 10 volumes of digestion solution containing 1% collagenase (Sigma, Cat#C9891) and 0.5 mM CaCl2 in 1× PBS. The tissue was then minced and incubated at room temperature for 1 hour, then homogenized at 4°C using a Bullet Beads (Next Advance, Model #BBX24) according to the manufacturer's instructions. Stock solutions of standards were prepared in DMSO and diluted with 50% methanol to make the spiking solution. For the spiked standard curve, 25 μL of the standard spike solution (1 ng / mL to 1000 ng / mL) was added to 25 μL of blank skin homogenate or plasma. After vortexing all standards and samples, 150 μL of methanol / acetonitrile 20:80 (v / v) was added to the mixture, vortexed vigorously for 1 minute, and then centrifuged at 3000 rpm for 15 minutes. The supernatant was diluted 1:1 with ultrapure water. The LC-MS / MS system consisted of a QTRAP 4000 mass spectrometer (AB SCIEX) coupled to a Shimadzu UFLC system. The levels of the test compounds were measured using LC and MS conditions, and data were analyzed using Analyst 1.6.1 software (AB SCIEX).

[0642] Western Blot Analysis: Skin samples were lysed in 10 volumes (10 μL per mg of tissue) of lysis buffer (RIPA buffer + 0.5 mM EDTA + 1× stop protease and phosphatase inhibitor cocktail) and homogenized on ice using an ultrasonic probe. Homogenized samples were centrifuged at 12,000 rpm for 10 minutes at 4°C, and the supernatant was transferred to a fresh tube and stored at -80°C until Western blot analysis. Protein concentration was determined using a BCA protein assay kit with bovine serum albumin (BSA) as a standard. 10–20 μg of total protein was separated on NuPAGE 4–12% Bis-Tris gels (Thermo Fisher Scientific) in 1× NuPAGE MESSDS running buffer (Thermo Fisher Scientific, cat# NP0002) and then transferred to a PVDF membrane. After blocking the membrane for 1 hour with 5% skim milk (for phosphorylated MEK, total ERK, and actin) or 5% bovine serum albumin (for phosphorylated ERK and tubulin) in 1× TBST (Tris-buffered saline + 0.1% Tween 20), the membrane was probed with primary antibody at 4°C overnight, washed, and incubated with secondary antibody at room temperature for 1-3 hours. After washing three times with 1× TBST, the blot was developed with WesternBright ECL HRP substrate (Advansta, CAT# K12045-D50).

[0643] Primary antibodies included monoclonal rabbit anti-phospho-p44 / 42 MAPK (Erk1 / 2) (Thr202 / Tyr204) antibody at 1:3000 (Cell Signaling, Cat#4370L), monoclonal rabbit anti-phospho-MEK1 / 2 (Ser217 / 221) antibody at 1:3000 (Cell Signaling, Cat#9154S), monoclonal rabbit anti-p44 / 42 MAPK (Erk1 / 2) antibody at 1:3000 (Cell Signaling, Cat#4695S), and monoclonal mouse anti-β-actin at 1:5000-1:10000 (Sigma, Cat#A1978). Secondary antibodies included goat anti-rabbit IgG (H+L), HRP (Thermo Fisher Scientific, Cat#31460) and peroxidase-conjugated affinity-pure goat anti-mouse IgG (H+L) (Jackson Immuno Research, Cat#115-035-062).

[0644] Evaluation of cell viability after application of MEK inhibitors to keratinocytes derived from normal skin and squamous cell carcinoma

[0645] Primary human keratinocytes (ATCC PCS200-11) and SCC cell lines (SRB12 and SCC13) were plated in triplicate in 96-well, flat, clear-bottom, white-walled microplates and allowed to attach overnight in a humidified incubator at 37°C and 5% CO2. Test compounds dissolved in DMSO and diluted in culture medium to a final concentration of 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01 μM (each concentration was repeated once) were incubated with cells at 37°C and 5% CO2 for 72 hours. DMSO served as a negative control and doxorubicin (30 μM) served as a positive control. Cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Assay (Promega) based on the quantification of the ATP present, which indicates the presence of metabolically active cells. Z', a test of assay performance and data quality, will be calculated based on the mean (μ) and standard deviation (σ) of the positive (p) and negative (n) controls as follows (Z' > 0.5 indicates acceptable data):

[0646] Test well values ​​(x) will be normalized to the positive and negative controls and expressed as normalized percent inhibition (NPI) as follows:

[0647]

[0648] The IC will be defined using a nonlinear fit of the NPI and log10 concentration. 50 .

[0649]

[0650] Example 3: cSCC in vivo model

[0651] Research objectives : To determine the efficacy of a MEK inhibitor as disclosed and described as a chemopreventive agent for cSCC in a spontaneous UV-irradiated cSCC mouse model.

[0652] Research Objective-1 : To evaluate the short-term pharmacokinetic and pharmacodynamic profiles and durability of response to a MEK inhibitor as disclosed and described herein as a cSCC chemopreventive agent in a spontaneous UV-irradiated cSCC mouse model.

[0653] The cSCC mouse model irradiated by ultraviolet light is described in the Journal of Dermatology Research published by Adelmann, CH et al. This mouse model was also used in Example 1 to obtain the following results: Figures 1 to 4 Data are shown. Importantly, these mice harbor Trp53 hotspot mutations, RAS mutations, and CDKN2A mutations at ratios similar to those seen in human cSCC. Biochemical pharmacodynamic endpoints for these studies could be phospho-ERK status assessed by skin immunohistochemistry. Alternatively, validated, highly sensitive SOX peptide-based ERK sensors capable of quantitatively measuring ERK activity in lysates could be used. Histological assessment of inflammation, immune infiltration, and edema could also be used to assess potential adverse effects.

[0654] The efficacy of the test compounds was tested using the spontaneous hairless mouse model of UV-irradiated precancerous AK (papilloma) and cSCC described above. Unlike xenograft models, this model allows us to evaluate the potential of chemopreventive agents. To evaluate the pharmacokinetic and pharmacodynamic properties of the test compounds and the ERK pathway inhibition produced in skin vs plasma / systemic exposure, a topical formulation comprising a specific concentration of the test compound was administered once to hairless mice, and tissue and blood samples were obtained every 6 hours for 24 hours. Pharmacokinetic analysis was based on measurement of test compound levels in intact skin and plasma every 6 hours for 24 hours (n=5 time points). Pharmacodynamic analysis was based on quantitative IHC and / or Western blot analysis of p-ERK expression in intact mouse skin, and FACS analysis of lymphocytes from whole blood every 6 hours for 24 hours (n=5 time points). For LCMS analysis, samples were processed by protein precipitation and dilution, in which homogenized skin or plasma was mixed with 4 volumes of organic solvent. After vortex centrifugation, the supernatant was diluted with HPLC-grade water and analyzed. Calibration standards were prepared by spiking neat standards into blank skin homogenate or plasma. The LCMS system consisted of a Shimadzu UFLC system coupled to a QTRAP 4000 mass spectrometer (AB SCIEX) operating in multiple reaction monitoring mode. Quantitative results were obtained by comparing unknown samples to the calibration standards. A total of 15 mice were required to perform these studies in triplicate.

[0655] Research Objective-2 : Evaluation of the durability of response to a topical formulation comprising a MEK inhibitor as disclosed and described herein in the chemoprevention of papilloma and cSCC

[0656] The study was conducted in a UV-irradiated mouse model of cSCC to assess the durability of response (n=12 / arm x 3 - 1 control, 2 active compounds as defined and described herein)

[0657] Primary outcome: Durability of response plotted at 30 days post-dose x time to next new lesion / progression of existing lesions to permissible endpoint

[0658] Secondary outcomes: Durability of reversion to UV-induced mutational burden in exposed epidermis or reduction of UV-induced mutations / mutational burden in exposed epidermis using whole exome sequencing (WES)

[0659] The in vivo persistence of the chemopreventive effect of the test compound against the development of precancerous papilloma or cSCC was evaluated. Gel formulations containing 0.1% and 0.5% by weight of the test compound were tested relative to vehicle. Thus, there were three groups of mice (n = 36 female mice for the entire trial). The mice were irradiated using a standard protocol developed by the Journal of Investigative Dermatology, which is a 90-day chronic UV exposure protocol (Oriel; 12.5 kJ / m2 UVB three times per week) at the Moffitt Mouse Facility. After cessation of UV exposure, the mice developed papilloma within 30 days. Once they developed lesions greater than 3 mm in maximum dimension, they were treated with topical vehicle or test compound as described above for 30 days, during which time the size of individual tumors was tracked. Toxicity was monitored by measuring body weight and monitoring the skin every two weeks. The primary outcome was the persistence of the response after dosing, plotted as 30 days - time to next new lesion / time for existing lesions to progress to the permitted endpoint (maximum tumor diameter 1.5 cm). These figures provide 97% or 83% power to detect a 2-fold decrease in the ratio of the sum of the largest linear dimensions of tumors in the active group versus the placebo group (at baseline on day 30) with a one-sided α of 0.05, if the coefficient of variation is 0.5 or 0.7, respectively. A secondary outcome was the durability of the reversion to UV-induced mutational burden in exposed epidermis.

[0660] Example 4: MEK inhibition test-1

[0661] The following methods can be used to determine biochemical activity. The following methods were used to test the MEK1 inhibitory activity of the compounds. See Anastassiadis T, et al. Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol. 2011, 29(11), 1039-45.

[0662] Reagents:

[0663] Reaction buffer: 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO

[0664] Enzyme: MEK1, Invitrogen Cat#PV3303

[0665] N-terminally His-tagged recombinant human full-length protein expressed in insect cells. Activated by RAF1 in vitro. MW = 49.2 kDa. GenBank accession number NP_002746.

[0666] Substrate: 5 μM ERK2(K52R),

[0667] Kinase-dead mutant (GenBank Accession No. NM_0011949), aa2-358 with an N-terminal His6 tag, MW = 43.63 kDa, was expressed in E. coli.

[0668] The substrate was prepared in freshly prepared reaction buffer. The kinase was added to the substrate solution and mixed gently. The test compound was delivered to the kinase reaction mixture in 100% DMSO by acoustic technology (ECHO550; nanoliter range) and incubated at room temperature for 20 minutes. 33 The reaction was initiated with P-ATP. The reaction mixture was incubated at room temperature for 2 hours. Kinase activity was detected using the P81 filter-binding assay.

[0669] Example 5: MEK inhibition test-2

[0670] The compounds were tested for MEK1 inhibitory activity using the following method (protocol available at

[0671] The Z′-LYTE biochemical assay (ThermoFisher) uses a fluorescence-based, coupled-enzyme format and is based on the differential susceptibility of phosphorylated and nonphosphorylated peptides to proteolytic cleavage.

[0672] Test compounds in 100% DMSO were screened in wells with 1% DMSO (final).For 10 point titrations, 3-fold serial dilutions were performed starting from a starting concentration of 30 μM.

[0673] The peptide / kinase, MAP2K1 (MEK1) / inactive MAPK1 (ERK2) / Ser / Thr 03, mixture ("Peptide / Kinase Mix") was diluted to a 2X working concentration in the following buffer ("Kinase Buffer"): 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA. The final 10 μL kinase reaction included 0.06-0.25 ng MAP2K1 (MEK1), 105 ng inactive MAPK1 (ERK2), and 2 μM Ser / Thr 03 in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, and 1 mM EGTA. After a 1-hour incubation, 5 μL of a 1:1024 dilution of Development Reagent A (available from Invitrogen, catalog number PV3295) was added.

[0674] ATP solution was diluted to a 4X working concentration in kinase buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA). The apparent ATP Km value was previously determined using the Z'-LYTE assay. The developing reagent was diluted in developing buffer (available from Invitrogen, catalog number P3127).

[0675] Assay Procedure: 2.5 μL of 4X test compound or 100 nL of 100X test compound plus 2.4 μL of kinase buffer, 5 μL of 2X peptide / kinase mix, and 2.5 μL of 4X ATP solution were added to the plate and placed on a shaker for 30 seconds. The kinase reaction was allowed to proceed at room temperature for 60 minutes before adding 5 μL of developer solution and agitating the mixture on a shaker for 30 seconds. The mixture was incubated at room temperature for 60 minutes. Fluorescence was measured using a plate reader, and the data were analyzed.

[0676] The maximum emission rate is established by a 0% phosphorylation control (100% inhibition control), which contains no ATP and therefore exhibits no kinase activity. This control produces 100% cleaved peptide in the development reaction. The 100% phosphorylation control consists of a synthetic phosphorylated peptide with the same sequence as the peptide substrate and is designed to be used for calculating percent phosphorylation. This control produces a very low percentage of cleaved peptide in the development reaction. The 0% phosphorylation and 100% phosphorylation controls allow calculation of the percent phosphorylation achieved in a particular reaction well. The control wells do not include any kinase inhibitors.

[0677] The minimum emission rate in the screen was determined by a 0% inhibition control containing active kinase. This control was designed to produce 10-50% phosphorylated peptides in the kinase reaction. Cascade assays can produce up to 70% phosphorylated peptides.

[0678] Run a known inhibitor control standard curve with a 10-point titration for each individual kinase on the same plate as the kinase to ensure that the kinase is within the expected, previously determined IC. 50 Suppressed within the range.

[0679] Prepare the following controls for each concentration of test compound being assayed. Establish development reaction interference by comparing test compound control wells without ATP to the 0% phosphorylation control (no test compound). Expected values ​​for non-interfering compounds should be 100%. Flag any values ​​outside the 90% to 110% range. Determine test compound fluorescence interference by comparing test compound control wells without the kinase / peptide mixture (zero peptide control) to the 0% inhibition control. Expected values ​​for non-fluorescent compounds should be 0%. Flag any values ​​greater than 20%.

[0680] Calculations were performed on the data in Table A. XLfit from IDBS was used. The dose-response curve was fitted with a model number of 205 (sigmoidal dose-response model). If the bottom of the curve did not fit between -20% and 20% inhibition, it was set to 0% inhibition. If the top of the curve did not fit between 70% and 130% inhibition, it was set to 100% inhibition.

[0681] Table A

[0682]

[0683] FI = fluorescence intensity

[0684] C100% = average coumarin emission signal of 100% Phos control

[0685] C0% = average coumarin emission signal of 0% Phos control

[0686] F100% = average fluorescein emission signal of 100% Phos control

[0687] F0% = average fluorescein emission signal of 0% Phos control

[0688] DRI = Development Reaction Interference

[0689] TCFI = Test Compound Fluorescence Interference

[0690] Table 6 lists the MEK1 inhibition assay results of the compounds selected according to the above method. A represents IC 50 Less than or equal to 150nM, B represents IC 50 Greater than 150nM and less than or equal to 1.5μM, C represents IC 50 Greater than 1.5μM.

[0691] Table 6: MEK inhibition test results

[0692]

[0693]

[0694] ND - Not Determined

[0695] Example 6: Cell-based test-1

[0696] Preparation of cell lines for testing soft MEK inhibitors in NF1-related cell proliferation assays can be found in Basu et al., Nature 356:713-715, 1992; and DeClue et al., Cell 69:265-273, 1992. In addition, exemplary in vitro and in vivo models for determining the efficacy of the soft MEK inhibitors described herein can be found in U.S. Pat. Nos. 8,211,875 and 8,487,004, the entire contents of which are incorporated by reference.

[0697] Example 7: Cell-based test-2

[0698] Alternatively, cell-based activity was determined using the following method. Test compounds were dissolved in DMSO as a 10 mM stock solution. Cell titer - (Cell Titer- )2.0 Luminescent Cell Viability Assay Reagent was purchased from Promega (Madison, Wisconsin). A375 and HCT116 cell lines were purchased from the American Type Culture Collection (Manassas, Virginia). The cell culture medium for A375 cells was DMEM + 10% FBS. The cell culture media are listed in the table below. For HCT116 cells, the cell culture medium was McCoy's 5A + 10% FBS. All media were supplemented with 100 μg / mL penicillin and 100 μg / mL streptomycin. Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2 and 95% air.

[0699] The test compound was diluted in DMSO solution, starting from 10mM and performing 10 doses and 3-fold dilutions in the source plate. 25nL of each test compound was delivered from the source plate to each well of a 384-well cell culture plate (T = final) by Echo550. 25μL of culture medium containing 2000 A375 or HCT116 cells was added to each well of the cell culture plate (T = 0 and T = final) in duplicate. 25μL of cell titer Glo2.0 reagent was added to each well of the cell culture plate (T = 0). The contents were mixed on an orbital shaker for 2 minutes and incubated at room temperature for 15 minutes to stabilize the luminescent signal. Luminescence was recorded using an Envision2104 multi-label plate reader (PerkinElmer, Santa Clara, California). The number of viable cells in the culture medium was determined based on the ATP present in each culture well. The cells in the cell culture plate (T = final) were incubated with the compound at 37°C, 5% CO2 for 72 hours. 25 μL of cell titer Glo2.0 reagent was added to each well. The contents were mixed on an orbital shaker for 2 minutes and incubated at room temperature for 15 minutes to stabilize the luminescent signal. Luminescence was recorded using an Envision 2104 multi-label plate reader (PerkinElmer, Santa Clara, California). The number of viable cells in the culture medium was determined based on the ATP present in each culture well. GraphPad Prism4 was used to plot the GI based on the sigmoidal dose-response equation Y=Bottom+(Top-Bottom) / (1+10^((LogEC50-X)*HillSlope)). 50 All parameters in the equation were calculated using GraphPad Prism 4. 50 It is based on [(T i -T z ) / (CT z )]*100=50, where T i T = data of the cell line containing the test compound at the final time; T z =A is the data of the cell line without compound at T=0h; C is the data of the cell line with control compound staurosporine (Sigma-Aldrich) at T=72h. 50 10 X where X is calculated using Excel using a curve fitting equation at Y = 50.

[0700] Example 8: Assay results of test compounds

[0701] Test compound of formula (I)

[0702] Table 7 below applies to test compounds of formula (I).

[0703] Test 1 is biochemical MEK IC 50 (nM) was determined as described in Example 4. A1 represents IC 50 Less than or equal to 150nM, B1 represents IC 50 Greater than 150 nM and less than or equal to 1.5 μM.

[0704] Test 2 for A375(BRAF)GI 50 (nM) Cell-based assay, as described in Example 7. A2 represents IC 50 Less than or equal to 500nM, B2 represents IC 50 Greater than 500 nM and less than or equal to 1.5 μM.

[0705] Test 3 is HCT116(Kras)GI 50 (nM) was determined as described in Example 7. A3 represents IC 50 Less than or equal to 750nM, B3 indicates IC 50 Greater than 750 nM and less than or equal to 2 μM.

[0706] Table 7: Assay results of test compounds of formula (I)

[0707]

[0708] Test compound of formula (II)

[0709] Table 8 below applies to test compounds of formula (II). NT indicates that the compound was not tested in a particular assay. Assay 1 is a biochemical MEK IC50 (nM) assay as described in Example 4 and used for all test compounds except compounds 2.042, 2.044, 2.047, and 2.048, which were tested in Example 5. Assay 2 is A375 (BRAF) GI 50 (nM) Cell-based assay, as described in Example 7. Test 3 is HCT116 (Kras) GI 50 (nM) was determined as described in Example 7.

[0710] Table 8: Assay results of test compounds of formula (III)

[0711]

[0712] Test compound of formula (III)

[0713] Table 9 below applies to the test compounds of formula (III). NT indicates that the compound was not tested in the specific assay. Assay 1 is a biochemical MEK IC50 (nM) assay as described in Example 4 and for compounds 2 and 6; compounds 1, 3, 5, and 7-8 were tested using the method of Example 5. Assay 2 is a biochemical MEK IC50 (nM) assay for compounds 2 and 6; compounds 1, 3, 5, and 7-8 were tested using the method of Example 5. 50 (nM) Cell-based assay, as described in Example 7. Test 3 is HCT116 (Kras) GI 50 (nM) was determined as described in Example 7.

[0714] Table 9: Assay results of test compounds of formula (III)

[0715]

[0716] Test compound of formula (IV)

[0717] Table 10 below applies to the test compounds of formula (IV).

[0718] Test 1 is biochemical MEK IC 50 (nM) was determined as described in Example 4. A1 represents IC 50 Less than or equal to 500nM, B1 represents IC 50 Greater than 500nM and less than or equal to 1μM; C3 represents IC 50 Greater than 1μM and less than or equal to 5μM, D1 represents IC 50 Greater than 5 μM and less than or equal to 10 μM.

[0719] Test 2 for A375(BRAF)GI 50 (nM) Cell-based assay, as described in Example 7. A2 represents IC 50 Less than or equal to 1 μM, B2 represents IC 50 Greater than 1μM, less than or equal to 2μM.

[0720] Test 3 is HCT116(Kras)GI 50 (nM) was determined as described in Example 7. A3 represents IC 50 Less than or equal to 5 μM, B3 indicates IC 50 Greater than 5 μM and less than or equal to 10 μM.

[0721] Table 10: Assay results of test compounds

[0722]

[0723] Example 9: In vivo model

[0724] Research steps:Topical formulations of the compounds described herein and vehicle were applied to the skin of nude mice in duplicate. Skin biopsies were taken at discrete time intervals and bisected, with one half snap-frozen in liquid nitrogen and the other half fixed in formalin and embedded in paraffin. Protein was isolated and analyzed for p-ERK levels by Western blot. Immunostaining for p-ERK was performed on FFPE sections for cell-specific analysis of p-ERK levels. Additional analyses included H&E staining to investigate skin integrity.

[0725] Compounds were evaluated for their ability to inhibit p-ERK, a downstream biomarker of RAS / MAPK signaling in mouse skin. Additionally, they were evaluated for mouse skin proliferation, mouse skin apoptosis, and histological integrity of mouse skin.

[0726] mice Before the study began, 129 8-week-old mice obtained from Jackson Laboratories were shaved. Approximately 21 mice were used for the study. Compounds were applied to the hairless dorsal skin of the mice, and skin biopsies were obtained using 6 mm punch biopsies at 12-hour intervals before, 24 hours, 72 hours, and 96 hours after treatment.

[0727] Western blot analysis For immunoblotting, epidermal skin was snap-frozen in liquid nitrogen immediately after biopsy. Epidermis was lysed in lysis buffer and protein Antibodies used for immunoblotting included rabbit anti-phospho-p44 / 42 MAPK (1:3000, Cell Signaling) and rabbit anti-p44 / 42 MAPK (1:3000, Cell Signaling), mouse anti-actin (1:5000, Sigma-Aldrich), donkey anti-mouse IgG conjugated to horseradish peroxidase (HRP; 1:40,000, Amersham), and goat anti-rabbit IgG conjugated to HRP (1:40,000, Jackson ImunoResearch).

[0728] Immunohistochemistry: Immunohistochemistry was performed on 5 μm paraffin sections. Antigen retrieval was performed using standard enzymatic treatment (1:1000). The antibody used was rabbit p-ERK (Cell Signaling Technology, 4307S, 1:100). Detection was performed using a polymer-bound anti-rabbit HRP (Leica Biosystems) according to the manufacturer's protocol. Sections were then counterstained with hematoxylin, dehydrated, and coverslipped using a TissueTek-Prisma and a Coverslipper (Sakura).

[0729] Histological analysis:H&E was performed on 5 μM paraffin sections, and tissues were examined to assess cytotoxicity, inflammation, or other changes in the integrity of mouse skin.

[0730] Exogenous RAS activation in mouse skin Experiments will be performed on untreated mouse skin. Alternatively, the skin can be pretreated with TPA to increase p-ERK levels. TPA-induced RAS / MAPK activation will be assessed in nude mouse skin using 12.5 μL TPA in 100 μL acetone for 96 hours. Studies will be conducted for 48 hours after TPA exposure.

[0731] The t-test was used to evaluate the differences in p-ERK and Ki-67 in samples treated with topical MEK1 inhibitor compared with vehicle control.

[0732] Example 10: 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid

[0733]

[0734] A solution of 4-cyano-2-fluorobenzoic acid (3.0 g, 18.1 mmol) in THF (30 mL) stirred at -78°C under N2 was treated dropwise with LDA (2.0 M in THF, 27.2 mL, 54.5 mmol). After 20 minutes, a solution of 2-fluoro-4-iodoaniline (12.9 g, 54.5 mmol) in dry THF (15 mL) was added dropwise, and the reaction mixture was further stirred and allowed to warm to room temperature. After 16 h, the reaction mixture was concentrated in vacuo, acidified with 1 M HCl, and extracted twice with Et2O. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was triturated and purified in boiling DCM to give the product as a yellow solid (1.57 g, 22.7%). m / z 381.1 [MH] - . 1 H NMR(400MHz,DMSO-d6)δppm 13.91(s,1H),9.74(s,1H),8.04(d,J=8.2Hz,1H),7.77(dd,J=10.3,2.0Hz,1H ),7.58(dt,J=8.5,1.3Hz,1H),7.42-7.33(m,2H),7.24(dd,J=8.2,1.6Hz,1H)

[0735] Example 11: 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid

[0736]

[0737] A microwave vial was charged with 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (80% pure) (0.19 g, 0.4 mmol), 3-hydroxyazetidine hydrochloride (0.07 g, 0.6 mmol), HATU (0.25 g, 0.6 mmol), diisopropylethylamine (140 μL, 0.8 mmol) and N,N-dimethylformamide (6 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The organics were washed with water, brine and dried over sodium sulfate. The solvent was evaporated. The residue was purified by flash chromatography (12 g silica, 0-5% methanol in dichloromethane) and again by reverse phase HPLC (30-95% acetonitrile / water) to give the product as a light yellow solid (71 mg, 41%). m / z 438.1 [M+1] + . 1 H NMR (300MHz, DMSO-d6): δ8.97 (s, 1H), 7.69-7.65 (dd, J = 1.2Hz and 0.9Hz,1H),7.55-7.47(m,2H),7.40(s,1H),7.28-7.18(m,2H),5.80(s,1H),4.45(s,1 H),4.35(t,J=7.6Hz,1H),4.21(t,J=8.9Hz,1H),4.00-3.98(m,1H),3.76-3.73(m,1H).

[0738] The following compounds were prepared as described in Example 9, substituting 3-hydroxyazetidine hydrochloride for the appropriate amine, which was either commercially available or prepared using conditions known to one of ordinary skill in the art.

[0739]

[0740]

[0741]

[0742]

[0743] Example 25: N-(azetidin-3-ylmethoxy)-4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0744]

[0745] Step 1: 3-(((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)methyl)azacyclic Butane-1-carboxylic acid tert-butyl ester

[0746] A solution of 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (0.100 g, 0.3 mmol), tert-butyl 3-((aminooxy)methyl)azetidine-1-carboxylate (60% pure) (0.13 g, 0.4 mmol), HATU (0.15 g, 0.4 mmol) and diisopropylethylamine (135 μL 0.8 mmol) in N,N-dimethylformamide (3 mL) was placed in a microwave vial. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The organics were washed with water, brine and dried over sodium sulfate. The solvent was evaporated. The residue was purified by flash chromatography (12 g silica, 0-70% ethyl acetate in hexane). The product fractions were collected and the solvent was removed to give a yellow oil (77 mg, 52%). m / z 565.2 [M-1] - .

[0747] Step 2: N-(azetidin-3-ylmethoxy)-4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoyl amine

[0748] A solution of tert-butyl 3-(((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)methyl)azetidine-1-carboxylate (0.077 g, 0.1 mmol) in dichloromethane (6 mL) was placed in a round-bottom flask, and hydrogen chloride (4.0 M in 1,4-dioxane, 0.510 mL, 2.0 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase HPLC (10-95% acetonitrile / water (0.1% TFA)). The product fractions were collected, washed with sodium bicarbonate and dried in vacuo to give the product as a yellow solid. m / z 461.7 [M+1] + .

[0749] 1 H NMR (300MHz, CDCl3): δ8.41 (s, 1H), 7.67 (d, J = 8.1Hz, 1H), 7.50-7.42 (m, 2H), 7.35 (s, 1H), 7.12-7.03 ( m,1H),4.16-4.10(m,1H),4.06-4.00(m,1H),3.94-3.90(m,1H),3.73-3.68(m,1H),2.89-2.79(m,3H).

[0750] Example 26: 4-cyano-2-((2-fluoro-4-iodophenyl)amino)-N-hydroxybenzamide

[0751]

[0752] A solution of hydroxylamine hydrochloride (333 mg, 0.52 mmol) in dry DMF (2.4 mL) and dry acetonitrile (2.4 mL) was stirred at room temperature and treated with Et3N (1.33 mL, 9.6 mmol). After 1 h, the suspension was diluted with DCM (2.4 mL), cooled to 0 ° C, and a solution of 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoyl chloride (209 mg, 0.52 mmol) in dry THF (2.4 mL) was added. After 1 h, the reaction mixture was diluted with EtOAc, quenched with saturated aqueous NH4Cl solution, extracted, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC to give the product as a yellow solid (37 mg, 17.8%). m / z 396.1 [MH] - . 1 H NMR (400MHz, DMSO-d6): δppm11.60(s,1H),9.46(s,1H),9.41(s,1H),7.72(dd,J=10.5 ,2.0Hz,1H),7.64(d,J=8.0Hz,1H),7.56-7.49(m,1H),7.46(s,1H),7.37-7.28(m,2H).

[0753] Example 27: 2-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)ethan-1-aminium 2,2,2-trifluoroacetate

[0754] Step 1: (2-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)ethyl)amino Tert-butyl ester

[0755]

[0756] A solution of 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (150 mg, 0.39 mmol) and HATU (298 mg, 0.78 mmol) in dry DMF (3.9 mL) was treated with dry DIPEA (0.13 mL, 0.78 mmol). The reaction mixture was stirred at 50° C. for 30 min, cooled to room temperature, and tert-butyl (2-(aminooxy)ethyl)carbamate (103 mg, 0. The product was purified by flash column chromatography (silica, 1-40% EtOAc in hexane) to give the product as a yellow oil (87 mg, 41%). UPLC-MS (acidic method, 2 min): rt 1.27 min. m / z 539.1 [MH] - . 1 H NMR (400MHz, CDCl3): δppm 10.56(s,1H),9.45(s,1H),7.59(d,J=8.1Hz,1H),7.57-7.46(m,2H),7.32(s,1H),7. 16-7.07(m,2H),5.06(s,1H),4.01(t,J=4.9Hz,2H),3.54-3.45(m,2H),1.49(s,9H).

[0757] Step 2: 2-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)ethan-1-ammonium 2,2,2- trifluoroacetate

[0758]

[0759] A solution of tert-butyl (2-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)ethyl)carbamate (67 mg, 0.12 mmol) in dioxane (1.0 mL) was stirred at room temperature and treated with 4N HCl in dioxane (62 μL, 0.24 mmol). After 1 h, an additional portion of 4N HCl in dioxane (62 μL, 0.24 mmol) was added, and a similar procedure was followed 16 h later. After 48 h, an additional portion of 4N HCl in dioxane (0.25 mL, 1 mmol) was added. After 48 h, the reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to afford the product as a yellow solid (21.1 mg, 32%) as the trifluoroacetate salt. m / z 441.1 [M+H] + . 1H NMR (400MHz, DMSO-d6): δppm 7.79-7.69(m,2H),7.54(dd,J=8.3,1.9Hz,1H),7.45(d,J=1.5Hz,1H),7.35(dd,J=8 .1,1.5Hz,1H),7.29(t,J=8.6Hz,1H),4.07(t,J=5.1Hz,2H),3.08(t,J=5.2Hz,2H).

[0760] Example 28: Methyl 2-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)acetate

[0761]

[0762] A solution of 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (500 mg, 1.30 mmol) and HATU (995 mg, 2.61 mmol) in dry DMF (13.0 mL) was treated with dry DIPEA (0.45 mL, 2.61 mmol). The reaction mixture was stirred at 50 ° C for 30 min, cooled to room temperature, and a solution of methyl (2-(aminooxy))acetate hydrochloride (270 mg, 1.96 mmol) in dry DMF (1.0 mL) was added, followed by dry DIPEA (0.34 mL, 2.0 mmol). After 48 h, the reaction mixture was diluted with EtOAc, quenched with H2O, partitioned, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica, 10-41% EtOAc in hexanes) to give the product as a yellow solid (373 mg, 61%). m / z 468.1 [MH] - . 1 H NMR (400MHz, DMSO-d6): δppm 12.29(s,1H),9.16(s,1H),7.76-7.60(m,2H),7.52(dt,J=8.4,1.4Hz,1H),7.41(s,1H),7.35-7.19(m,2H),4.72-4.55(m,2H),3.70(s,3H).

[0763] Example 29: 2-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)acetic acid

[0764]

[0765] A solution of methyl 2-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)acetate (306 mg, 0.64 mmol) in THF (1.93 mL), MeOH (0.64 mL), and H₂O (1.28 mL) was stirred at room temperature and treated with 1M LiOH (0.64 mL, 0.64 mmol). After 24 h, an additional portion of 1M LiOH (0.64 mL, 0.64 mmol) was added and stirring continued. After 24 h, the reaction mixture was diluted with saturated aqueous NaHCO₃, partitioned with EtOAc, and the aqueous phase was acidified with 1M HCl and extracted with EtOAc. The organic phase was washed with 1M HCl and brine, dried over NaHCO₃, filtered, and concentrated in vacuo to afford the product as a yellow solid (238 mg, 81%). m / z 454.0 [MH] - . 1 H NMR (400MHz, DMSO-d6): δppm 13.00(s,1H),12.30(s,1H),9.21(s,1H),7.72(dd,J=10.4,1.9Hz,1H),7.68(s,1H) ,7.53(dt,J=8.5,1.4Hz,1H),7.40(d,J=1.6Hz,1H),7.34-7.24(m,2H),4.52(s,2H).

[0766] Example 30: N-(2-amino-2-oxoethoxy)-4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0767]

[0768] Step 1: 2-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)acetyl chloride

[0769]

[0770] A solution of 2-((4-cyano-2-(((2-fluoro-4-iodophenyl)amino)benzamido)oxy)acetic acid (181 mg, 0.39 mmol) in dioxane (1.5 mL) was stirred at room temperature under N2 and treated with SOCl2 (0.3 mL, 3.9 mmol). After 24 h, the reaction mixture was concentrated in vacuo and azeotroped with dry toluene (3×5 mL). The resulting orange solid was used in the subsequent reaction without further purification. m / z 468.1 [m+h] - (Detected as the corresponding methyl ester after quenching an aliquot of the mixture with 10% pyridine in MeOH).

[0771] Step 2: N-(2-amino-2-oxoethoxy)-4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoyl amine

[0772]

[0773] A solution of 2-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)acetyl chloride (188 mg, 0.39 mmol) in dry dioxane (0.9 mL) was stirred at 0°C under N2 and treated with 0.5M NH3 in dioxane (0.91 mL). After 48 h, the reaction mixture was diluted with EtOAc, quenched with 1M HCl, partitioned, and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC to give the product as a yellow solid (49.7 mg, 28%). m / z 453.0 [MH] - .

[0774] 1 H NMR (400MHz, DMSO-d6): δppm 12.29(br s,1H),9.40(br s,1H),7.74-7.69(m,2H),7.54-7.48(m,1H),7.40(s,1H),7.34-7.24(m,2H),4.34(s,2H).

[0775] Example 31: Methyl 3-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)propanoate

[0776]

[0777] A solution of 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (500 mg, 1.30 mmol) and HATU (995 mg, 2.61 mmol) in dry DMF (13.0 mL) was stirred at room temperature and treated with dry DIPEA (0.45 mL, 2.61 mmol). The reaction mixture was stirred at 50 ° C for 30 min, cooled to room temperature, and a suspension of dry acetonitrile (2.9 mL) and dry THF (2.9 mL) of methyl 3-(aminooxy)propanoate hydrochloride (305 mg, 1.96 mmol) was added, followed by dry DIPEA (0.45 mL, 2.6 mmol). After 16 h, the reaction mixture was diluted with EtOAc, quenched with H O, partitioned, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na SO , filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica, 20-50% EtOAc in hexanes) to afford the product as a yellow solid (369 mg, 59%). m / z 482.0 [MH] - . 1H NMR (400MHz, DMSO-d6): δppm 12.05(s,1H),9.29(s,1H),7.72(dd,J=10.5,1.9Hz,1H),7.66(s,1H),7.53(d,J=8.6Hz,1H) ,7.42(d,J=1.7Hz,1H),7.36-7.25(m,2H),4.14(m,2H),3.61(s,3H),2.70(t,J=6.6Hz,2H).

[0778] Example 32: 3-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)propanoic acid

[0779]

[0780] A solution of methyl 3-((4-cyano-2-((2-fluoro-4-iodophenyl)))amino)benzamido)oxy)propanoate (321 mg, 0.66 mmol) in THF (4.0 mL), MeOH (1.33 mL), and H2O (2.65 mL) was stirred at room temperature and treated with 1M LiOH (1.33 mL, 1.33 mmol). After 3 days, an additional portion of 1M LiOH (0.32 mL, 0.32 mmol) was added and stirring continued. After 3 h, the reaction mixture was diluted with saturated aqueous NaHCO3, partitioned with EtOAc, and the aqueous phase was acidified and extracted with EtOAc. The first EtOAc extract was washed sequentially with 1M HCl and brine, dried over NaHCO3, filtered, and concentrated in vacuo to give the product as a yellow solid (203 mg, 65.5% yield, 79% purity). The second EtOAc extract was washed with brine, dried over NaHCO 3 , filtered and concentrated in vacuo to give the product as a yellow solid (46 mg, 14.8% yield, 100% purity). m / z 468.1 [MH] - . 1 H NMR (400MHz, DMSO-d6): δppm 12.37 (m, 2H), 9.29 (s, 1H), 7.76-

[0781] 7.62(m,2H),7.53(dd,J=8.1,1.9Hz,1H),7.42(d,J=1.7Hz,1H),7.35-7.24(m,2H),4.12(s,2H),2.61(t,J=6.1Hz,2H).

[0782] Example 33: 3-((2-fluoro-4-iodophenyl)amino)-4-(3-oxoisoxazolidine-2-carbonyl)benzonitrile

[0783]

[0784] A solution of 3-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)propanoic acid (203 mg, 0.43 mmol) in dioxane (1.7 mL) was stirred at room temperature under N2 and treated with SOCl2 (0.32 mL, 4.3 mmol). After 24 h, the reaction mixture was concentrated in vacuo and azeotroped with dry toluene (3 x 5 mL). The resulting orange solid was used in the next reaction without further purification. m / z 450.0 [M+H] - .

[0785] Example 34: N-(3-amino-3-oxopropoxy)-4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0786]

[0787] A solution of 3-((2-fluoro-4-iodophenyl)amino)-4-(3-oxoisoxazolidine-2-carbonyl)benzonitrile (195 mg, 0.43 mmol) in dry dioxane (1.03 mL) was stirred at 0°C under N2 and treated with a 0.5 M NH3 solution in dioxane (0.99 mL, 0.49 mmol). After 30 min, the reaction mixture was diluted with EtOAc, quenched with 1 M HCl, partitioned, and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC to give the product as a yellow solid (22.2 mg, 11%). m / z 467.1 [MH] - . 1 H NMR (400MHz, DMSO-d6): δppm 12.04 (br s, 1H), 9.47 (br s,1H),7.71(dd,J=10.4,2.0Hz,2H),7.52(d,J=8.0Hz,1H),7.41(s,1H),7.33-7.26(m,2H),6.90(br s, 2H), 4.09 (t, J = 5.1Hz, 2H), 2.44 (t, J = 6.3Hz, 2H).

[0788] Example 35: 3-Hydroxycyclobutyl 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoate

[0789]

[0790] Step 1: 4-Cyano-2-((2-fluoro-4-iodophenyl)amino)benzoyl-chloride (general preparation)

[0791]

[0792] A suspension of 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (200 mg, 0.52 mmol) in dioxane (1.61 mL) was stirred at room temperature and treated with SOCl (0.38 mL, 5.23 mmol). The reaction mixture was further stirred under N at 50°C. After 48 h, the reaction mixture was concentrated in vacuo and azeotroped with dry toluene (2 x 5 mL). The crude material obtained in the residual toluene was used in the next step without further purification.

[0793] Step 2: 3-Hydroxycyclobutyl 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoate

[0794] To a solution of cyclobutane-1,3-diol (159 mg, 1.8 mmol) and Et3N (0.16 mL, 1.1 mmol) in dry THF (1.0 mL) was added a solution of 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoyl chloride (157 mg, 0.39 mmol) in dry THF (1.3 mL) with stirring at 0°C under N2 atmosphere. After 1 h, the reaction mixture was diluted with EtOAc, quenched with saturated aqueous NH4Cl solution, partitioned, and the aqueous phase was re-extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica, 5-31% EtOAc in hexane) to give the product as a yellow solid (43.7 mg, 24.7%). m / z 451.1 [MH] - . 1 H NMR (400MHz, DMSO-d6): δppm 9.36(s,1H),8.06(d,J=8.2Hz,1H),7.76(dd,J=10.3,1.9Hz,1H),7.58(dt,J=8.4,1.3Hz,1H),7.38-7.30(m,2H),7.27(dd,J =8.2,1.6Hz,1H),5.26(d,J=6.5Hz,1H),4.74(p,J=7.3Hz,1H),3.88(h,J=6.9Hz,1H),2.86-2.70(m,2H),2.12-1.98(m,2H).

[0795] Example 36: 3-Hydroxy-2,2,4,4-tetramethylcyclobutyl 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoate

[0796]

[0797] To a solution of 2,2,4,4-tetramethylcyclobutane-1,3-diol (520 mg, 3.6 mmol) and Et3N (0.32 mL, 2.3 mmol) in dry THF (2.0 mL) was added a solution of 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoyl chloride (314 mg, 0.78 mmol) in dry THF (2.7 mL) under stirring at 0°C under N2 atmosphere. After 48 h, the reaction mixture was diluted with EtOAc, quenched with saturated aqueous NH4Cl solution, partitioned, and the aqueous phase was re-extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica, 0-50% EtOAc in hexane) to give the product as a yellow solid (26.6 mg, 6.7%). m / z 506.9 [MH] - . 1 H NMR (400 MHz, DMSO-d6): δ ppm (Note: mixture of diastereomers 2:1) 9.31 (s, 0.35H), 9.29 (s, 0.67H), 8.10 (d, J = 8.2 Hz, 0.37H), 8.06 (d, J = 8.2 Hz, 0.63H), 7.77 (dd, J = 10.3, 1.9 Hz, 1H), 7.59 (dd, J = 7.8, 1.9 Hz, 1H), 7.39 (s, 0.71H). .34(m,2H),7.34-7.27(m,1H),5.01(t,J=4.8Hz,1H),4.52(s,0.35H),4.41(d,J=0.9Hz,0.67H),3.5 3(d,J=4.8Hz,0.36H),3.37(d,J=4.8Hz,0.66H),1.18(s,4H),1.09(s,2H),1.07(s,2H),1.00(s,4H).

[0798] Example 37: 4-cyano-2- ( 2,3-Dihydroxypropyl (2-fluoro-4-iodophenyl)amino)benzoate

[0799]

[0800] To a solution of 1,2,3-propanetriol (332 mg, 3.6 mmol) and Et3N (0.32 mL, 2.3 mmol) in dry THF (2.7 mL) was added a solution of 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoyl chloride (314 mg, 0.78 mmol) in dry THF (2.0 mL) with stirring at 0°C under N2 atmosphere. After 16 h, the reaction mixture was diluted with EtOAc, quenched with saturated aqueous NH4Cl solution, partitioned, and the aqueous phase was re-extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. A portion of the crude material (198 mg) was purified by preparative HPLC to give the product as a glassy yellow solid (34 mg, 9.5%). m / z 455.0 [MH] - . 1 H NMR (400MHz, DMSO-d6): δppm 9.33(s,1H),8.12(d,J=8.2Hz,1H),7.77(dd,J=10.3,1.9Hz,1H),7.59(dt,J=8.4,1.4Hz,1H),7.39-7.30(m,2H),7.29(dd,J=8.2,1.6Hz,1H), 5.12(d,J=5.3Hz,1H),4.75(t,J=5.7Hz,1H),4.37(dd,J=11.1,3.9Hz,1H),4.23(dd,J=11.1,6.2Hz,1H),3.88-3.76(m,1H),3.53-3.38(m,2H).

[0801] Example 38: 4-Cyano-3-fluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid

[0802]

[0803] Step 1: 2-Fluoro-4-(trimethylsilyl)aniline

[0804] 4-Bromo-2-fluoroaniline (1.00 g, 5.3 mmol) and anhydrous tetrahydrofuran (8 mL) were added to a round-bottom flask, cooled to -78°C, and a 2.5 M solution of nBuLi in hexane (8 ml, 20 mmol) was added dropwise, keeping the internal temperature below -60°C. The reaction mixture was treated dropwise with chlorotrimethylsilane (2.26 ml, 17.4 mmol.), keeping the internal temperature below -60°C. The reaction mixture was heated to 0°C within 1 hour. The reaction mixture was poured into ice-cold 2 M hydrochloric acid and stirred vigorously for 10 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were dried over magnesium sulfate and evaporated to dryness to give a colorless oily product (0.58 g, 54%). m / z 184.2 [M+1] + .

[0805] Step 2: 4-Bromo-3-fluoro-2-((2-fluoro-4-(trimethylsilyl)phenyl)amino)benzoic acid

[0806] To a stirred solution of 2-fluoro-4-(trimethylsilyl)aniline (1.0 g, 5.1 mmol) in tetrahydrofuran (6 mL) was added lithium diisopropylamide (2.0 M in THF / heptane / ethylbenzene, 2.5 ml, 5.1 mmol) at -78 ° C. The resulting suspension was vigorously stirred for 10 minutes, after which a solution of 4-bromo-2,3-difluorobenzoic acid (0.400 g, 1.7 mmol) in tetrahydrofuran (5 mL) was added. The cooling bath was then removed and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the concentrate was treated with 3M hydrochloric acid (10 mL). The resulting suspension was extracted with diethyl ether. The combined organics were dried over sodium sulfate. The solvent was removed in vacuo. Hexane was added to the residue. The precipitated beige solid (382 mg) was washed with hexane and a few drops of ethyl acetate and separated by filtration. m / z 400.1 [M + ]. 1 H NMR (300MHz, DMSO-d6): δ9.06(s,1H),7.70-7.66(m,1H),7.38-7.33(m,1H) ,7.27(d,J=11.7Hz,1H),7.20-7.17(m,1H),6.93-6.86(m,1H),0.22(s,9H).

[0807] Step 3: 4-Cyano-3-fluoro-2-((2-fluoro-4-(trimethylsilyl)phenyl)amino)benzoic acid

[0808] Under argon, a solution of 4-bromo-3-fluoro-2-((2-fluoro-4-(trimethylsilyl)phenyl)amino)benzoic acid (0.180 g, 0.4 mmol), zinc cyanide (0.05 g, 0.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.05 g, 0.05 mmol) in N,N-dimethylformamide (3 mL) was added to a microwave vial. The reaction mixture was stirred at 90 ° C overnight. The reaction was quenched with water and extracted with ethyl acetate. The organics were washed with water, brine and dried over sodium sulfate. The solvent was evaporated. The residue was purified by flash chromatography (12 g silica, 0-70% ethyl acetate in hexane) to give the product as a yellow solid (50 mg, 32%). 1 H NMR (300MHz, CDCl3): δ8.95 (s, 1H), 7.93 (d, J = 8.4Hz, 1H), 7.24-7.21 (m, 2H), 7.19-7.08 (m, 1H), 7.00-6.93 (m, 1H), 0.28 (s, 9H).

[0809] Step 4: 4-Cyano-3-fluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid

[0810] A solution of 4-cyano-3-fluoro-2-((2-fluoro-4-(trimethylsilyl)phenyl)amino)benzoic acid (0.49 g, 1.4 mmol) in anhydrous methanol (6 mL) and anhydrous dichloromethane (6 mL) was added to a round-bottom flask. Silver trifluoroacetate (0.66 g, 3.0 mmol) was added. The reaction mixture was cooled to 0°C. Iodine (0.72 g, 2.8 mmol) was then added in one portion. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was filtered through celite and the solvent was removed. The residue was treated with saturated sodium thiosulfate and extracted with ethyl acetate. The combined organics were dried over sodium sulfate. The solvent was removed in vacuo. Dichloromethane was added to the residue to precipitate a solid. The solid was collected by filtration and dried to give the product as a beige solid (200 mg, 35%). 1 H NMR (300MHz, DMSO-d6): δ7.83-7.81(m,1H),7.59-7.54(dd,J=1.8and 1.8Hz,1H),7.39-7.36(m,2H),6.74-6.66(m,1H).

[0811] Example 39: 4-Cyano-3-fluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzamide

[0812]

[0813] 4-Cyano-3-fluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (0.100 g, 0.2 mmol), 2-(aminooxy)ethanol (0.03 g, 0.4 mmol), HATU (0.14 g, 0.4 mmol), diisopropylethylamine (86 μL, 0.5 mmol) and N,N-di...

Claims

1. A method for treating or preventing skin cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of formula (I), (II), (III), (IV) and (V) or its N-oxide, stereoisomer, mixture of stereoisomers and / or pharmaceutically acceptable salt thereof, in: X 1 For-CR 13b or N;X 2 is a C1-C6 alkyl group; X 3 is S or O; Subscript n is an integer from 0 to 2; Bond "a" is a single bond or a double bond; R 1 For-OR 4 、-NR 5 R 5a 、-N(OR 5b )R 5a or unsubstituted or replaced by one or two R 6 substituted N-linked heterocycloalkyl; R 2 is halogen, C1-C6 alkyl, -S-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl; R 2a Halogen or C 1-6 alkyl; R 4 , R 5 and R 5b Each of them is independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl or R 7 -C(O)-C1-C6 alkyl, wherein each C3-C8 cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 R 6 replaced; R 5a is hydrogen or C 1-6 alkyl; Each R 6 are independently halogen, hydroxy, oxo, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6-hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl or di-(C1-C6 alkyl)amino-C1-C6 alkyl; R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino; R 13 , R 13a and R 13b Each is independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; R 23 , R 23a and R 23b Each is independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C3-C8 cycloalkoxy; R 33 , R 33a and R 33b Each is independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C3-C8 cycloalkoxy; R 43 Cyano, -C(O)NR 48 R 48a or -C(O)R 46 ; R 43a is hydrogen, halogen, C1-C6 alkyl; or R 43 and R 43a together to form -CH2CH2C(O)- or -CH2CH2CH2C(O)-, each of which is unsubstituted or substituted by one or two R 49 replaced; R 46 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or heterocycloalkyl; R 48 and R 48a are each independently hydrogen or C1-C6 alkyl; and Each R 49 are independently C1-C6 alkyl, C3-C8 cycloalkyl or C3-C8 cycloalkyl-C1-C6 alkyl; R 51 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, R 7 -C(O)-C1-C6 alkyl or -OR 54 , wherein each C3-C8 cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 R 6 replaced; Each R 53 are independently halogen or C1-C6 alkyl; R 53a and R 53b are each independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; and R 54 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, or R 7 -C(O)-C1-C6 alkyl, wherein each C3-C8 cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 R 6 replaced.

2. The method according to claim 1, characterized in that The compound has a structure shown in formula (Ia) or (Ib):

3. The method according to claim 1 or 2, characterized in that R 13 , R 13a and R 13b Each is independently hydrogen, halogen or C1-C6 alkyl.

4. The method according to any one of claims 1 to 3, characterized in that R 13 For hydrogen.

5. The method according to any one of claims 1 to 4, characterized in that R 13a For hydrogen.

6. The method according to any one of claims 1 to 5, characterized in that R 13b For hydrogen.

7. The method according to any one of claims 1 to 5, characterized in that R 13b It is a halogen.

8. The method according to any one of claims 1 to 5 and 7, characterized in that R 13b For fluorine.

9. The method according to claim 1, characterized in that In formula (II), X 2 It is a C1-C3 alkyl group.

10. The method according to claim 1 or 9, characterized in that: X 2 It is methyl.

11. The method according to any one of claims 1, 9 to 10, characterized in that: R 23 , R 23a and R 23b Each is independently hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy.

12. The method according to any one of claims 1 and 9 to 11, characterized in that R 23 and R 23b All are hydrogen, R 23a is halogen, C1-C6 alkyl or C1-C6 alkoxy.

13. The method according to any one of claims 1, 9 to 11 and 12, characterized in that R 23 and R 23b are hydrogen, and R 23a is fluorine, methyl or methoxy.

14. The method according to any one of claims 1 and 9 to 11, characterized in that R 23 , R 23a and R 23b All are hydrogen.

15. The method according to claim 1, wherein: The compound has a structural formula shown in formula (IIIa) or (IIIb):

16. The method according to claim 1 or 15, characterized in that R 33 , R 33a and R 33b Each is independently hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy.

17. The method according to any one of claims 1 and 15-16, characterized in that R 33 , R 33a and R 33b Each is independently fluoro, methyl or methoxy.

18. The method according to any one of claims 1 and 15-17, characterized in that R 33a and R 33b All are hydrogen, R 33 is fluorine, methyl or methoxy.

19. The method according to any one of claims 1 and 15-17, characterized in that R 33 and R 33b All are hydrogen, R 33a is fluorine, methyl or methoxy.

20. The method according to any one of claims 1 and 15-17, characterized in that R 33 and R 33a All are hydrogen, R 33b is fluorine, methyl or methoxy.

21. The method according to any one of claims 1 and 15-16, characterized in that R 33 , R 33a and R 33b All are hydrogen.

22. The method of claim 1, wherein: The compound has a structure selected from the group consisting of:

23. The method according to claim 1 or 22, characterized in that R 48 and R 48a All are hydrogen.

24. The method according to claim 1 or 22, characterized in that R 46 It is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl.

25. The method according to any one of claims 1, 22 and 24, characterized in that R 46 It is a C1-C6 alkyl group.

26. The method according to any one of claims 1, 22 and 24-25, characterized in that R 46 It is methyl, ethyl, propyl or butyl.

27. The method according to any one of claims 1 and 22-26, characterized in that R 43a For hydrogen.

28. The method according to any one of claims 1 and 22-26, characterized in that R 43a It is a halogen.

29. The method according to any one of claims 1 and 22-26, characterized in that R 43a It is a C1-C6 alkyl group.

30. The method according to any one of claims 1, 22-26 and 29, characterized in that R 43a It is methyl.

31. The method according to claim 1 or 22, characterized in that Each R 9 are independently C1-C6 alkyl.

32. The method of claim 1 or 22, wherein: R 9 Does not exist.

33. The method according to any one of claims 1 to 32, characterized in that R 1 is -OR 4 , -NR 5 R 5a or -N(OR 5b )R 5a .

34. The method according to any one of claims 1 to 33, characterized in that R 1 For-OR 4 ; R 4 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, or R 7 -C(O)-C1-C6 alkyl; R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino; and each C3-C8 cycloalkyl and heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 replaced; and R 6 Each is independently hydroxyl or C1-C6 alkyl.

35. The method according to any one of claims 1 to 34, characterized in that R 1 Selected from the group consisting of: -OH, 36. The method according to any one of claims 1 to 33, characterized in that R 1 For-NR 5 R 5a ; R 5 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, or R 7 -C(O)-C1-C6 alkyl; R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino; and each C3-C8 cycloalkyl and heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 Each is independently hydroxyl or C1-C6 alkyl.

37. The method according to any one of claims 1 to 33 and 36, characterized in that R 5 Selected from the group consisting of hydrogen, 38. The method according to any one of claims 1 to 33, characterized in that R 1 For-NR 5 R 5a , and R 5 For-OR 5b .

39. The method according to any one of claims 1 to 33 and 38, characterized in that R 1 -N(OR 5b )R 5a ; R 5b is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, or R 7 -C(O)-C1-C6 alkyl; R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino; and each C3-C8 cycloalkyl and heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced, and R 6 Each is independently hydroxyl or C1-C6 alkyl.

40. The method according to any one of claims 1 to 33 and 38 to 39, characterized in that -OR 5b Select from the following group:

41. The method of any one of claims 1 to 33 and 36 to 40, wherein: R 1 For-NR 5 R 5a OR 5b )R 5a , and R 5a For hydrogen.

42. The method of any one of claims 1 to 33 and 36 to 40, wherein: R 1 For-NR 5 R 5a OR 5b )R 5a , and R 5a It is a C1-C6 alkyl group.

43. The method of any one of claims 1 to 32, characterized in that R 1 is unsubstituted or substituted with one or two R 6 Substituted N-linked heterocycloalkyl.

44. The method according to any one of claims 1 to 32 and 43, characterized in that The N-linked heterocycloalkyl group is N-linked azetidinyl, N-linked pyrrolidinyl or N-linked isoxazolidinyl.

45. The method of any one of claims 1-32 and 43-44, characterized in that R 7 Each is independently hydroxy, oxo or amino.

46. ​​The method of claim 1, wherein: The compound has a structure shown in formula (Va) or (Vb):

47. The method of claim 1 or 46, wherein: Each R 53 are independently halogen or C1-C3 alkyl.

48. The method of claim 1 or 46, wherein: The subscript n is 0.

49. The method according to any one of claims 1 to 48, wherein: R 53a and R 53b Each is independently hydrogen, halogen or C1-C6 alkyl.

50. The method of any one of claims 1 and 46-49, wherein: R 53a For hydrogen.

51. The method of any one of claims 1 and 46-50, wherein: R 53b For hydrogen.

52. The method of any one of claims 1 and 46-50, wherein: R 53b It is a halogen.

53. The method according to any one of claims 1, 46-50, 52, characterized in that: R 53b For fluorine.

54. The method of any one of claims 1 and 46-53, wherein: R 51 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl-C1-C6 alkyl, or R 7 -C(O)-C1-C6 alkyl; R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino; and each C3-C8 cycloalkyl and heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 Replaced; R 6 Each is independently hydroxyl or C1-C6 alkyl.

55. The method of any one of claims 1 and 46-53, wherein: R 51 For-OR 54b ; R 54b is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl-C1-C6 alkyl, or R 7 -C(O)-C1-C6 alkyl; R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino; and each C3-C8 cycloalkyl and heterocycloalkyl is unsubstituted or substituted by 1-6 R 6 replaced; and R 6 Each is independently hydroxyl or C1-C6 alkyl.

56. The method of any one of claims 1 and 46-53, characterized in that R 51 Selected from the group consisting of hydrogen, -OH, 57. The method according to any one of claims 1 to 56, characterized in that R 2 It is halogen, C1-C6 alkyl, -S-C1-C6 alkyl or C2-C6 alkynyl.

58. The method according to any one of claims 1 to 57, characterized in that R 2 It is a halogen.

59. The method according to any one of claims 1 to 58, characterized in that R 2 For iodine.

60. The method according to any one of claims 1 to 57, wherein: R 2 It is a C1-C6 alkyl group.

61. The method of any one of claims 1 to 57 and 60, characterized in that R 2 For CH3.

62. The method according to any one of claims 1 to 57, wherein: R 2 It is -S-C1-C6 alkyl.

63. The method of any one of claims 1 to 57 and 60, wherein: R 2 It is -SCH3.

64. The method according to any one of claims 1 to 57, wherein: R 2 It is a C2-C6 alkynyl group.

65. The method of any one of claims 1 to 57 and 60, wherein: R 2 It is ethynyl.

66. The method of any one of claims 1 to 61, wherein: R 2a It is a halogen.

67. The method of any one of claims 1 to 66, wherein: R 2a For fluorine.

68. The method of any one of claims 1 to 61, wherein: R 2a It is a C1-C6 alkyl group.

69. The method of any one of claims 1 to 61 and 68, wherein: R 2a It is methyl.

70. The method according to any one of claims 1 to 69, wherein The compound is selected from the compounds in Tables 1-5.

71. The method according to any one of claims 1 to 70, characterized in that The compounds are administered in pharmaceutical compositions together with a pharmaceutically acceptable carrier.

72. The method of any one of claims 1 to 71, wherein: The skin cancer is cutaneous squamous cell carcinoma.

73. The method of any one of claims 1 to 72, wherein: The skin cancer is MEK-inhibitor responsive or MEK-mediated cutaneous squamous cell carcinoma.

74. The method of any one of claims 1 to 73, wherein: The cutaneous squamous cell carcinoma is associated with the activation of p-ERK.

75. The method of any one of claims 1 to 74, wherein: The compound of any one of formulae (I) to (V) or a pharmaceutical composition thereof is administered topically, subcutaneously, intradermally or intralesionally.

76. The method of any one of claims 1 to 75, wherein: The compound having any one of formula (I) to (V) or a pharmaceutical composition thereof is administered as a lotion, spray, ointment, cream, gel, paste and patch.

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