Novel modulators of FSHR and uses thereof

Abstract

Disclosed herein are novel FSH modulator compounds, formulations thereof, and methods of treating diseases by administering one or more of the novel FSH modulator compounds.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 401,441, filed August 26, 2022, and U.S. Provisional Application No. 63 / 522,983, filed June 23, 2023, each of which is incorporated by reference in its entirety. [Background technology]

[0002] Glycoprotein hormones (e.g., gonadotropins and / or TSH) play important roles in various bodily functions, including metabolism, thermoregulation, and reproduction. Gonadotropins act on specific gonadal cell types to initiate ovarian and testicular differentiation and steroidogenesis. The gonadotropin FSH (follicle-stimulating hormone) is released from the anterior pituitary gland under the influence of gonadotropin-releasing hormone and estrogen, and from the placenta during pregnancy. FSH is a heterodimeric glycoprotein hormone with structural similarity to luteinizing hormone (LH) and thyroid-stimulating hormone (TSH), both produced in the pituitary gland, and chorionic gonadotropin (CG), produced in the placenta. In women, FSH plays an important role in stimulating the development and maturation of ovarian follicles. In addition, FSH is the primary hormone controlling estrogen secretion, while LH induces ovulation. In males, FSH is involved in the integrity of the seminiferous tubules and acts on Sertoli cells to support gametogenesis.

[0003] These hormones are relatively large (28–38 kDa) and consist of a common α-subunit noncovalently linked to distinct β-subunits, which confer receptor binding specificity. The cellular receptors for these hormones are expressed in testicular Sertoli cells and ovarian granulosa cells. The FSH receptor is a member of the G protein-coupled class of membrane-bound receptors, known to stimulate increased adenylyl cyclase activity upon activation. This results in increased levels of the intracellular second messenger 3',5'-adenosine monophosphate (cAMP), which in turn enhances steroid synthesis and secretion. Recent studies of the FSH receptor have shown that intracellular signaling extends beyond the classical Gs-mediated adenylyl cyclase (cAMP) pathway to include Gi and Gq proteins, changes in intracellular calcium, and serine / threonine kinases (e.g., MAPK, Akt). Hydropathicity plots of the amino acid sequences of these receptors reveal three general domains: a hydrophilic amino-terminal region that is thought to be the amino-terminal extracellular domain, including a hinge domain that functions as a tethered inverse agonist; a seven-spanning hydrophobic segment that is thought to be the transmembrane domain; and a carboxy-terminal region containing phosphorylation sites (serine, threonine, and tyrosine residues) that may be thought of as the carboxy-terminal intracellular or cytoplasmic domain. The glycoprotein hormone receptor family is distinguished from other G protein-coupled receptors, such as the beta-2-adrenergic receptor, rhodopsin receptor, and substance K receptor, by the large size of the hydrophilic amino-terminal domain responsible for hormone binding.

[0004] Millions of couples in the United States experience infertility each year and are potential candidates for treatment. FSH, extracted from urine or produced by recombinant DNA technology, is a parenterally administered protein product used by professionals for ovulation induction and controlled ovarian hyperstimulation. While ovulation induction is performed to induce ovulation in a single follicle, controlled ovarian hyperstimulation is performed to harvest multiple oocytes for use in various assisted extracorporeal reproductive technologies, such as in vitro fertilization (IVF). FSH is also used clinically to treat male hypogonadism and male infertility, including some types of spermatogenic hypoplasia.

[0005] FSHR is a highly specific target in the process of ovarian follicle development and is exclusively expressed in the ovaries. However, the use of FSH is limited by its high cost, lack of oral administration, and the need for extensive monitoring by specialists. Therefore, it is desirable to identify non-peptide small molecules that can be developed for oral administration to replace FSH. There remains a need for small molecular weight hormone mimetics that selectively regulate FSHR. Summary of the Invention

[0006] In one embodiment, a compound of formula (I):

[0007] [ka] Described herein are FSH modulator compounds of the formula: or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, R 1 is unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkenyl, unsubstituted or R5 C3-C substituted with one, two, three, four, or five groups selected from 16 Heteroaryl, unsubstituted or R 5 C aryl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C1-C substituted with one, two, three, four, or five groups selected from 16 It is alkynyl.

[0009] In some embodiments, Y is —OC(R 4 )2-.

[0010] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4 , -CF3, -OCF3, -OH, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Heteroalkyl, unsubstituted or R 5C1-C substituted with one, two, three, four, or five groups selected from 16 Alkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkenyl, unsubstituted or R 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalekenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C substituted with one, two, three, four, or five groups selected from 16 It is alkynyl.

[0011] In some embodiments, R 2 is -CF3, -OCF3, or -OCH2CH3.

[0012] In some embodiments, R 3 is hydrogen, halogen, -CF3, -OCF3, -OH, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Heteroalkyl, unsubstituted or R 5C1-C substituted with one, two, three, four, or five groups selected from 16 Alkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkenyl, unsubstituted or R 5 C3-C substituted with one, two, three, four, or five groups selected from 16 Heteroaryl, unsubstituted or R 5 C aryl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalekenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C1-C substituted with one, two, three, four, or five groups selected from 16 It is alkynyl.

[0013] In some embodiments, each R 4 are independently hydrogen, halogen, -CF3, -OCF3, -OH, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16Heteroalkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkenyl, unsubstituted or R 5 C3-C substituted with one, two, three, four, or five groups selected from 16 Heteroaryl, unsubstituted or R 5 C aryl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalekenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C1-C substituted with one, two, three, four, or five groups selected from 16 It is alkynyl.

[0014] In some embodiments, each R 5 are independently deuterium, halogen, -OH, -NO2, -CN, -SR 6 , -S(=O)R 6 , -S(=O)2R6 , -N(R 6 )2, -C(=O)R 6 , -OC(=O)R 6 , -C(=O)OR 6 , -C(=O)N(R 6 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0015] In some embodiments, each R 6 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0016] In some embodiments, Y is —O—, —S—, —NR 4 -, -SC(R 4 )2-, -C(R 4 )2O-, -C(R 4 )2S-, -C(R 4 )2NR 4 -, -C(R 4 )2-, -S(=O)C(R 4 )2-, -C(R 4 )2S(=O)-, -S(=O)2C(R 4 )2-, -C(R 4 )2S(=O)2-, or -CR 4 =CR 4 -It is.

[0017] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4, -CF3, -OCF3, -OH, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Heteroalkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkenyl, unsubstituted or R 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalekenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C substituted with one, two, three, four, or five groups selected from 16 It is alkynyl.

[0018] In some embodiments, R 2 is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —CF3, —OCF3, —S02R, —SOR, —C(O)R, —C02R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or —N(R)2.

[0019] In some embodiments, Y is —O—, —S—, —NR 4 -, -OC(R 4 )2-, -SC(R 4 )2-, -C(R 4 )2O-, -C(R 4 )2S-, -C(R 4 )2NR 4 -, -C(R 4 )2-, -C(R 4 )2-C(R 4 )2-, or -CR 4 =CR 4 -It is.

[0020] In some embodiments, R is hydrogen, halogen, —CF, —OCF, —OH, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Heteroalkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkenyl, unsubstituted or R 5 C3-C substituted with one, two, three, four, or five groups selected from 16 Heteroaryl, unsubstituted or R 5 C aryl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalekenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C1-C substituted with one, two, three, four, or five groups selected from 16 It is alkynyl.

[0021] In some embodiments, Z is -Ot-butyl.

[0022] In some embodiments, R 3 is unsubstituted or R 5 C3-C substituted with one, two, three, four, or five groups selected from 16 Heteroaryl, unsubstituted or R 5 C aryl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalekenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 and heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from:

[0023] In some embodiments, R 3 is unsubstituted or R 5 C3-C substituted with 1, 2, 3, 4, or 5 groups selected from 16 It is heteroaryl.

[0024] In some embodiments, R 3 teeth,

[0025] [ka]

[0026] [ka]

[0027] [ka] and permutations thereof.

[0028] In some embodiments, R 3 teeth,

[0029] [ka] and permutations thereof.

[0030] In some embodiments, R 3 teeth,

[0031] [ka] is selected from.

[0032] In some embodiments, R 3 teeth

[0033] [ka] is.

[0034] In some embodiments, R 3 teeth

[0035] [ka] is.

[0036] In some embodiments, R 3 teeth

[0037] [ka] is.

[0038] In some embodiments, R 3 teeth

[0039] [ka] is.

[0040] In some embodiments, R 3 teeth

[0041] [ka] is.

[0042] In some embodiments, R 3 teeth

[0043] [ka] is.

[0044] In some embodiments, R 3 teeth

[0045] [ka] is.

[0046] In some embodiments, R 3 teeth

[0047] [ka] is.

[0048] In some embodiments, R 3 teeth

[0049] [ka] is.

[0050] In some embodiments, R 3 teeth

[0051] [ka] is.

[0052] In some embodiments, R 2 is -halogen, -OR, -SR, -CN, -NO2, -CF3, -OCF3, or -C(=O)CH3.

[0053] In some embodiments, R 2 is -OCH3, -SCH3, -CN, -NO2, -CF3, or -OCF3.

[0054] In some embodiments, R 2 is -OCH3, -SCH3, or -OCF3.

[0055] In some embodiments, R 2 is -SCH3.

[0056] In some embodiments, R 2 is -OCF3.

[0057] In some embodiments, R 2 is -CF3.

[0058] In some embodiments, R 2 is -OCH2CH3.

[0059] In some embodiments, R 2 is -OCH3.

[0060] In some embodiments, R 1 is unsubstituted or R 5 C3-C substituted with one, two, three, four, or five groups selected from 16 Heteroaryl, unsubstituted or R 5 C aryl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5and heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from:

[0061] In some embodiments, R 1 is unsubstituted or R 5 and C6 aryl substituted with 1, 2, 3, 4, or 5 groups selected from:

[0062] In some embodiments, R 1 is unsubstituted or R 5 C3-C substituted with 1, 2, 3, 4, or 5 groups selected from 16 It is heteroaryl.

[0063] In some embodiments, R 1 teeth,

[0064] [ka]

[0065] [ka]

[0066] [ka] and permutations thereof.

[0067] In some embodiments, R 1 teeth,

[0068] [ka] and permutations thereof.

[0069] In some embodiments, R 1 teeth

[0070] [ka] is.

[0071] In some embodiments, R 1 teeth

[0072] [ka] is.

[0073] In some embodiments, R 1 teeth

[0074] [ka] is.

[0075] In some embodiments, R 1 teeth

[0076] [ka] is.

[0077] In some embodiments, R 1 teeth

[0078] [ka] is.

[0079] In some embodiments, R 1 teeth

[0080] [ka] is.

[0081] In some embodiments, R 1 teeth

[0082] [ka] is.

[0083] In some embodiments, R 1 teeth

[0084] [ka] is.

[0085] In some embodiments, R 1 teeth

[0086] [ka] is.

[0087] In some embodiments, R 1 teeth

[0088] [ka] is.

[0089] In some embodiments, Y is —O—, —S—, —NR 4 -, -OC(R 4 )2-, -SC(R 4 )2-, -C(R 4 )2O-, -C(R 4 )2S-, -C(R 4 )2NR 4 -, -C(R 4 )2-, or -CR 4 =CR 4 -It is.

[0090] In some embodiments, Y is —O—, —S—, —NR 4 -, -OC(R 4 )2-, -SC(R 4 )2-, -C(R 4 )2O-, -C(R 4 )2S-, -C(R4 )2-.

[0091] In some embodiments, Y is -O-, -S-, -NH-, -OCH2-, -SCH2-, -CH2O-, -CH2S-, or -CH2-.

[0092] In some embodiments, Y is —O—.

[0093] In some embodiments, Y is -S-.

[0094] In some embodiments, Y is -S(=O)-.

[0095] In some embodiments, Y is -S(=O)2-.

[0096] In some embodiments, Y is —S(═O)C(R 4 )2-.

[0097] In some embodiments, Y is —C(R 4 )2S(=O)-.

[0098] In some embodiments, Y is —S(═O)C(R 4 )2-.

[0099] In some embodiments, Y is —C(R 4 )2S(=O)2-.

[0100] In some embodiments, Y is -S(=O)CH2-.

[0101] In some embodiments, Y is —CH 2 S(═O)—.

[0102] In some embodiments, Y is -S(=O)2CH2-.

[0103] In some embodiments, Y is —CH 2 S(═O) 2 —.

[0104] In some embodiments, Y is —NR 4 -It is.

[0105] In some embodiments, Y is —OC(R 4 )2-.

[0106] In some embodiments, Y is —SC(R 4 )2-.

[0107] In some embodiments, Y is —C(R 4 )2O-.

[0108] In some embodiments, Y is —C(R 4 )2S-.

[0109] In some embodiments, Y is —C(R 4 )2NR 4 -It is.

[0110] In some embodiments, Y is —C(R 4 )2-.

[0111] In some embodiments, Y is —C(R 4 )2-C(R 4 )2-.

[0112] In some embodiments, Y is -CR 4 =CR 4 -It is.

[0113] In some embodiments, Y is -NH-. In some embodiments, Y is -OCH2-. In some embodiments, Y is -SCH2-. In some embodiments, Y is -CH2O-. In some embodiments, Y is -CH2S-. In some embodiments, Y is -CH2NR 4In some embodiments, Y is -CH2-. In some embodiments, Y is -CH2-CH2-. In some embodiments, Y is -CH=CH-.

[0114] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4 , -CF3, -OCF3, -OH, unsubstituted or R 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 and heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from:

[0115] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4 , -CF3, -OCF3, or

[0116] [ka] is selected from.

[0117] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4 is.

[0118] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4 and at least one R in Z 4 teeth,

[0119] [ka] is selected from.

[0120] In some embodiments, Z is -OR 4 or -SR 4 and Z's R 4 teeth,

[0121] [ka] is selected from.

[0122] In some embodiments, Z is

[0123] [ka] is selected from.

[0124] In some embodiments, Z is

[0125] [ka] is.

[0126] In some embodiments, Z is

[0127] [ka] is.

[0128] In some embodiments, Z is

[0129] [ka] is.

[0130] In some embodiments, Z is

[0131] [ka] is.

[0132] In some embodiments, Z is

[0133] [ka] is.

[0134] In some embodiments, Z is

[0135] [ka] is.

[0136] In some embodiments, Z is

[0137] [ka] is.

[0138] In some embodiments, Z is

[0139] [ka] is.

[0140] In some embodiments, Z is

[0141] [ka] is.

[0142] In some embodiments, Z is

[0143] [ka] is.

[0144] In some embodiments, Z is

[0145] [ka] is.

[0146] In some embodiments, Z is

[0147] [ka] is.

[0148] In some embodiments, Z is

[0149] [ka] is.

[0150] In some embodiments, Z is

[0151] [ka] is.

[0152] In some embodiments, Z is

[0153] [ka] is.

[0154] In some embodiments, Z is

[0155] [ka] is.

[0156] In some embodiments, Z is

[0157] [ka] is.

[0158] In some embodiments, Z is

[0159] [ka] is.

[0160] In some embodiments, Z is

[0161] [ka] is.

[0162] In some embodiments, Z is

[0163] [ka] is.

[0164] In some embodiments, Z is

[0165] [ka] is.

[0166] In some embodiments, Z is

[0167] [ka] is.

[0168] In some embodiments, Z is

[0169] [ka] is.

[0170] In some embodiments, Z is

[0171] [ka] is.

[0172] In some embodiments, Z is

[0173] [ka] is.

[0174] In some embodiments, Z is

[0175] [ka] is.

[0176] In some embodiments, Z is

[0177] [ka] is.

[0178] In some embodiments, Z is

[0179] [ka] is.

[0180] In some embodiments, Z is

[0181] [ka] is.

[0182] In some embodiments, Z is

[0183] [ka] is.

[0184] In some embodiments, Z is

[0185] [ka] is.

[0186] In some embodiments, Z is

[0187] [ka] is.

[0188] In some embodiments, Z is

[0189] [ka] is.

[0190] In some embodiments, Z is

[0191] [ka] is.

[0192] In some embodiments, R 1 or R 3 is substituted with halogen.

[0193] In some embodiments, R 1 or R 3 is substituted with chlorine.

[0194] In some embodiments, R 1 or R 3 is substituted with fluorine.

[0195] In some embodiments, R 1 or R 3 is substituted with C1-C4 heteroalkyl.

[0196] In some embodiments, at least one R in Z 4 teeth,

[0197] [ka] is selected from.

[0198] In some embodiments, the FSH modulators disclosed herein include Compound 1-01, Compound 1-02A, Compound 1-02, Compound 1-03, Compound 1-04, Compound 1-05, Compound 1-06, Compound 2-01, Compound 2-02, Compound 2-03, Compound 2-04, Compound 2-05, Compound 2-06, Compound 2-07, Compound 2-08, Compound 3-01, Compound 3-02, Compound 3-03, Compound 3-04, Compound 3-07, Compound 3-08, Compound 3-09, Compound 3-10A, Compound 3-10, Compound 3-11, Compound 3-12, Compound 4-01A, Compound 4-01, Compound 4-02A, Compound 4-02, Compound 4-03A, Compound 4-03, Compound 4-04A, Compound Compound 4-04, Compound 4-05A, Compound 4-05, Compound 4-06A, Compound 4-06, Compound 4-07A, Compound 4-07, Compound 4-08A, Compound 4-08, Compound 5-01, Compound 5-02, Compound 5-03, Compound 5- 04, compound 5-05, compound 5-06, compound 5-07, compound 5-08, compound 6-01A, compound 6-01B, compound 6-01, compound 6-02A, compound 6-02B, compound 6-02, compound 6-03, compound 6-04, Compound 6-05, Compound 6-06, Compound 6-07, Compound 6-08, Compound 8-01, Compound 8-02, Compound 8-03, Compound 8-05, Compound 8-06, Compound 8-07A, Compound 8-07, Compound 8-09, Compound 8-1 0, Compound 8-14, Compound 8-15, Compound 8-16B, Compound 8-16, Compound 8-17, Compound 8-20, Compound 8-21, Compound 8-22, Compound 8-23, Compound 8-24, Compound 8-25, Compound 8-26A, Compound 8-26, Compound 8-27, Compound 8-28, Compound 8-29, Compound 8-30, Compound 8-31, Compound 8-32, Compound 8-33, Compound 8-34, Compound 8-39, and Compound 8-44.

[0199] In some embodiments, the FSH modulators disclosed herein include Compound 8-77, Compound 8-75, Compound 8-76, Compound 8-78, Compound 8-81, Compound 8-61, Compound 8-60, Compound 8-63, Compound 8-58, Compound 8-51, Compound 8-67, Compound 8-74, Compound 8-4, Compound 8-8, Compound 8-4a, Compound 8-13, Compound 8-57, Compound 8-18, Compound 8-35, Compound 8-36, Compound 8-37, Compound 8-38, Compound 8-41, Compound 8-42, Compound 8-43, Compound 8-45, Compound 8-46 , compound 8-47, compound 8-49, compound 8-50, compound 8-52A, compound 8-54A, compound 8-55, compound 8-56, compound 8-62, compound 8-64, compound 8-65, compound 8-69, compound 8-70, compound 8-71, compound 8-79, compound 8-82, compound Compound 8-83, Compound 8-84, Compound 8-86, Compound 8-87, Compound 8-89, Compound 9-13, Compound 9-21, Compound 9-4, Compound 9-5, Compound 9-11, Compound 9-14, Compound 9-9, Compound 9-15, Compound 9-2, Compound 9-7, Compound 9-12, Compound 9 -16, Compound 9-17, Compound 9-18, Compound 9-19, Compound 9-20, Compound 10-1, Compound 10-2, Compound 10-3, Compound 10-6, Compound 10-7, Compound 10-8, Compound 10-9, Compound 10-10, Compound 11-1A, Compound 11-2, Compound 11-1 , Compound 11-3, Compound 12-2, Compound 12-23, Compound 12-13, Compound 12-15, Compound 12-16, Compound 12-1, Compound 12-4, Compound 12-18, Compound 12-19, Compound 13-1, Compound 13-4, Compound 13-9, Compound 13-7, Compound 13- 8, Compound 13-2, Compound 13-5, Compound 15-1, Compound 15-3, Compound 15-4, Compound 15-5, Compound 15-9, Compound 15-2, Compound 15-6, Compound 15-10, Compound 12-05, Compound 12-07, Compound 12-11, Compound 12-12, Compound 14- 03, compound 15-08, compound 15-10, compound 3-05, compound 3-06, compound 4-03B, compound 8-04A, compound 8-16A, compound 8-23A, compound 8-25A, compound 8-26B, compound 8-31A, compound 8-33A, compound 8-44, compound 8-66,The compound has a structure selected from the group consisting of Compound 8-72, Compound 8-90, Compound 8-90A, Compound 9-01, Compound 9-03, Compound 9-06, Compound 9-08, Compound 9-08A, Compound 9-10, Compound 9-19A, and Compound 9-24.

[0200] In another aspect, methods for modulating FSH using the compounds described herein are described herein. In some embodiments, the compounds described herein selectively modulate FSH and do not substantially modulate TSH. In some embodiments, the method comprises administering a compound described herein to a subject. In some embodiments, the compounds described herein are FSH agonists. In some embodiments, the compounds described herein are at least 3-fold selective for FSH over TSH (e.g., at least 3-fold, 5-fold, 10-fold, 20-fold, 50-fold, or 100-fold). In some embodiments, the in vitro or in vivo EC200 / ... 50 is about 100 nM or less (e.g., 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, or 500 pM or less).

[0201] In some embodiments, the methods described herein include treating a disease or condition, which includes administering a compound described herein to a subject in need thereof. In some embodiments, the disease or condition is a fertility disorder or male hypogonadism. In some embodiments, the disease or condition is cancer. In some embodiments, the cancer is breast cancer, prostate cancer, colon cancer, pancreatic cancer, bladder cancer, kidney cancer, lung cancer, liver cancer, stomach cancer, testicular cancer, or ovarian cancer. In some embodiments, the disease or condition is a cardiovascular disease. In some embodiments, the cardiovascular disease is atherosclerosis. In some embodiments, the disease or condition is a body composition disorder (e.g., obesity). In some embodiments, the disease or condition is non-alcoholic fatty liver disease. In some embodiments, the disease or condition is a bone density disorder (e.g., osteoporosis). In some embodiments, the disease or condition is Turner syndrome, Klinefelter syndrome, polycystic ovary syndrome (PCOS), and / or premature ovarian insufficiency (POI).

[0202] In some embodiments, the disease or condition is polycystic ovary syndrome (PCOS).

[0203] In some embodiments, the disease or condition is Turner syndrome.

[0204] In some embodiments, the disease or condition is Klinefelter's syndrome.

[0205] In some embodiments, the disease or condition is premature ovarian insufficiency (POI).

[0206] In another aspect, described herein are pharmaceutical compositions comprising any of the compounds described herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient or carrier.

[0207] In another aspect, described herein are pharmaceutically acceptable lipid nanoparticle formulations comprising the compounds described herein.

[0208] In some embodiments, the methods include treating a disease or condition, comprising administering to a subject in need thereof a compound described herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

[0209] In some embodiments, the method includes use of a compound described herein, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder. [Brief explanation of the drawings]

[0210] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings.

[0211] [Figure 1] 1 shows the nuclear magnetic resonance of compound 1-01. [Figure 2] 1 shows the nuclear magnetic resonance of compound 1-02A. [Figure 3] 1 shows the nuclear magnetic resonance of compound 1-02. [Figure 4] 1 shows the nuclear magnetic resonance of compound 1-03. [Figure 5] 1 shows the nuclear magnetic resonance of compound 1-04. [Figure 6] 1 shows the nuclear magnetic resonance of compound 1-05. [Figure 7] 1 shows the nuclear magnetic resonance of compound 1-06. [Figure 8] 1 shows the nuclear magnetic resonance of compound 2-01. [Figure 9] 1 shows the nuclear magnetic resonance of compound 2-02. [Figure 10] 1 shows the nuclear magnetic resonance of compound 2-03. [Figure 11] 1 shows the nuclear magnetic resonance of compound 2-04. [Figure 12] 1 shows the nuclear magnetic resonance of compound 2-05. [Figure 13] 1 shows the nuclear magnetic resonance of compound 2-06. [Figure 14] 1 shows the nuclear magnetic resonance of compound 2-07. [Figure 15] 1 shows the nuclear magnetic resonance of compound 2-08. [Figure 16] 1 shows the nuclear magnetic resonance of compound 3-01. [Figure 17] 1 shows the nuclear magnetic resonance of compound 3-02. [Figure 18] 1 shows the nuclear magnetic resonance of compound 3-03. [Figure 19] 1 shows the nuclear magnetic resonance of compound 3-04. [Figure 20] 1 shows the nuclear magnetic resonance of compound 3-07. [Figure 21] 1 shows the nuclear magnetic resonance of compound 3-08. [Figure 22] 1 shows the nuclear magnetic resonance of compound 3-09. [Figure 23] 1 shows the nuclear magnetic resonance of compound 3-10A. [Figure 24] 1 shows the nuclear magnetic resonance of compounds 3-10. [Figure 25] 1 shows the nuclear magnetic resonance of compound 3-11. [Figure 26] 1 shows the nuclear magnetic resonance of compound 3-12. [Figure 27] 1 shows the nuclear magnetic resonance of compound 4-01A. [Figure 28] 1 shows the nuclear magnetic resonance of compound 4-01. [Figure 29] 1 shows the nuclear magnetic resonance of compound 4-02A. [Figure 30] 1 shows the nuclear magnetic resonance of compound 4-02. [Figure 31] 1 shows the nuclear magnetic resonance of compound 4-03A. [Figure 32] 1 shows the nuclear magnetic resonance of compound 4-03. [Figure 33] 1 shows the nuclear magnetic resonance of compound 4-04A. [Figure 34] 1 shows the nuclear magnetic resonance of compound 4-04. [Figure 35] 1 shows the nuclear magnetic resonance of compound 4-05A. [Figure 36] 1 shows the nuclear magnetic resonance of compound 4-05. [Figure 37] 1 shows the nuclear magnetic resonance of compound 4-06A. [Figure 38] 1 shows the nuclear magnetic resonance of compound 4-06. [Figure 39] 1 shows the nuclear magnetic resonance of compound 4-07A. [Figure 40] 1 shows the nuclear magnetic resonance of compound 4-07. [Figure 41] 1 shows the nuclear magnetic resonance of compound 4-08A. [Figure 42] 1 shows the nuclear magnetic resonance of compound 4-08. [Figure 43] 1 shows the nuclear magnetic resonance of compound 5-01. [Figure 44] 1 shows the nuclear magnetic resonance of compound 5-02. [Figure 45] 1 shows the nuclear magnetic resonance of compound 5-03. [Figure 46] 1 shows the nuclear magnetic resonance of compound 5-04. [Figure 47] 1 shows the nuclear magnetic resonance of compound 5-05. [Figure 48] 1 shows the nuclear magnetic resonance of compound 5-06. [Figure 49] 1 shows the nuclear magnetic resonance of compound 5-07. [Figure 50] 1 shows the nuclear magnetic resonance of compound 5-08. [Figure 51] 1 shows the nuclear magnetic resonance of compound 6-01A. [Figure 52] 1 shows the nuclear magnetic resonance of compound 6-01B. [Figure 53] 1 shows the nuclear magnetic resonance of compound 6-01. [Figure 54] 1 shows the nuclear magnetic resonance of compound 6-02A. [Figure 55] 1 shows the nuclear magnetic resonance of compound 6-02B. [Figure 56] 1 shows the nuclear magnetic resonance of compound 6-02. [Figure 57] 1 shows the nuclear magnetic resonance of compound 6-03. [Figure 58] 1 shows the nuclear magnetic resonance of compound 6-04. [Figure 59] 1 shows the nuclear magnetic resonance of compound 6-05. [Figure 60] 1 shows the nuclear magnetic resonance of compound 6-06. [Figure 61] 1 shows the nuclear magnetic resonance of compound 6-07. [Figure 62] 1 shows the nuclear magnetic resonance of compound 6-08. [Figure 63] 1 shows the nuclear magnetic resonance of compound 8-01. [Figure 64] 1 shows the nuclear magnetic resonance of compound 8-02. [Figure 65] 1 shows the nuclear magnetic resonance of compound 8-03. [Figure 66] 1 shows the nuclear magnetic resonance of compound 8-05. [Figure 67] 1 shows the nuclear magnetic resonance of compound 8-06. [Figure 68] 1 shows the nuclear magnetic resonance of compound 8-07A. [Figure 69] 1 shows the nuclear magnetic resonance of compound 8-07. [Figure 70] 1 shows the nuclear magnetic resonance of compound 8-09. [Figure 71] 1 shows the nuclear magnetic resonance spectra of compounds 8-10. [Figure 72] 1 shows the nuclear magnetic resonance spectra of compounds 8-14. [Figure 73] 1 shows the nuclear magnetic resonance of compounds 8-15. [Figure 74] 1 shows the nuclear magnetic resonance of compound 8-16B. [Figure 75] 1 shows the nuclear magnetic resonance spectra of compounds 8-16. [Figure 76] 1 shows the nuclear magnetic resonance of compounds 8-17. [Figure 77] 1 shows the nuclear magnetic resonance of compounds 8-20. [Figure 78] 1 shows the nuclear magnetic resonance of compound 8-21. [Figure 79] 1 shows the nuclear magnetic resonance of compound 8-22. [Figure 80]1 shows the nuclear magnetic resonance of compound 8-23. [Figure 81] 1 shows the nuclear magnetic resonance of compound 8-24. [Figure 82] 1 shows the nuclear magnetic resonance of compound 8-25. [Figure 83] 1 shows the nuclear magnetic resonance of compound 8-26A. [Figure 84] 1 shows the nuclear magnetic resonance of compound 8-26. [Figure 85] 1 shows the nuclear magnetic resonance of compound 8-27. [Figure 86] 1 shows the nuclear magnetic resonance of compound 8-28. [Figure 87] 1 shows the nuclear magnetic resonance of compound 8-29. [Figure 88] 1 shows the nuclear magnetic resonance of compound 8-30. [Figure 89] 1 shows the nuclear magnetic resonance of compound 8-31. [Figure 90] 1 shows the nuclear magnetic resonance of compound 8-32. [Figure 91] 1 shows the nuclear magnetic resonance of compound 8-33. [Figure 92] 1 shows the nuclear magnetic resonance of compound 8-34. [Figure 93] 1 shows the nuclear magnetic resonance of compound 8-39. [Figure 94] 1 shows the nuclear magnetic resonance of compound 8-44. [Figure 95] 1 shows the nuclear magnetic resonance of compound 8-77. [Figure 96] 1 shows the nuclear magnetic resonance of compound 8-75. [Figure 97] 1 shows the nuclear magnetic resonance of compound 8-76. [Figure 98] 1 shows the nuclear magnetic resonance of compound 8-78. [Figure 99] 1 shows the nuclear magnetic resonance of compound 8-81. [Figure 100] 1 shows the nuclear magnetic resonance of compound 8-61. [Figure 101] 1 shows the nuclear magnetic resonance of compound 8-60. [Figure 102] 1 shows the nuclear magnetic resonance of compound 8-63. [Figure 103]1 shows the nuclear magnetic resonance of compound 8-58. [Figure 104] 1 shows the nuclear magnetic resonance of compound 8-51. [Figure 105] 1 shows the nuclear magnetic resonance of compound 8-67. [Figure 106] 1 shows the nuclear magnetic resonance of compound 8-74. [Figure 107] 1 shows the nuclear magnetic resonance of compound 8-4. [Figure 108] 1 shows the nuclear magnetic resonance of compound 8-8. [Figure 109] 1 shows the nuclear magnetic resonance of compound 8-4a. [Figure 110] 1 shows the nuclear magnetic resonance spectra of compounds 8-13. [Figure 111] 1 shows the nuclear magnetic resonance of compound 8-57. [Figure 112] 1 shows the nuclear magnetic resonance of compounds 8-18. [Figure 113] 1 shows the nuclear magnetic resonance of compound 8-35. [Figure 114] 1 shows the nuclear magnetic resonance of compound 8-36. [Figure 115] 1 shows the nuclear magnetic resonance of compound 8-37. [Figure 116] 1 shows the nuclear magnetic resonance of compound 8-38. [Figure 117] 1 shows the nuclear magnetic resonance of compound 8-41. [Figure 118] 1 shows the nuclear magnetic resonance of compound 8-42. [Figure 119] 1 shows the nuclear magnetic resonance of compound 8-43. [Figure 120] 1 shows the nuclear magnetic resonance of compound 8-45. [Figure 121] 1 shows the nuclear magnetic resonance of compound 8-46. [Figure 122] 1 shows the nuclear magnetic resonance of compound 8-47. [Figure 123] 1 shows the nuclear magnetic resonance of compound 8-49. [Figure 124] 1 shows the nuclear magnetic resonance of compound 8-50. [Figure 125] 1 shows the nuclear magnetic resonance of compound 8-52A. [Figure 126]1 shows the nuclear magnetic resonance of compound 8-54A. [Figure 127] 1 shows the nuclear magnetic resonance of compound 8-55. [Figure 128] 1 shows the nuclear magnetic resonance of compound 8-56. [Figure 129] 1 shows the nuclear magnetic resonance of compound 8-62. [Figure 130] 1 shows the nuclear magnetic resonance of compound 8-64. [Figure 131] 1 shows the nuclear magnetic resonance of compound 8-65. [Figure 132] 1 shows the nuclear magnetic resonance of compound 8-69. [Figure 133] 1 shows the nuclear magnetic resonance of compound 8-70. [Figure 134] 1 shows the nuclear magnetic resonance of compound 8-71. [Figure 135] 1 shows the nuclear magnetic resonance of compound 8-79. [Figure 136] 1 shows the nuclear magnetic resonance of compound 8-82. [Figure 137] 1 shows the nuclear magnetic resonance of compound 8-83. [Figure 138] 1 shows the nuclear magnetic resonance of compound 8-84. [Figure 139] 1 shows the nuclear magnetic resonance of compound 8-86. [Figure 140] 1 shows the nuclear magnetic resonance of compound 8-87. [Figure 141] 1 shows the nuclear magnetic resonance of compound 8-89. [Figure 142] 1 shows the nuclear magnetic resonance spectra of compounds 9-13. [Figure 143] 1 shows the nuclear magnetic resonance of compounds 9-21. [Figure 144] 1 shows the nuclear magnetic resonance of compound 9-4. [Figure 145] 1 shows the nuclear magnetic resonance of compound 9-5. [Figure 146] 1 shows the nuclear magnetic resonance spectra of compounds 9-11. [Figure 147] 1 shows the nuclear magnetic resonance spectra of compounds 9-14. [Figure 148] 1 shows the nuclear magnetic resonance of compound 9-9. [Figure 149]1 shows the nuclear magnetic resonance spectra of compounds 9-15. [Figure 150] 1 shows the nuclear magnetic resonance of compound 9-2. [Figure 151] 1 shows the nuclear magnetic resonance of compound 9-7. [Figure 152] 1 shows the nuclear magnetic resonance spectra of compounds 9-12. [Figure 153] 1 shows the nuclear magnetic resonance spectra of compounds 9-16. [Fig. 154] 1 shows the nuclear magnetic resonance of compounds 9-17. [Figure 155] 1 shows the nuclear magnetic resonance spectra of compounds 9-18. [Figure 156] 1 shows the nuclear magnetic resonance of compounds 9-19. [Figure 157] 1 shows the nuclear magnetic resonance of compounds 9-20. [Figure 158] 1 shows the nuclear magnetic resonance of compound 10-1. [Figure 159] 1 shows the nuclear magnetic resonance of compound 10-2. [Figure 160] 1 shows the nuclear magnetic resonance of compound 10-3. [Figure 161] 1 shows the nuclear magnetic resonance of compound 10-6. [Figure 162] 1 shows the nuclear magnetic resonance of compound 10-7. [Figure 163] 1 shows the nuclear magnetic resonance of compound 10-8. [Fig. 164] 1 shows the nuclear magnetic resonance of compound 10-9. [Figure 165] 1 shows the nuclear magnetic resonance of compound 10-10. [Figure 166] 1 shows the nuclear magnetic resonance of compound 11-1A. [Figure 167] 1 shows the nuclear magnetic resonance of compound 11-2. [Figure 168] 1 shows the nuclear magnetic resonance of compound 11-1. [Figure 169] 1 shows the nuclear magnetic resonance of compound 11-3. [Figure 170] 1 shows the nuclear magnetic resonance of compound 12-2. [Figure 171] 1 shows the nuclear magnetic resonance of compounds 12-23. [Fig. 172]1 shows the nuclear magnetic resonance of compounds 12-13. [Figure 173] 1 shows the nuclear magnetic resonance spectra of compounds 12-15. [Fig. 174] 1 shows the nuclear magnetic resonance spectra of compounds 12-16. [Figure 175] 1 shows the nuclear magnetic resonance of compound 12-1. [Figure 176] 1 shows the nuclear magnetic resonance of compound 12-4. [Figure 177] 1 shows the nuclear magnetic resonance spectra of compounds 12-18. [Figure 178] 1 shows the nuclear magnetic resonance spectra of compounds 12-19. [Figure 179] 1 shows the nuclear magnetic resonance of compound 13-1. [Figure 180] 1 shows the nuclear magnetic resonance of compound 13-4. [Figure 181] 1 shows the nuclear magnetic resonance of compound 13-9. [Figure 182] 1 shows the nuclear magnetic resonance of compound 13-7. [Figure 183] 1 shows the nuclear magnetic resonance of compound 13-8. [Figure 184] 1 shows the nuclear magnetic resonance of compound 13-2. [Figure 185] 1 shows the nuclear magnetic resonance of compound 13-5. [Figure 186] 1 shows the nuclear magnetic resonance of compound 15-1. [Figure 187] 1 shows the nuclear magnetic resonance of compound 15-3. [Figure 188] 1 shows the nuclear magnetic resonance of compound 15-4. [Figure 189] 1 shows the nuclear magnetic resonance of compound 15-5. [Figure 190] 1 shows the nuclear magnetic resonance of compound 15-9. [Figure 191] 1 shows the nuclear magnetic resonance of compound 15-2. [Figure 192] 1 shows the nuclear magnetic resonance of compound 15-6. [Figure 193] 1 shows the nuclear magnetic resonance of compound 15-10. DETAILED DESCRIPTION OF THE INVENTION

[0212] definition The terminology used herein is for the purpose of describing particular instances only and is not intended to be limiting. In this application, the use of the singular includes the plural unless otherwise specified.

[0213] As used in this specification and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless the context clearly dictates otherwise. Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed disclosure.

[0214] Abbreviations used herein have their conventional meaning within the chemical and biological arts unless otherwise specified. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0215] symbol"

[0216] [ka] " indicates the point of attachment of the chemical moiety to the rest of the molecule or chemical formula.

[0217] As used herein, the terms "about" or "approximately" may mean within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, which may depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" may mean within one or more standard deviations, in accordance with practice in the art. Alternatively, "about" may mean within a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term may mean within an order of magnitude, within five-fold, or within two-fold of a value. When particular values ​​are described in this application and claims, unless otherwise specified, the term "about" should be assumed to mean within an acceptable range of error for the particular value.

[0218] As used herein, the terms "comprising" (and any form of "comprising," e.g., "comprise" and "comprises"), "having" (and any form of "having," e.g., "have" and "has"), "including" (and any form of "comprising," e.g., "includes" and "include"), or "containing" (and any form of "containing," e.g., "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed herein may be implemented with respect to any method or composition of the disclosure, and vice versa. Furthermore, the compositions of the disclosure can be used to achieve the methods of the disclosure.

[0219] As used herein, the term "derivative" refers to a chemical or biological substance that is structurally related to and derivable from a second substance through modification of the second substance. In particular, when a first compound is a derivative of a second compound, and the second compound is associated with chemical and / or biological activity, the first compound differs from the second compound in at least one structural feature while retaining (at least to some extent) the chemical and / or biological activity of the second compound and at least one structural feature associated therewith (e.g., sequence, fragment, functional group, etc.). Non-limiting examples of "derivatives" include prodrugs, metabolites, enantiomers, diastereomers, esters (e.g., acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sulfonate esters, sulfate esters, and disulfide-containing esters), ethers, amides, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts, sulfonate esters, etc. In some cases, derivatives may contain insignificant substitutions (i.e., additional alkyl / alkylene groups) on the parent compound that retain the chemical and / or biological activity of the parent compound.

[0220] As used herein, the term "pharmaceutically acceptable salt" generally refers to an acid or base salt generally considered in the art to be suitable for use in contact with the tissues of humans or animals without undue toxicity, irritation, allergic response, or other problem or complication. Such salts include mineral and organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, malic acid, glycolic acid, fumaric acid, sulfuric acid, sulfamic acid, sulfanilic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethanedisulfonic acid, 2-hydroxyethylsulfonic acid, nitric acid, benzoic acid, 2-acetoxybenzoic acid, citric acid, tartaric acid, lactic acid, stearic acid, salicylic acid, glutamic acid, ascorbic acid, pamoic acid, succinic acid, fumaric acid, maleic acid, propionic acid, hydroxymaleic acid, hydroiodic acid, phenylacetic acid, alkanoic acids, e.g., acetic acid, HOOC-(CH)-COOH (where n is 0-4), etc. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. Those skilled in the art will understand from this disclosure and knowledge in the art that additional pharmaceutically acceptable salts include those listed by Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, p. 1418 (1985). In general, pharmaceutically acceptable acid or base salts can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in a suitable solvent.

[0221] As used herein, the term "pharmaceutically acceptable excipient, carrier, or diluent" refers to an excipient, carrier, or diluent that can be administered to a subject together with a drug, does not destroy its pharmacological activity, and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the drug.

[0222] As used herein, the term "therapeutically effective amount" means an amount of a delivered agent (e.g., nucleic acid, drug, payload, composition, therapeutic agent, diagnostic agent, prophylactic agent, etc.) that, when administered to a subject suffering from or susceptible to an infection, disease, disorder, and / or condition, is sufficient to treat, ameliorate, diagnose, prevent symptoms of, and / or delay the onset of, the infection, disease, disorder, and / or condition.

[0223] Ranges provided herein are understood to be shorthand for all values ​​within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all decimal values ​​between the aforementioned integers, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to subranges, "nested subranges" extending from either end of the range are specifically contemplated. For example, nested subranges of the exemplary range of 1 to 50 could include 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0224] As used herein, the term "subject" refers to an animal that is the object of treatment, observation, or experiment. By way of example only, a subject includes, but is not limited to, a mammal, including, but not limited to, a human or a non-human mammal, such as a non-human primate, cow, horse, dog, sheep, or cat.

[0225] As used herein, the term "aromatic" generally refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons, where n is an integer. Aromatics may be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0226] As used herein, the term "halo" or "halogen" generally refers to bromo, chloro, fluoro, and iodo.

[0227] As used herein, the term "haloalkyl" generally refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.

[0228] As used herein, the term "haloalkoxy" generally refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, etc. Unless stated otherwise specifically in the specification, a haloalkoxy group can be optionally substituted.

[0229] As used herein, the term "fluoroalkyl" generally refers to an alkyl group in which one or more hydrogen atoms are replaced with fluorine.

[0230] As used herein, the term "tautomer" generally refers to the migration of a proton from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by the migration of a hydrogen atom, accompanied by the conversion of a single bond and an adjacent double bond. In bond arrangements that allow tautomerization, a chemical equilibrium of tautomers may exist. All tautomeric forms of the compounds disclosed herein are considered. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversions include the following:

[0231] [ka]

[0232] As used herein, the term "effective amount" or "therapeutically effective amount" generally refers to a sufficient amount of an agent or compound administered to ameliorate to some extent one or more symptoms of the disease or condition being treated. The result is a reduction and / or alleviation of the symptoms, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein required to clinically significantly reduce a symptom of the disease. An appropriate "effective" amount in a particular case may be determined using techniques such as a dose escalation study. An "effective amount" is an amount of a compound sufficient to achieve the stated purpose (e.g., achieve the effect for which the compound is administered, treat the disease, decrease enzyme activity, increase enzyme activity, decrease a signal transduction pathway, or alleviate one or more symptoms of the disease or condition). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or alleviation of a symptom(s) of a disease, which may also be referred to as a "therapeutically effective amount." "Relief" of a symptom(s) (and grammatical equivalents of this phrase) means a decrease in the severity or frequency of the symptom(s), or the elimination of the symptom(s). A "prophylactically effective amount" of a drug is an amount of drug that, when administered to a subject, will produce the intended prophylactic effect, e.g., prevent or delay the onset (or recurrence) of an injury, disease, lesion, or illness, or reduce the likelihood of the onset (or recurrence) of an injury, disease, lesion, or illness, or symptoms thereof. A complete prophylactic effect does not necessarily occur with the administration of a single dose, but may occur only after the administration of a series of doses. Thus, a prophylactically effective amount can be administered in one or more administrations. As used herein, an "activity-reducing amount" refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of the antagonist. As used herein, a "function-disrupting amount" refers to the amount of antagonist required to disrupt the function of an enzyme or protein compared to the absence of the antagonist.The exact amount may depend on the purpose of the treatment, and may be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 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).

[0233] As used herein, the term "substituted," unless otherwise indicated, refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent, including, but not limited to, halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, oxo, thioxy, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic groups. It is understood that the substituent can be further substituted. Examples of the substituent include amino, alkylamino, and the like.

[0234] As used herein, the term "substituent" generally refers to a positional variable on an atom of a core molecule that is substituted at the designated atomic position, replacing one or more hydrogens on the designated atom, provided that the substitution does not exceed the normal valence of the designated atom and results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. Those of skill in the art should note that any carbon and heteroatom having an unsatisfied valence as described or shown herein is assumed to have a sufficient number of hydrogen atoms to satisfy the valences described or shown. In certain cases, one or more substituents having a double bond (e.g., "oxo" or "=O") as the point of attachment may be described, displayed, or listed within a substituent group, and the structure may show only a single bond as the point of attachment to the core structure of Formula (I). Those of skill in the art will understand that although only a single bond is shown, a double bond is intended for those substituents.

[0235] The term "alkyl" generally refers to a straight or branched hydrocarbon chain radical having from 1 to 20 carbon atoms and attached to the rest of the molecule by a single bond. Alkyl containing up to 10 carbon atoms includes C1-C 10 Similarly, when referred to as alkyl, for example, an alkyl containing up to 6 carbon atoms is a C1-C6 alkyl. Alkyl groups containing other numbers of carbon atoms (and other moieties defined herein) are similarly represented. Alkyl groups include, but are not limited to, C1-C 10

[0023] Examples of alkyl include alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl, and C4-C8 alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethyl-propyl, and the like. In some embodiments, alkyl is methyl or ethyl. In some embodiments, alkyl is -CH(CH3)2 or -C(CH3)3. Unless otherwise specified specifically in the specification, alkyl groups may be optionally substituted as described below. "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group. In some embodiments, alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, alkylene is -CH2-. In some embodiments, alkylene is -CH2CH2-. In some embodiments, alkylene is -CH2CH2CH2-. In some embodiments, alkylene is -CH2CH2CH2-.

[0236] As used herein, the term "aryl" refers to a radical derived from a hydrocarbon ring system containing at least one aromatic ring. In some embodiments, an aryl contains hydrogen and 6 to 30 carbon atoms. An aryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, an aryl is a 6- to 10-membered aryl. In some embodiments, an aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, an aryl is phenyl. Unless otherwise specified specifically in the specification, an aryl can be optionally substituted with, for example, halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)NH-C1-C6 alkyl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, -NO2, -S(O)2NH2, -S(O)2NHCH3, -S(O)2NHCH2CH3, -S(O)2NHCH(CH3)2, -S(O)2N(CH3)2, or -S(O)2NHC(CH3)3. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with a halogen.In some embodiments, the aryl is substituted with an alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, and each alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl is independently unsubstituted or substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.

[0237] As used herein, the term "alkenyl" generally refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R a )=CR a 2, where R a refers to the remainder of the alkenyl group and may be the same or different. In some embodiments, R a is H or alkyl. In some embodiments, alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2. "Alkenylene" or "alkenylene chain" refers to an alkylene group in which at least one carbon-carbon double bond is present. In some embodiments, alkenylene is -CH=CH-, -CH2CH2CH=CH-, or -CH=CHCH2CH2-. In some embodiments, alkenylene is -CH=CH-. In some embodiments, alkenylene is -CH2CH2CH=CH-. In some embodiments, alkenylene is -CH=CHCH2CH2-.

[0238] As used herein, the term "alkynyl" generally refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkynyl group has the formula -C≡CR a and R a refers to the remainder of the alkynyl group. In some embodiments, Ra is H or alkyl. In some embodiments, alkynyl is selected from ethynyl (i.e., acetylenyl), propynyl (i.e., propargyl), butynyl, pentynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH, and -CHC≡CH. "Alkynylene" or "alkynylene chain" refers to an alkylene group in which at least one carbon-carbon triple bond is present. In some embodiments, alkynylene is -C≡C-, -CHCHC≡C-, or -C≡CCHCH-. In some embodiments, alkynylene is -C≡C-. In some embodiments, alkynylene is -CHCHC≡C-. In some embodiments, alkynylene is -C≡C-.

[0239] As used herein, the term "cycloalkyl" generally refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is saturated or partially unsaturated. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is fused to an aromatic ring (in which case the cycloalkyl is attached via a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetraynyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. Unless otherwise specified in the specification, cycloalkyl groups can be optionally substituted. Depending on the structure, cycloalkyl groups can be monovalent or divalent (i.e., cycloalkylene groups).

[0240] As used herein, the term "heterocycle" or "heterocyclic" generally refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, each heterocyclic group having 3 to 12 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. A "heterocyclyl" is a monovalent group formed by removing a hydrogen atom from any ring atom of a heterocyclic compound. In some embodiments, the heterocycle is a monocyclic, bicyclic, polycyclic, spirocyclic, or bridged compound. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) contain rings having 3 to 12 atoms in their ring system, and aromatic heterocyclic groups contain rings having 5 to 12 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems.Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithio ranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3h-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolidinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-attached where possible. For example, a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).Further, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0241] As used herein, the term "heterocycloalkyl" generally refers to a cycloalkyl group containing at least one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified specifically in the specification, a heterocycloalkyl radical may be a monocyclic or bicyclic ring system, which may include a fused ring system (when fused with an aryl ring or heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or a bridged ring system. The nitrogen, carbon, or sulfur atom in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical may be partially or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycloalkyls have 2-10 carbons in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons and 1 or 2 N atoms in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons and 3 or 4 N atoms in the ring. In some embodiments, heterocycloalkyls have 2-12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring.In some embodiments, a heterocycloalkyl has 2 to 12 carbons, 1 to 3 N atoms, 0 to 2 O atoms, and 0 to 2 S atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) comprising the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Unless otherwise specified specifically in this specification, a heterocycloalkyl group can be optionally substituted. As used herein, the term "heterocycloalkylene" can refer to a divalent heterocycloalkyl group.

[0242] As used herein, the term "heteroaryl" generally refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryls are monocyclic or bicyclic. Specific examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Specific examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Specific examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furyl. In some embodiments, heteroaryl contains 0 to 6 N atoms in the ring. In some embodiments, the heteroaryl contains 1 to 4 N atoms in the ring. In some embodiments, the heteroaryl contains 4 to 6 N atoms in the ring. In some embodiments, the heteroaryl contains 0 to 4 N atoms, 0 to 1 O atoms, 0 to 1 P atoms, and 0 to 1 S atoms in the ring. In some embodiments, the heteroaryl contains 1 to 4 N atoms, 0 to 1 O atoms, and 0 to 1 S atoms in the ring.In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl. In some embodiments, the heteroaryl group is partially reduced to form a heterocycloalkyl group as defined herein. In some embodiments, the heteroaryl group is fully reduced to form a heterocycloalkyl group as defined herein.

[0243] As used herein, the term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl is selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -N(aryl)-), sulfur (e.g., -S-, -S(=O)-, or -S(=O)-), or combinations thereof. In some embodiments, a heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the remainder of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C-C heteroalkyl. Representative heteroalkyl groups include, but are not limited to, -OCHOMe, -OCHCHOH, -OCHCHOMe, or -OCHCHOCHCHNH. "Heteroalkylene" or "heteroalkylene chain" refers to a straight or branched divalent heteroalkyl chain connecting the rest of the molecule to a radical group. Unless stated otherwise specifically in the specification, a heteroalkyl or heteroalkylene group may be optionally substituted. Representative heteroalkylene groups include, but are not limited to, -OCH2CH2O-, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-.

[0244] As used herein, the term "heteroalkenyl" refers to an alkenyl group in which one or more skeletal atoms of the alkenyl is selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -N(aryl)-), sulfur (e.g., -S-, -S(=O)-, or -S(=O)-), or combinations thereof. In some embodiments, a heteroalkenyl is attached to the remainder of the molecule at a carbon atom of the heteroalkenyl. In some embodiments, a heteroalkenyl is attached to the remainder of the molecule at a heteroatom of the heteroalkenyl. In some embodiments, a heteroalkyl is a C-C heteroalkenyl.

[0245] As used herein, the term "heteroalkynyl" refers to an alkynyl group in which one or more skeletal atoms of the alkynyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -N(aryl)-), sulfur (e.g., -S-, -S(=O)-, or -S(=O)-), or combinations thereof. In some embodiments, the heteroalkynyl is attached to the remainder of the molecule at a carbon atom of the heteroalkynyl. In some embodiments, the heteroalkynyl is attached to the remainder of the molecule at a heteroatom of the heteroalkynyl. In some embodiments, the heteroalkyl is a C1-C6 heteroalkynyl.

[0246] As used herein, the term "heteroatom" or "ring heteroatom" generally refers to atoms including oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si), or any combination thereof.

[0247] As used herein, the term "substituent" refers to a group selected from the following moieties: (A) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl substituted with at least one substituent selected from the following: (i) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted with at least one substituent selected from the following: (a) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl substituted with at least one substituent selected from oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -S04H, -SON2NH2, NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHS02H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.

[0248] In some embodiments, each substituent described in the compounds herein is substituted with at least one substituent. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein is substituted with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower-rank substituent.

[0249] FSH modulators The only medication approved to date for ovulation induction is clomiphene citrate, a mixture of estrogen agonist and antagonist isomers used to increase endogenous FSH and LH secretion. Prescription clomiphene aims to increase endogenous plasma FSH and LH levels to levels sufficient to promote the development of one or two follicles so that they are ovulated. The mechanism of action of clomiphene and the off-label use of aromatase inhibitors is indirect, resulting in a homogeneous response in the hypothalamic-pituitary-ovarian axis across patient subgroups, achieving comparable responders across patients. The FSH modulators described herein (e.g., orally active FSH receptor agonists) do not require hypothalamic-pituitary administration for efficacy, for example, by acting directly on the ovaries, and can demonstrate improved ovulation induction with lower doses of FSH agonists. In this regard, the FSH modulators (e.g., oral FSH receptor agonists) described herein can provide improved efficacy and precision of control in ovulation induction over that which can be achieved by administration of (approved) clomiphene or (off-label) aromatase inhibitors.

[0250] According to one embodiment, the present disclosure relates to a method for allosterically modulating FSHR activity in a biological sample, the method comprising contacting the biological sample with a compound of the present disclosure or a composition comprising the compound. According to another embodiment, the present disclosure relates to a method for positively allosterically modulating the activity of FSHR or a variant thereof in a biological sample, the method comprising contacting the biological sample with a compound of the present disclosure or a composition comprising the compound.

[0251] The compounds of the present disclosure are potent and selective modulators of the FSH receptor. In some instances, their selectivity for the FSH receptor is 3-10 times greater than that for the LH receptor, and even 10-100 times greater than that for the TSH receptor. In some embodiments, EC 50 or IC 50or greater than 10 μM in total at unrelated G protein-coupled receptors (GPCRs) or non-GPCR targets. In some instances, the selectivity of an FSH modulator for the FSH receptor can be 100-200 fold greater than the LH receptor. The present disclosure includes the use of compounds of the present disclosure in the control and / or modulation of the FSHR signaling cascade, which can be advantageously applied as research tools for the diagnosis and / or treatment of any disorder resulting from FSHR signaling.

[0252] For example, the compounds of the present disclosure are useful in vitro as unique tools for understanding the biological involvement of FSH, including evaluating the many factors that affect and are thought to be affected by FSH production and the interaction between FSH and FSHR (e.g., FSH signaling / receptor activation mechanisms). The compounds are also useful for the development of other compounds that interact with FSHR, because they provide important structure-activity relationship (SAR) information that facilitates such development. Compounds of the present disclosure that bind to FSHR can be used as reagents for detecting FSHR in live cells, fixed cells, biological fluids, tissue homogenates, purified natural biomaterials, and the like. For example, by labeling such compounds, cells bearing FSHR on their surface can be identified. In addition, based on their ability to bind to FSHR, the compounds of the present disclosure can be used in receptor purification, or purification of cells expressing FSHR on the cell surface or inside permeabilized cells, such as in situ staining, FACS (fluorescence-activated cell sorting), Western blotting, and ELISA (enzyme-linked immunosorbent assay). Compounds of the present disclosure that bind to FSHR can also be used to distinguish the actions of FSH independent of the carbohydrate moiety, including the glycoprotein nature of FSH, and to identify essential and alternative cellular responses of small molecule FSHR agonists to glycoprotein FSH.

[0253] The compounds of the present disclosure can also be used as commercially available research reagents for various medical research and diagnostic applications. Such uses include, but are not limited to, use as calibration standards for quantifying the activity of candidate FSH agonists in various functional assays, use as blocking agents in random compound screening (i.e., in the search for a new family of FSH receptor ligands, this compound can be used to prevent the recovery of the claimed FSH compound), use in co-crystallization with FSHR receptor (i.e., the compounds of the present disclosure can form crystals of the compound bound to FSHR, allowing the determination of receptor / compound structure by X-ray crystallography or cryoEM), other research and diagnostic applications, where FSHR is preferably activated, or this activation can be easily calibrated against a known amount of FSH agonist, etc., use as a probe in assays to determine the expression of FSHR on the surface of cells, and development of assays to detect compounds that bind to the same site as the ligand that binds to FSHR.

[0254] The compounds of the present disclosure can be applied alone and / or in combination with physical measurement means to diagnose the treatment effect. Pharmaceutical compositions containing the compounds and the use of the compounds to treat FSHR-mediated diseases are promising new approaches for a wide range of treatments that directly and immediately improve the condition in either humans or animals. The effects, alone or in combination with other fertility-inducing treatments, are of particular interest for effectively combating infertility.

[0255] In particular, the compounds of the present disclosure enhance the inherent FSH effects for both ovulation induction and assisted reproductive techniques. The novel chemical entities of the present disclosure that are orally bioavailable and active allow for increased convenience for patients and compliance for physicians.

[0256] The compounds of the present disclosure are active in the primary screen (CHO with or without FSH), selective in the secondary screen (inactive or low activity against TSHR and LHR), and potent in the granulosa cell estradiol assay. No adverse effects on hERG were observed in vitro.

[0257] In certain embodiments, the present disclosure provides (a) treating a mammal according to the method described above; (b) collecting eggs from the mammal; (c) fertilizing the eggs; and (d) implanting the fertilized egg into a host mammal. The present invention provides an in vitro fertilization method comprising:

[0258] Described herein are FSH modulator compounds, pharmaceutically acceptable salts or solvates thereof, pharmaceutical compositions comprising the FSH modulator compounds (or pharmaceutically acceptable salts or solvates thereof), lipid nanoparticle compositions comprising an FSH modulator, and methods of treating disease comprising administering to a subject in need thereof an FSH modulator compound, a pharmaceutically acceptable salt or solvate thereof, a pharmaceutical composition comprising the FSH modulator compound (or a pharmaceutically acceptable salt or solvate thereof) and / or a lipid nanoparticle composition comprising an FSH modulator (or a pharmaceutically acceptable salt or solvate thereof) described herein.

[0259] In some embodiments, the compounds of the present disclosure can exhibit low or no activity against FSHR as agonists. Such low-activity agonists can have similar structural characteristics to potent FSHR agonists that are antagonists of the glycoprotein hormone FSH. In some embodiments, inactive (e.g., low-activity) FSHR compounds can displace potent FSHR agonists with similar structural characteristics and inhibit their activity. Such compounds can also be useful as diagnostic agents by displacing agonists that do not have agonist activity themselves.

[0260] In some instances, an inactive compound of the present disclosure can attenuate the activity of a more active compound by displacing the agonist activity of the more active compound. In some embodiments, the inactive compound may be useful, for example, to prevent overstimulation of agonist responses in women and / or to avoid or alleviate ovarian hyperstimulation syndrome.

[0261] In some examples, the FSH modulators or compositions described herein have the formula (I):

[0262] [ka] or a pharmaceutically acceptable salt thereof.

[0263] In some embodiments, R 1 is unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkenyl, unsubstituted or R 5 C3-C substituted with one, two, three, four, or five groups selected from 16Heteroaryl, unsubstituted or R 5 C aryl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C1-C substituted with one, two, three, four, or five groups selected from 16 It is alkynyl.

[0264] In some embodiments, Y is —OC(R 4 )2-.

[0265] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4 , -CF3, -OCF3, -OH, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Heteroalkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkyl, unsubstituted or R 5C1-C substituted with one, two, three, four, or five groups selected from 16 Alkenyl, unsubstituted or R 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalekenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C substituted with one, two, three, four, or five groups selected from 16 It is alkynyl.

[0266] In some embodiments, R 2 is -CF3, -OCF3, or -OCH2CH3.

[0267] In some embodiments, R 3 is hydrogen, halogen, -CF3, -OCF3, -OH, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Heteroalkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkyl, unsubstituted or R 5C1-C substituted with one, two, three, four, or five groups selected from 16 Alkenyl, unsubstituted or R 5 C3-C substituted with one, two, three, four, or five groups selected from 16 Heteroaryl, unsubstituted or R 5 C aryl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalekenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C1-C substituted with one, two, three, four, or five groups selected from 16 It is alkynyl.

[0268] In some embodiments, each R 4 are independently hydrogen, halogen, -CF3, -OCF3, -OH, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Heteroalkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16Alkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkenyl, unsubstituted or R 5 C3-C substituted with one, two, three, four, or five groups selected from 16 Heteroaryl, unsubstituted or R 5 C aryl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalekenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C1-C substituted with one, two, three, four, or five groups selected from 16 It is alkynyl.

[0269] In some embodiments, each R 5 are independently deuterium, halogen, -OH, -NO2, -CN, -SR 6 , -S(=O)R 6 , -S(=O)2R 6 , -N(R 6 )2, -C(=O)R 6 , -OC(=O)R 6 , -C(=O)OR6 , -C(=O)N(R 6 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0270] In some embodiments, each R 6 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0271] In some embodiments, Y is —O—, —S—, —NR 4 -, -SC(R 4 )2-, -C(R 4 )2O-, -C(R 4 )2S-, -C(R 4 )2NR 4 -, -C(R 4 )2-, -S(=O)C(R 4 )2-, -C(R 4 )2S(=O)-, -S(=O)2C(R 4 )2-, -C(R 4 )2S(=O)2-, or -CR 4 =CR 4 -It is.

[0272] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4 , -CF3, -OCF3, -OH, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16Heteroalkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkenyl, unsubstituted or R 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalekenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C substituted with one, two, three, four, or five groups selected from 16 It is alkynyl.

[0273] In some embodiments, R 2 is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —CF3, —OCF3, —S02R, —SOR, —C(O)R, —C02R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or —N(R)2.

[0274] In some embodiments, Y is —O—, —S—, —NR 4 -, -OC(R 4)2-, -SC(R 4 )2-, -C(R 4 )2O-, -C(R 4 )2S-, -C(R 4 )2NR 4 -, -C(R 4 )2-, -C(R 4 )2-C(R 4 )2-, or -CR 4 =CR 4 -It is.

[0275] In some embodiments, R is hydrogen, halogen, —CF, —OCF, —OH, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Heteroalkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkyl, unsubstituted or R 5 C1-C substituted with one, two, three, four, or five groups selected from 16 Alkenyl, unsubstituted or R 5 C3-C substituted with one, two, three, four, or five groups selected from 16 Heteroaryl, unsubstituted or R 5 C aryl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalekenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C1-C substituted with one, two, three, four, or five groups selected from 16 It is alkynyl.

[0276] In some embodiments, Z is -Ot-butyl.

[0277] In some embodiments, R 3 is unsubstituted or R 5 C3-C substituted with one, two, three, four, or five groups selected from 16 Heteroaryl, unsubstituted or R 5 C aryl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalekenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 and heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from:

[0278] In some embodiments, R 3 is unsubstituted or R 5 C3-C substituted with 1, 2, 3, 4, or 5 groups selected from 16 It is heteroaryl.

[0279] In some embodiments, R 3 teeth,

[0280] [ka]

[0281] [ka]

[0282] [ka]

[0283] [ka] and permutations thereof.

[0284] In some embodiments, R 3 teeth,

[0285] [ka]

[0286] [ka] and permutations thereof.

[0287] In some embodiments, R 3 teeth,

[0288] [ka] is selected from.

[0289] In some embodiments, R 3 teeth

[0290] [ka] is.

[0291] In some embodiments, R 3 teeth

[0292] [ka] is.

[0293] In some embodiments, R 3 teeth

[0294] [ka] is.

[0295] In some embodiments, R 3 teeth

[0296] [ka] is.

[0297] In some embodiments, R 3 teeth

[0298] [ka] is.

[0299] In some embodiments, R 3 teeth

[0300] [ka] is.

[0301] In some embodiments, R 3 teeth

[0302] [ka] is.

[0303] In some embodiments, R 3 teeth

[0304] [ka] is.

[0305] In some embodiments, R 3 teeth

[0306] [ka] is.

[0307] In some embodiments, R 3 teeth

[0308] [ka] is.

[0309] In some embodiments, R 2 is -halogen, -OR, -SR, -CN, -NO2, -CF3, -OCF3, or -C(=O)CH3.

[0310] In some embodiments, R 2 is -OCH3, -SCH3, -CN, -NO2, -CF3, or -OCF3.

[0311] In some embodiments, R 2 is -OCH3, -SCH3, or -OCF3.

[0312] In some embodiments, R 2 is -SCH3.

[0313] In some embodiments, R 2 is -OCF3.

[0314] In some embodiments, R 2 is -CF3.

[0315] In some embodiments, R 2 is -OCH2CH3.

[0316] In some embodiments, R 2 is -OCH3.

[0317] In some embodiments, R 1 is unsubstituted or R 5 C3-C substituted with one, two, three, four, or five groups selected from 16 Heteroaryl, unsubstituted or R 5 C aryl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5and heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from:

[0318] In some embodiments, R 1 is unsubstituted or R 5 and C6 aryl substituted with 1, 2, 3, 4, or 5 groups selected from:

[0319] In some embodiments, R 1 is unsubstituted or R 5 C3-C substituted with 1, 2, 3, 4, or 5 groups selected from 16 It is heteroaryl.

[0320] In some embodiments, R 1 teeth,

[0321] [ka]

[0322] [ka]

[0323] [ka] and permutations thereof.

[0324] In some embodiments, R 1 teeth,

[0325] [ka] and permutations thereof.

[0326] In some embodiments, R 1 teeth

[0327] [ka] is.

[0328] In some embodiments, R 1 teeth

[0329] [ka] is.

[0330] In some embodiments, R 1 teeth

[0331] [ka] is.

[0332] In some embodiments, R 1 teeth

[0333] [ka] is.

[0334] In some embodiments, R 1 teeth

[0335] [ka] is.

[0336] In some embodiments, R 1 teeth

[0337] [ka] is.

[0338] In some embodiments, R 1 teeth

[0339] [ka] is.

[0340] In some embodiments, R 1 teeth

[0341] [ka] is.

[0342] In some embodiments, R 1 teeth

[0343] [ka] is.

[0344] In some embodiments, R 1 teeth

[0345] [ka] is.

[0346] In some embodiments, Y is —O—, —S—, —NR 4 -, -OC(R 4 )2-, -SC(R 4 )2-, -C(R 4 )2O-, -C(R 4 )2S-, -C(R 4 )2NR 4 -, -C(R 4 )2-, or -CR 4 =CR 4 -It is.

[0347] In some embodiments, Y is —O—, —S—, —NR 4 -, -OC(R 4 )2-, -SC(R 4 )2-, -C(R 4 )2O-, -C(R 4 )2S-, -C(R4 )2-.

[0348] In some embodiments, Y is -O-, -S-, -NH-, -OCH2-, -SCH2-, -CH2O-, -CH2S-, or -CH2-.

[0349] In some embodiments, Y is —O—.

[0350] In some embodiments, Y is -S-.

[0351] In some embodiments, Y is -S(=O)-.

[0352] In some embodiments, Y is -S(=O)2-.

[0353] In some embodiments, Y is —S(═O)C(R 4 )2-.

[0354] In some embodiments, Y is —C(R 4 )2S(=O)-.

[0355] In some embodiments, Y is —S(═O)C(R 4 )2-.

[0356] In some embodiments, Y is —C(R 4 )2S(=O)2-.

[0357] In some embodiments, Y is -S(=O)CH2-.

[0358] In some embodiments, Y is —CH 2 S(═O)—.

[0359] In some embodiments, Y is -S(=O)2CH2-.

[0360] In some embodiments, Y is —CH 2 S(═O) 2 —.

[0361] In some embodiments, Y is —NR 4 -It is.

[0362] In some embodiments, Y is —OC(R 4 )2-.

[0363] In some embodiments, Y is —SC(R 4 )2-.

[0364] In some embodiments, Y is —C(R 4 )2O-.

[0365] In some embodiments, Y is —C(R 4 )2S-.

[0366] In some embodiments, Y is —C(R 4 )2NR 4 -It is.

[0367] In some embodiments, Y is —C(R 4 )2-.

[0368] In some embodiments, Y is —C(R 4 )2-C(R 4 )2-.

[0369] In some embodiments, Y is -CR 4 =CR 4 -It is.

[0370] In some embodiments, Y is -NH-. In some embodiments, Y is -OCH2-.

[0371] In some embodiments, Y is -SCH2-.

[0372] In some embodiments, Y is —CH 2 O—.

[0373] In some embodiments, Y is -CH2S-.

[0374] In some embodiments, Y is —CH 2 NR 2 4 -It is.

[0375] In some embodiments, Y is —CH 2 —.

[0376] In some embodiments, Y is -CH2-CH2-.

[0377] In some embodiments, Y is -CH=CH-.

[0378] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4 , -CF3, -OCF3, -OH, unsubstituted or R 5 C3-C8 cycloalkyl substituted with one, two, three, four, or five groups selected from 5 C3-C8 cycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 heterocycloalkyl substituted with one, two, three, four, or five groups selected from 5 heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from 5 and heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from:

[0379] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4, -CF3, -OCF3, or

[0380] [ka] is selected from.

[0381] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4 is.

[0382] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4 and at least one R in Z 4 teeth,

[0383] [ka] is selected from.

[0384] In some embodiments, Z is -OR 4 or -SR 4 and Z's R 4 teeth,

[0385] [ka] is.

[0386] In some embodiments, Z is

[0387] [ka] is selected from.

[0388] In some embodiments, Z is

[0389] [ka] is.

[0390] In some embodiments, Z is

[0391] [ka] is.

[0392] In some embodiments, Z is

[0393] [ka] is.

[0394] In some embodiments, Z is

[0395] [ka] is.

[0396] In some embodiments, Z is

[0397] [ka] is.

[0398] In some embodiments, Z is

[0399] [ka] is.

[0400] In some embodiments, Z is

[0401] [ka] is.

[0402] In some embodiments, Z is

[0403] [ka] is.

[0404] In some embodiments, Z is

[0405] [ka] is.

[0406] In some embodiments, Z is

[0407] [ka] is.

[0408] In some embodiments, Z is

[0409] [ka] is.

[0410] In some embodiments, Z is

[0411] [ka] is.

[0412] In some embodiments, Z is

[0413] [ka] is.

[0414] In some embodiments, Z is

[0415] [ka] is.

[0416] In some embodiments, Z is

[0417] [ka] is.

[0418] In some embodiments, Z is

[0419] [ka] is.

[0420] In some embodiments, Z is

[0421] [ka] is.

[0422] In some embodiments, Z is

[0423] [ka] is.

[0424] In some embodiments, Z is

[0425] [ka] is.

[0426] In some embodiments, Z is

[0427] [ka] is.

[0428] In some embodiments, Z is

[0429] [ka] is.

[0430] In some embodiments, Z is

[0431] [ka] is.

[0432] In some embodiments, Z is

[0433] [ka] is.

[0434] In some embodiments, Z is

[0435] [ka] is.

[0436] In some embodiments, Z is

[0437] [ka] is.

[0438] In some embodiments, Z is

[0439] [ka] is.

[0440] In some embodiments, Z is

[0441] [ka] is.

[0442] In some embodiments, Z is

[0443] [ka] is.

[0444] In some embodiments, Z is

[0445] [ka] is.

[0446] In some embodiments, Z is

[0447] [ka] is.

[0448] In some embodiments, Z is

[0449] [ka] is.

[0450] In some embodiments, Z is

[0451] [ka] is.

[0452] In some embodiments, Z is

[0453] [ka] is.

[0454] In some embodiments, Z is

[0455] [ka] is.

[0456] In some embodiments, R 1 or R 3 is substituted with halogen.

[0457] In some embodiments, R 1 or R 3 is substituted with chlorine.

[0458] In some embodiments, R 1 or R 3 is substituted with fluorine.

[0459] In some embodiments, R 1 or R 3 is substituted with C1-C4 heteroalkyl.

[0460] In some embodiments, at least one R in Z 4 teeth,

[0461] [ka] is selected from.

[0462] In some embodiments, the FSH modulators disclosed herein include Compound 1-01, Compound 1-02A, Compound 1-02, Compound 1-03, Compound 1-04, Compound 1-05, Compound 1-06, Compound 2-01, Compound 2-02, Compound 2-03, Compound 2-04, Compound 2-05, Compound 2-06, Compound 2-07, Compound 2-08, Compound 3-01, Compound 3-02, Compound 3-03, Compound 3-04, Compound 3-07, Compound 3-08, Compound 3-09, Compound 3-10A, Compound 3-10, Compound 3-11, Compound 3-12, Compound 4-01A, Compound 4-01, Compound 4-02A, Compound 4-02, Compound 4-03A, Compound 4-03, Compound 4-04A, Compound Compound 4-04, Compound 4-05A, Compound 4-05, Compound 4-06A, Compound 4-06, Compound 4-07A, Compound 4-07, Compound 4-08A, Compound 4-08, Compound 5-01, Compound 5-02, Compound 5-03, Compound 5- 04, compound 5-05, compound 5-06, compound 5-07, compound 5-08, compound 6-01A, compound 6-01B, compound 6-01, compound 6-02A, compound 6-02B, compound 6-02, compound 6-03, compound 6-04, Compound 6-05, Compound 6-06, Compound 6-07, Compound 6-08, Compound 8-01, Compound 8-02, Compound 8-03, Compound 8-05, Compound 8-06, Compound 8-07A, Compound 8-07, Compound 8-09, Compound 8-1 0, Compound 8-14, Compound 8-15, Compound 8-16B, Compound 8-16, Compound 8-17, Compound 8-20, Compound 8-21, Compound 8-22, Compound 8-23, Compound 8-24, Compound 8-25, Compound 8-26A, Compound 8-26, Compound 8-27, Compound 8-28, Compound 8-29, Compound 8-30, Compound 8-31, Compound 8-32, Compound 8-33, Compound 8-34, Compound 8-39, and Compound 8-44.

[0463] In some embodiments, the FSH modulators disclosed herein include Compound 8-77, Compound 8-75, Compound 8-76, Compound 8-78, Compound 8-81, Compound 8-61, Compound 8-60, Compound 8-63, Compound 8-58, Compound 8-51, Compound 8-67, Compound 8-74, Compound 8-4, Compound 8-8, Compound 8-4a, Compound 8-13, Compound 8-57, Compound 8-18, Compound 8-35, Compound 8-36, Compound 8-37, Compound 8-38, Compound 8-41, Compound 8-42, Compound 8-43, Compound 8-45, Compound 8-46 , compound 8-47, compound 8-49, compound 8-50, compound 8-52A, compound 8-54A, compound 8-55, compound 8-56, compound 8-62, compound 8-64, compound 8-65, compound 8-69, compound 8-70, compound 8-71, compound 8-79, compound 8-82, compound Compound 8-83, Compound 8-84, Compound 8-86, Compound 8-87, Compound 8-89, Compound 9-13, Compound 9-21, Compound 9-4, Compound 9-5, Compound 9-11, Compound 9-14, Compound 9-9, Compound 9-15, Compound 9-2, Compound 9-7, Compound 9-12, Compound 9 -16, Compound 9-17, Compound 9-18, Compound 9-19, Compound 9-20, Compound 10-1, Compound 10-2, Compound 10-3, Compound 10-6, Compound 10-7, Compound 10-8, Compound 10-9, Compound 10-10, Compound 11-1A, Compound 11-2, Compound 11-1 , Compound 11-3, Compound 12-2, Compound 12-23, Compound 12-13, Compound 12-15, Compound 12-16, Compound 12-1, Compound 12-4, Compound 12-18, Compound 12-19, Compound 13-1, Compound 13-4, Compound 13-9, Compound 13-7, Compound 13- 8, Compound 13-2, Compound 13-5, Compound 15-1, Compound 15-3, Compound 15-4, Compound 15-5, Compound 15-9, Compound 15-2, Compound 15-6, Compound 15-10, Compound 12-05, Compound 12-07, Compound 12-11, Compound 12-12, Compound 14- 03, compound 15-08, compound 15-10, compound 3-05, compound 3-06, compound 4-03B, compound 8-04A, compound 8-16A, compound 8-23A, compound 8-25A, compound 8-26B, compound 8-31A, compound 8-33A, compound 8-44, compound 8-66,The compound has a structure selected from the group consisting of Compound 8-72, Compound 8-90, Compound 8-90A, Compound 9-01, Compound 9-03, Compound 9-06, Compound 9-08, Compound 9-08A, Compound 9-10, Compound 9-19A, and Compound 9-24.

[0464] In some cases, the FSH modulators described herein can have the structure of any of the compounds in Table 1.

[0465] [Table 1-1]

[0466] [Table 1-2]

[0467] [Table 1-3]

[0468] [Table 1-4]

[0469] [Table 1-5]

[0470] [Table 1-6]

[0471] In some cases, the FSH modulators described herein can have any structure described herein, including, but not limited to, those depicted in Figures 1-193, the Examples, and / or synthetic schemes throughout this application, as well as pharmaceutically acceptable salts, solvates, or formulations thereof.

[0472] In another aspect, methods for modulating FSH using the compounds described herein are described herein. In some embodiments, the compounds described herein selectively modulate FSH and do not substantially modulate TSH. In some embodiments, the method comprises administering a compound described herein to a subject. In some embodiments, the compounds described herein are FSH agonists. In some embodiments, the compounds described herein are at least 3-fold selective for FSH over TSH (e.g., at least 3-fold, 5-fold, 10-fold, 20-fold, 50-fold, or 100-fold). In some embodiments, the in vitro or in vivo EC200 / ... 50 is about 100 nM or less (e.g., 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, or 500 pM or less).

[0473] Any of the methods described herein can include treating a disease or condition, which includes administering any of the compounds described herein (or a pharmaceutically acceptable salt or solvate thereof) to a subject in need thereof. In some embodiments, the disease or condition is a fertility disorder or male hypogonadism. In some embodiments, the disease or condition is cancer. In some embodiments, the cancer is breast cancer, prostate cancer, colon cancer, pancreatic cancer, bladder cancer, kidney cancer, lung cancer, liver cancer, stomach cancer, testicular cancer, or ovarian cancer. In some embodiments, the disease or condition is a cardiovascular disease. In some embodiments, the cardiovascular disease is atherosclerosis. In some embodiments, the disease or condition is a body composition disorder (e.g., obesity). In some embodiments, the disease or condition is non-alcoholic fatty liver disease. In some embodiments, the disease or condition is a bone density disorder (e.g., osteoporosis). In some embodiments, the disease or condition is Turner syndrome, Klinefelter syndrome, polycystic ovary syndrome (PCOS), and / or premature ovarian insufficiency (POI).

[0474] In some embodiments, the disease or condition is polycystic ovary syndrome (PCOS).

[0475] In some embodiments, the disease or condition is Turner syndrome.

[0476] In some embodiments, the disease or condition is Klinefelter's syndrome.

[0477] In some embodiments, the disease or condition is premature ovarian insufficiency (POI).

[0478] Further described herein are pharmaceutical compositions comprising a compound according to any of the claims, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient or carrier.

[0479] The pharmaceutically acceptable lipid nanoparticle formulations can include any of the compounds described herein.

[0480] Any of the methods described herein can include treating a disease or disorder by administering to a subject in need thereof any of the compounds, pharmaceutically acceptable salts and / or pharmaceutically acceptable solvates described herein.

[0481] Any of the methods described herein can include use of a compound described herein, a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof in the manufacture of a medicament for the treatment of a disease or disorder.

[0482] The compounds of formula (I), their salts, isomers, tautomers, enantiomeric forms, diastereomers, racemates, derivatives, prodrugs and / or metabolites are characterized by high specificity and stability, low production costs and easy handling. These properties form the basis for reproducible action (no cross-reactivity implied) and for reliable and safe interaction with target structures.

[0483] Modulation of the activity of FSHR or its variants in biological samples is useful for a variety of purposes known to those skilled in the art, including, but not limited to, blood transfusion, organ transplantation, biological sample storage, and biological assays.

[0484] Further forms of the compound In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in certain situations, they may be easier to administer than the parent drug. A prodrug may be, for example, bioavailable by oral administration, while the parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases its effective water solubility. An example, without limitation, of a prodrug is a compound described herein that is administered as an ester ("prodrug") to facilitate transport across cell membranes where water solubility is detrimental to mobility, but is then metabolically hydrolyzed to the carboxylic acid, the active form, once inside cells where water solubility is beneficial. A further example of a prodrug may be a short-chain peptide (polyamino acid) bonded to an acid group, where the peptide is metabolized to reveal the active moiety. In certain embodiments, after in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

[0485] In one aspect, prodrugs are designed to alter the metabolic stability or transport properties of a drug, to mask side effects or toxicity, to improve the flavor of a drug, or to alter other characteristics or properties of a drug. With knowledge of pharmacodynamics, pharmacodynamic processes, and in vivo drug metabolism, those skilled in the art can design prodrugs of pharmaceutically active compounds once they know the compound (see, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992) The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Aesop Cho, "Recent Advances in Oral Prodrug Discovery", Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series).

[0486] In some embodiments, some of the compounds described herein may be prodrugs of another derivative or active compound.

[0487] In some embodiments, sites on the aromatic ring portion of the compounds described herein are susceptible to various metabolic reactions, and therefore, incorporation of appropriate substituents on the aromatic ring structure can reduce, minimize, or eliminate this metabolic pathway. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogens or alkyl groups.

[0488] In another embodiment, the compounds described herein may be labeled with isotopes (e.g., with radioisotopes) or by other methods, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0489] The compounds described herein include isotopically labeled compounds, which are identical to those depicted in the various formulas and structures set forth herein, except that one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds include, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Cl, and 125 I. In one embodiment, the isotopically labeled compounds described herein, e.g., 3 H and 14 Incorporation of radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. In one embodiment, substitution with isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0490] In additional or further embodiments, the compounds described herein are metabolized after administration to an organism in need thereof to produce metabolic products that are subsequently used to provide a desired effect, including a desired therapeutic effect.

[0491] The compounds described herein can be formed as and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to, (1) salts formed by reacting the free base form of the compound with pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, or salts formed by reacting the free base form of the compound with pharmaceutically acceptable inorganic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]octanoic acid, or the like. (2) acid addition salts formed by reacting the parent compound with an organic acid such as thiazolinone, ... In other cases, the compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, etc. Acceptable inorganic bases used with compounds containing acidic protons to form salts include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0492] It should be understood that the reference to pharmaceutically acceptable salts includes solvent addition forms, particularly solvates.Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and can be formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, etc.Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein.In addition, the compounds provided herein can exist in unsolvated and solvated forms.In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0493] Synthesis method In some embodiments, synthesis of the compounds described herein is achieved using means described in the chemical literature, using methods described herein, or by a combination thereof. Additionally, solvents, temperatures, and other reaction conditions presented herein may vary.

[0494] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics.

[0495] In further embodiments, the compounds described herein, and other related compounds with different substituents, can be synthesized using techniques and materials other than those described herein, such as, for example, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley The compounds are synthesized using art-recognized techniques and materials, such as those described in "Compounds of the Invention" (1999), all of which are incorporated by reference for such disclosure. General methods for the preparation of compounds as disclosed herein can be derived from reactions, which can be modified by using appropriate reagents and conditions for the introduction of the various moieties found in the formulae as provided herein. For reference, the following synthetic methods can be used.

[0496] In the reactions described, it may be necessary to protect reactive functional groups, such as hydroxy, amino, imino, thio, or carboxy groups (if desired in the final product) to prevent their undesired participation in the reaction. Detailed descriptions of the techniques applicable to the creation of protecting groups and their removal are found in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure.

[0497] It is understood that other similar procedures and reagents can be used and that these schemes are meant only as non-limiting examples.

[0498] Pharmaceutical Composition In one embodiment, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients, which allow the active compound to be easily processed into a pharmaceutical preparation. Appropriate formulation depends on the selected route of administration. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosure.

[0499] As used herein, a pharmaceutical composition refers to a mixture of a compound disclosed herein with other chemical compounds (i.e., pharmaceutically acceptable components), such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, coloring agents, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. A pharmaceutical composition facilitates administration of the compound to an organism.

[0500] The pharmaceutical compositions described herein can be administered to a subject in a variety of ways by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intracerebroventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, buccal, topical, or transdermal routes of administration. Pharmaceutical compositions described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast-dissolve formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and combined immediate and controlled release formulations.

[0501] In some embodiments, the compounds disclosed herein are administered orally.

[0502] In some embodiments, the compounds disclosed herein are administered topically. In such embodiments, the compounds disclosed herein are formulated into various topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages, balms, creams, or ointments. In one aspect, the compounds disclosed herein are administered topically to the skin. In another aspect, the compounds disclosed herein are administered directly to the female genitalia (vaginal gel, vaginal ring, intrauterine delivery) using a non-degradable or degradable delivery system. In another aspect, the compounds disclosed herein are administered directly to the male genitalia using a non-degradable or degradable delivery system.

[0503] In another embodiment, the compounds disclosed herein are administered by inhalation.

[0504] In another embodiment, the compounds disclosed herein are formulated for intranasal administration, including nasal sprays, nasal mists, and the like.

[0505] In another embodiment, the compounds disclosed herein are formulated as eye drops.

[0506] In any of the foregoing aspects, there are further embodiments in which an effective amount of a compound disclosed herein is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by inhalation to a mammal, and / or (e) administered by nasal administration to a mammal, or, and / or (f) administered by injection to a mammal, and / or (g) administered topically to a mammal, and / or (h) administered by ophthalmic administration, and / or (i) administered rectally to a mammal, and / or (j) administered non-systemically or topically to a mammal.

[0507] In any of the foregoing aspects, further embodiments include a single administration of an effective amount of a compound disclosed herein, including further embodiments in which (i) the compound is administered once, (ii) the compound is administered to the mammal multiple times during the day, (iii) the compound is administered continuously, or (iv) the compound is administered continuously.

[0508] In any of the foregoing aspects, further embodiments include multiple administrations of an effective amount of a compound disclosed herein, including further embodiments in which (i) the compound is administered continuously or intermittently as a single dose, (ii) the multiple administrations are spaced apart every 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the mammal every 12 hours, or (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday, during which administration of a compound disclosed herein is temporarily suspended or the dose of the compound administered is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0509] In certain embodiments, the compounds disclosed herein are administered in a local rather than systemic manner.

[0510] In some embodiments, the compounds disclosed herein are administered locally. In some embodiments, the compounds disclosed herein are administered systemically.

[0511] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, the pharmaceutical formulation of the compounds disclosed herein is in the form of a capsule.

[0512] In one embodiment, the dosage form of the liquid formulation for oral administration is in the form of an aqueous suspension or solution selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.

[0513] For administration by inhalation, the compounds disclosed herein are formulated for use as an aerosol, mist, or powder.

[0514] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in conventional manner.

[0515] In some embodiments, the compounds disclosed herein are formulated as transdermal dosage forms.

[0516] In one aspect, the compounds disclosed herein are formulated into pharmaceutical compositions suitable for intramuscular, subcutaneous, or intravenous injection.

[0517] In some embodiments, the compounds disclosed herein are administered topically and can be formulated into a variety of topically administrable compositions such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments.

[0518] In some embodiments, the compounds disclosed herein are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas.

[0519] Dosage and treatment regimens In one embodiment, the compounds disclosed herein are used in the preparation of a medicament for treating a disease or condition described herein. Additionally, a method for treating any of the diseases or conditions described herein comprises administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one compound disclosed herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or solvate thereof.

[0520] In certain embodiments, compositions containing the compounds disclosed herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially halt at least one symptom of the disease or condition. Amounts effective for this use will vary depending on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation clinical trials.

[0521] In prophylactic applications, compositions containing the compounds disclosed herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition.

[0522] In certain embodiments, the dose of the administered drug may be temporarily reduced or temporarily stopped for a period of time (ie, a "drug holiday").

[0523] Doses utilized for adult human treatment typically range from 0.01 mg to 5000 mg per day, or from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in single or divided doses.

[0524] In some embodiments, the dose is from about 0.1 mg per day to about 5,000 mg per day, from about 0.1 mg per day to about 1 mg per day, from about 0.1 mg per day to about 50 mg per day, from about 0.1 mg per day to about 100 mg per day, from about 0.1 mg per day to about 300 mg per day, from about 0.1 mg per day to about 500 mg per day, from about 0.1 mg per day to about 600 mg per day, from about 0.1 mg per day to about 700 mg per day, from about 0.1 mg per day to about 800 mg per day, from about 0.1 mg per day to about 900 mg per day, or from about 0.1 mg per day to about 100 mg per day. 00mg, about 0.1mg per day to about 1,000mg per day, about 0.1mg per day to about 5,000mg per day, about 1mg per day to about 50mg per day, about 1mg per day to about 100mg per day, about 1mg per day to about 300mg per day, about 1mg per day to about 500mg per day, about 1mg per day to about 600mg per day, about 1mg per day to about 700mg per day, about 1mg per day to about 800mg per day, about 1mg per day to about 9 00mg, about 1mg per day to about 1,000mg per day, about 1mg per day to about 5,000mg per day, about 50mg per day to about 100mg per day, about 50mg per day to about 300mg per day, about 50mg per day to about 500mg per day, about 50mg per day to about 600mg per day, about 50mg per day to about 700mg per day, about 50mg per day to about 800mg per day, about 50mg per day to about 900mg per day, about 50mg per day to about 100mg per day Approximately 1,000mg per day, approximately 50mg per day to approximately 5,000mg per day, approximately 100mg per day to approximately 300mg per day, approximately 100mg per day to approximately 500mg per day, approximately 100mg per day to approximately 600mg per day, approximately 100mg per day to approximately 700mg per day, approximately 100mg per day to approximately 800mg per day, approximately 100mg per day to approximately 900mg per day, approximately 100mg per day to approximately 1,000mg per day, approximately 100mg per day to approximately 5,000mg, about 300mg per day to about 500mg per day, about 300mg per day to about 600mg per day, about 300mg per day to about 700mg per day, about 300mg per day to about 800mg per day, about 300mg per day to about 900mg per day, about 300mg per day to about 1,000mg per day, about 300mg per day to about 5,000mg per day, Approximately 500mg per day to approximately 600mg per day, approximately 500mg per day to approximately 700mg per day, approximately 500mg per day to approximately 800mg per day, approximately 500mg per day to approximately 900mg per day, approximately 500mg per day to approximately 1,000mg per day, approximately 500mg per day to approximately 5,000mg per day, approximately 600mg per day to approximately 700mg per day, approximately 600mg to about 800mg per day, about 600mg per day to about 900mg per day, about 600mg per day to about 1,000mg per day, about 600mg per day to about 5,000mg per day, about 700mg per day to about 800mg per day, about 700mg per day to about 900mg per day, about 700mg per day to about 1,000mg per day, about 700mg per day g to about 5,000 mg per day, about 800 mg per day to about 900 mg per day, about 800 mg per day to about 1,000 mg per day, about 800 mg per day to about 5,000 mg per day, about 900 mg per day to about 1,000 mg per day, about 900 mg per day to about 5,000 mg per day, or about 1,000 mg per day to about 5,000 mg per day. In some embodiments, the dose is about 0.1 mg per day, about 1 mg per day, about 50 mg per day, about 100 mg per day, about 300 mg per day, about 500 mg per day, about 600 mg per day, about 700 mg per day, about 800 mg per day, about 900 mg per day, about 1,000 mg per day, or about 5,000 mg per day.In some embodiments, the dose is at least about 0.1 mg per day, about 1 mg per day, about 50 mg per day, about 100 mg per day, about 300 mg per day, about 500 mg per day, about 600 mg per day, about 700 mg per day, about 800 mg per day, about 900 mg per day, or about 1,000 mg per day. In some embodiments, the dose is up to about 1 mg per day, about 50 mg per day, about 100 mg per day, about 300 mg per day, about 500 mg per day, about 600 mg per day, about 700 mg per day, about 800 mg per day, about 900 mg per day, about 1,000 mg per day, or about 5,000 mg per day.

[0525] In some embodiments, the dose is from about 1 mg per day to about 1,000 mg per day. In some embodiments, the dose is from about 1 mg per day to about 50 mg per day, from about 1 mg per day to about 100 mg per day, from about 1 mg per day to about 200 mg per day, from about 1 mg per day to about 300 mg per day, from about 1 mg per day to about 400 mg per day, from about 1 mg per day to about 500 mg per day, from about 1 mg per day to about 600 mg per day, from about 1 mg per day to about 700 mg per day, from about 1 mg per day to about 800 mg per day, or from about 1 mg per day to about 100 mg per day. ~ about 900mg per day, about 1mg per day to about 1,000mg per day, about 50mg per day to about 100mg per day, about 50mg per day to about 200mg per day, about 50mg per day to about 300mg per day, about 50mg per day to about 400mg per day, about 50mg per day to about 500mg per day, about 50mg per day to about 600mg per day, about 50mg per day to about 700mg per day, about 50mg per day to about 800mg per day, Approximately 50mg to approximately 900mg per day, approximately 50mg per day to approximately 1,000mg per day, approximately 100mg per day to approximately 200mg per day, approximately 100mg per day to approximately 300mg per day, approximately 100mg per day to approximately 400mg per day, approximately 100mg per day to approximately 500mg per day, approximately 100mg per day to approximately 600mg per day, approximately 100mg per day to approximately 700mg per day, approximately 100mg per day to approximately 800mg per day, approximately 100mg per day to approximately 1 Approximately 900mg per day, approximately 100mg per day to approximately 1,000mg per day, approximately 200mg per day to approximately 300mg per day, approximately 200mg per day to approximately 400mg per day, approximately 200mg per day to approximately 500mg per day, approximately 200mg per day to approximately 600mg per day, approximately 200mg per day to approximately 700mg per day, approximately 200mg per day to approximately 800mg per day, approximately 200mg per day to approximately 900mg per day, approximately 200mg per day to approximately 1,000mg, about 300mg per day to about 400mg per day, about 300mg per day to about 500mg per day, about 300mg per day to about 600mg per day, about 300mg per day to about 700mg per day, about 300mg per day to about 800mg per day, about 300mg per day to about 900mg per day, about 300mg per day to about 1,000mg per day g, approximately 400mg per day to approximately 500mg per day, approximately 400mg per day to approximately 600mg per day, approximately 400mg per day to approximately 700mg per day, approximately 400mg per day to approximately 800mg per day, approximately 400mg per day to approximately 900mg per day, approximately 400mg per day to approximately 1,000mg per day, approximately 500mg per day to approximately 600mg per day, approximately Approximately 500mg to approximately 700mg per day, approximately 500mg to approximately 800mg per day, approximately 500mg to approximately 900mg per day, approximately 500mg to approximately 1,000mg per day, approximately 600mg to approximately 700mg per day, approximately 600mg to approximately 800mg per day, approximately 600mg to approximately 900mg per day, approximately 6 In some embodiments, the dose is about 1 mg per day, about 50 mg per day, about 100 mg per day, about 200 mg per day, about 300 mg per day, about 400 mg per day, about 500 mg per day, about 600 mg per day, about 700 mg per day, about 800 mg per day, about 900 mg per day, about 700 mg per day, about 1,000 mg per day, about 800 mg per day, about 900 mg per day, about 800 mg per day, about 1,000 mg per day, or about 900 mg per day, about 1,000 mg per day. In some embodiments, the dose is about 1 mg per day, about 50 mg per day, about 100 mg per day, about 200 mg per day, about 300 mg per day, about 400 mg per day, about 500 mg per day, about 600 mg per day, about 700 mg per day, about 800 mg per day, about 900 mg per day, or about 1,000 mg per day.In some embodiments, the dose is at least about 1 mg per day, about 50 mg per day, about 100 mg per day, about 200 mg per day, about 300 mg per day, about 400 mg per day, about 500 mg per day, about 600 mg per day, about 700 mg per day, about 800 mg per day, or about 900 mg per day. In some embodiments, the dose is up to about 50 mg per day, about 100 mg per day, about 200 mg per day, about 300 mg per day, about 400 mg per day, about 500 mg per day, about 600 mg per day, about 700 mg per day, about 800 mg per day, about 900 mg per day, or about 1,000 mg per day.

[0526] In some embodiments, the dose is about 0.1 mg / kg to about 200 mg / kg. In some embodiments, the dose is about 0.1 mg / kg to about 1 mg / kg, about 0.1 mg / kg to about 3 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 70 mg / kg, about 0.1 mg / kg to about 90 mg / kg, about 0.1 mg / kg to about 120 mg / kg, about 0.1 mg / kg to about 150 mg / kg, about 0.1mg / kg to about 200mg / kg, about 1mg / kg to about 3mg / kg, about 1mg / kg to about 5mg / kg, about 1mg / kg to about 10mg / kg, about 1mg / kg to about 50mg / kg, about 1mg / kg to about 70mg / kg, about 1mg / kg~about 90mg / kg, about 1mg / kg~about 120mg / kg, about 1mg / kg~about 150mg / kg, about 1mg / kg~about 200mg / kg, about 3mg / kg~about 5mg / kg, about 3mg / kg~about 10mg / kg, about 3mg / kg~about 50mg / kg, about 3mg / kg~about 70mg / kg, about 3mg / kg~about 90mg / kg, about 3mg / kg~about 120mg / kg, about 3mg / kg~about 150mg / kg, about 3mg / kg~about 200mg / kg, about 5m g / kg~about 10mg / kg, about 5mg / kg~about 50mg / kg, about 5mg / kg~about 70mg / kg, about 5mg / kg~about 90mg / kg, about 5mg / kg~about 120mg / kg, about 5mg / kg~about 150mg / kg, about 5m g / kg~about 200mg / kg, about 10mg / kg~about 50mg / kg, about 10mg / kg~about 70mg / kg, about 10mg / kg~about 90mg / kg, about 10mg / kg~about 120mg / kg, about 10mg / kg~about 150mg / kg kg, about 10 mg / kg to about 200 mg / kg, about 50 mg / kg to about 70 mg / kg, about 50 mg / kg to about 90 mg / kg, about 50 mg / kg to about 120 mg / kg, about 50 mg / kg to about 150 mg / kg, about 50 mg / kg about 70 mg / kg to about 90 mg / kg, about 70 mg / kg to about 120 mg / kg, about 70 mg / kg to about 150 mg / kg, about 70 mg / kg to about 200 mg / kg, about 90 mg / kg to about 120 mg / kg, about 90 mg / kg to about 150 mg / kg, about 90 mg / kg to about 200 mg / kg, about 120 mg / kg to about 150 mg / kg, about 120 mg / kg to about 200 mg / kg, or about 150 mg / kg to about 200 mg / kg. In some embodiments, the dose is about 0.1 mg / kg, about 1 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 50 mg / kg, about 70 mg / kg, about 90 mg / kg, about 120 mg / kg, about 150 mg / kg, or about 200 mg / kg. In some embodiments, the dose is at least about 0.In some embodiments, the dose is up to about 1 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 50 mg / kg, about 70 mg / kg, about 90 mg / kg, about 120 mg / kg, or about 150 mg / kg. In some embodiments, the dose is up to about 1 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 50 mg / kg, about 70 mg / kg, about 90 mg / kg, about 120 mg / kg, about 150 mg / kg, or about 200 mg / kg. [Example]

[0527] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0528] chemical synthesis All reactions were carried out in oven-dried glassware. NMR was performed on a 400 MHz Bruker.

[0529] Example 1 Reaction Scheme 1

[0530] [ka]

[0531] Synthesis of 1-bromo-4-(bromomethyl)-2-methoxy-benzene

[0532] [ka] To a mixture of 1-bromo-2-methoxy-4-methyl-benzene (10 g, 49.74 mmol, 1 equiv.) in CCl4 (100 mL), AIBN (816.71 mg, 4.97 mmol, 0.1 equiv.) and NBS (9.29 g, 52.22 mmol, 1.05 equiv.) were added, and the mixture was stirred at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent of 0–10% ethyl acetate / petroleum ether, 60 mL / min gradient). The compound 1-bromo-4-(bromomethyl)-2-methoxy-benzene (13.9 g, 49.65 mmol, 99% yield) was obtained as a yellow oil. 1H NMR (400MHz, CHLOROFORM-d) δ=7.50(d,J=8.0Hz,1H),6.93(s,1H),6.88(br d,J=8.0Hz,1H),4.46(s,2H),3.92(s,3H).

[0533] Synthesis of methyl 2-[(4-bromo-3-methoxy-phenyl)methoxy]acetate

[0534] [ka] To a mixture of methyl 2-hydroxyacetate (4.50 g, 50.01 mmol, 3.86 mL, 2 equiv.) in THF (50 mL), NaH (2.10 g, 52.51 mmol, 60% purity, 2.1 equiv.) was added, and the mixture was stirred at 25 °C for 15 min. Then, a mixture of 1-bromo-4-(bromomethyl)-2-methoxy-benzene (7 g, 25.00 mmol, 1 equiv.) in THF (25 mL) was added, and the mixture was stirred at 20–40 °C for 34 h. The reaction mixture was quenched with saturated NH Cl (100 mL) and extracted with EtOAc (100 mL*3). The combined organic phase was washed with brine (100 mL*1), dried over anhydrous Na SO , filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent: 0–11% ethyl acetate / petroleum ether, 60 mL / min gradient). The compound, methyl 2-[(4-bromo-3-methoxyphenyl)methoxy]acetate (3.88 g, 13.42 mmol, 54% yield), was obtained as a yellow oil. H NMR (400 MHz, CHLOROFORM-d) δ = 7.51 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 1.6 Hz, 1H), 6.82 (dd, J = 1.6, 8.0 Hz, 1H), 4.60 (s, 2H), 4.13 (s, 2H), 3.92 (s, 3H), 3.78 (s, 3H).

[0535] Synthesis of 2-[(4-bromo-3-methoxy-phenyl)methoxy]acetic acid

[0536] [ka] To a solution of methyl 2-[(4-bromo-3-methoxy-phenyl)methoxy]acetate (3.68 g, 12.73 mmol, 1 equiv.) in THF (20 mL) was added a solution of LiOH.HO (2.14 g, 50.91 mmol, 4 equiv.) in HO (20 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was acidified to pH = 6 with 1 M aqueous HCl, and a precipitate formed in the reaction mixture. The mixture was filtered, and the filter cake was collected and dried under vacuum. The compound 2-[(4-bromo-3-methoxy-phenyl)methoxy]acetic acid (2.9 g, 10.54 mmol, 83% yield) was obtained as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ=12.70(br s,1H),7.53(d,J=8.0Hz,1H),7.08(d,J=1.2Hz,1H),6.87(d,J=8.0Hz,1H),4.52(s,2H),4.08(s,2H),3.84(s,3H).

[0537] Synthesis of 6-bromo-7-methoxy-isochroman-4-one

[0538] [ka] To a solution of 2-[(4-bromo-3-methoxy-phenyl)methoxy]acetic acid (2.5 g, 9.09 mmol, 1 equiv.) in DCM (25 mL) was added (COCl) (1.79 g, 14.09 mmol, 1.23 mL, 1.55 equiv.) and DMF (0.1 mL) at 0 °C. The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The compound 2-[(4-bromo-3-methoxy-phenyl)methoxy]acetyl chloride (2.67 g, crude) was obtained as a yellow oil.

[0539] To a solution of 2-[(4-bromo-3-methoxy-phenyl)methoxy]acetyl chloride (2.67 g, 9.10 mmol, 1 equiv.) in chlorobenzene (25 mL) was added tetrachlorostannane (1 M, 18.65 mL, 2.05 equiv.) at 0 °C under a N atmosphere. The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with saturated NaHCO (100 mL) and HO (100 mL) and extracted with EtOAc (200 mL*3). The combined organic phases were washed with brine (200 mL) and dried over anhydrous NaSO. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0–20% ethyl acetate / petroleum ether, 50 mL / min gradient). The compound 6-bromo-7-methoxy-isochroman-4-one (1.08 g, 4.20 mmol, 46% yield) was obtained as a yellow solid. 1 H NMR(400MHz,CHLOROFORM-d)δ=8.25(s,1H),6.67(s,1H),4.85(s,2H),4.33(s,2H),3.98(s,3H).

[0540] Synthesis of 2-(6-bromo-7-methoxy-4-oxo-isochroman-3-yl)-2-oxo-ethyl acetate

[0541] [ka] To a solution of N-isopropylpropan-2-amine (393.61 mg, 3.89 mmol, 549.74 μL, 2 equiv.) in THF (10 mL) was added n-BuLi (2.5 M, 1.01 mL, 1.3 equiv.) dropwise at −78° C. under a N atmosphere. The mixture was stirred at −78° C. for 15 min, then gradually warmed to −10° C. and stirred under a N atmosphere for 30 min. To the reaction mixture was added 6-bromo-7-methoxy-isochroman-4-one (500 mg, 1.94 mmol, 1 equiv.) in THF (5 mL) dropwise at −78° C. under a N atmosphere. The mixture was stirred at −78° C. under a N atmosphere for 1 h. After 1 h, diethyl oxalate was added dropwise to the mixture (454.77 mg, 3.11 mmol, 425.02 μL, 1.6 equiv) in THF (2 mL) at −78° C. The reaction mixture was gradually brought to 0° C. and stirred under N2 for 1 h. The reaction mixture was cooled to −5° C. and then acidified to pH=6 with 1 M aqueous HCl, resulting in the formation of a precipitate in the reaction mixture. The mixture was filtered, and the filter cake was collected and dried under vacuum to give 2-(6-bromo-7-methoxy-4-oxo-isochroman-3-yl)-2-oxo-ethyl acetate (410 mg, crude) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=7.96(s,1H),7.17(s,1H),5.10(s,2H),4.30-4.15(m,2H),3.95(s,3H),1.26(t,J=7.2Hz,3H).

[0542] Synthesis of ethyl 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazole-3-carboxylate

[0543] [ka] To a solution of 2-(6-bromo-7-methoxy-4-oxo-isochroman-3-yl)-2-oxo-ethyl acetate (410 mg, 1.15 mmol, 1 equiv.) in t-BuOH (5 mL), AcOH (344.68 mg, 5.74 mmol, 328.58 μL, 5 equiv.) and (3,5-dichlorophenyl)hydrazine hydrochloride (245.08 mg, 1.15 mmol, 1 equiv.) were added under a N atmosphere. The mixture was stirred at 110° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with EtOH (20 mL) at 25° C. for 30 minutes. It was filtered, and the filter cake was collected and dried under vacuum. The compound ethyl 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazole-3-carboxylate (420 mg, 843.11 μmol, 73% yield) was obtained as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=7.90(t,J=2.0Hz,1H),7.80(d,J=2.0Hz,2H),7.29(s,1H), 6.94(s,1H),5.30(s,2H),4.32(q,J=7.2Hz,2H),3.89(s,3H),1.30(t,J=7.2Hz,3H).

[0544] Synthesis of 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazole-3-carboxylic acid

[0545] [ka] To a solution of ethyl 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazole-3-carboxylate (420 mg, 843.11 μmol, 1 equiv.) in THF (5 mL) and EtOH (2 mL) was added a solution of LiOH.HO (70.76 mg, 1.69 mmol, 2 equiv.) in HO (5 mL). The mixture was stirred at 40 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction mixture was acidified to pH = 6 with 1 M aqueous HCl, causing a precipitate to form in the reaction mixture. The mixture was filtered, and the filter cake was collected and dried under vacuum. The compound 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazole-3-carboxylic acid (500 mg, crude) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=7.88(t,J=2.0Hz,1H),7.79(d,J=2.0Hz,2H),7.30(s,1H),6.96(s,1H),5.27(s,2H),3.89(s,3H).

[0546] Synthesis of [8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone

[0547] [ka] To a solution of 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazole-3-carboxylic acid (250 mg, 531.80 μmol, 1 equiv.) in DMF (2 mL) was added HATU (202.21 mg, 531.80 μmol, 1 equiv.) and DIEA (206.19 mg, 1.60 mmol, 277.89 μL, 3 equiv.). The mixture was stirred at 25 °C for 30 min. Then, a mixture of 3,3-dimethylmorpholine (73.50 mg, 638.16 μmol, 1.2 equiv.) in DMF (1 mL) was added. The mixture was stirred at 25-40 °C for 18 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent: 0–40% ethyl acetate / petroleum ether, 40 mL / min gradient). The compound [8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (180 mg, 317.32 μmol, 60% yield) was obtained as a yellow solid. 1 H NMR(400MHz,CHLOROFORM-d)δ=7.52(d,J=1.6Hz,2H),7.46(t,J=1.6Hz,1H),7.17(s,1H),6.82(s,1 H),5.22(s,2H),3.94(s,3H),3.86-3.80(m,2H),3.73-3.67(m,2H),3.50-3.47(m,2H),1.55(s,6H).

[0548] Synthesis of 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazol-8-yl]pyridine-3-carbonitrile

[0549] [ka] To a mixture of [8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (108 mg, 190.39 μmol, 1 equiv.) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (45.99 mg, 199.91 μmol, 1.05 equiv.) in dioxane (3 mL) and HO (1.5 mL) was added KCO (52.63 mg, 380.78 μmol, 2 equiv.), Pd(dppf)Cl (13.93 mg, 19.04 μmol, 0.1 equiv.), and the mixture was stirred at 60 °C under N for 16 h. The reaction mixture was diluted with ice water (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL*3). The combined organic layers were dried over anhydrous Na2SO4, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent: 0–42% ethyl acetate / petroleum ether, 40 mL / min gradient). The desired compound, 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl-7-methoxy-5H-isochromeno[4,3-c]pyrazol-8-yl]pyridine-3-carbonitrile (75 mg, 127.02 μmol, 67% yield), was obtained as a yellow solid.

[0550] Synthesis of 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazol-8-yl]pyridine-3-carboxamide

[0551] [ka] To a solution of 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazol-8-yl]pyridine-3-carbonitrile (75 mg, 127.02 μmol, 1 equiv.) in DMSO (1 mL) was added KCO (3 M, 84.68 μL, 2 equiv.) and HO (120 mg, 1.06 mmol, 101.69 μL, 30% purity, 8.33 equiv.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with saturated NaSO (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (TFA)-ACN]; gradient: 38% to 68% B / min (over min)), followed by lyophilization. The compound 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazol-8-yl]pyridine-3-carboxamide (22.74 mg, 31.47 μmol, 25% yield, 100% purity, TFA) was obtained as a yellow solid. LCMS (ESI): m / z [M+H] calculated for C 30 H 28 C l2 N5O5:608.14;found:608.3. 1 H NMR(400MHz,CHLOROFORM-d)δ=9.34-9.09(m,1H),8.95-8.77(m,1H),8.53(s,1H),7.57(s,2H),7.45(s,1H),7.00(d,J=7.2Hz,3H),6 .39-6.06(m,1H),5.33(s,2H),3.91(s,3H),3.88-3.82(m,2H),3.78-3.70(m,2H),3.51(s,2H),1.56(s,6H). Figure 8 shows the nuclear magnetic resonance of compound 2-01.

[0552] Synthesis of [1-(3,5-dichlorophenyl)-7-methoxy-8-(1-methylpyrazol-3-yl)-5H-isochromeno[4,3-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone

[0553] [ka] To a mixture of [8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (72 mg, 126.93 μmol, 1 equiv.) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (31.69 mg, 152.31 μmol, 1.2 equiv.) in dioxane (2 mL) and HO (1 mL) was added KCO (35.08 mg, 253.85 μmol, 2 equiv.), Pd(dppf)Cl (9.29 mg, 12.69 μmol, 0.1 equiv.), and the mixture was stirred at 80 °C under N for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (TFA)-ACN]; gradient: 55% to 85% B / min (over min)) followed by lyophilization. The compound [1-(3,5-dichlorophenyl)-7-methoxy-8-(1-methylpyrazol-3-yl)-5H-isochromeno[4,3-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (25.06 mg, 36.72 μmol, 29% yield, 100% purity, TFA) was obtained as a gray solid. LCMS (ESI): m / z [M+H] calculated for C 28 H 28 C l2 N5O4:568.14;found:568.3. 1H NMR(400MHz,CHLOROFORM-d)δ=7.59(s,2H),7.46(br d,J=13.2Hz,2H),7.41-7.36(m,1H),6.91-6.82(m,1H),6.54(s,1H),5.28(br s,2H),3.94(br d.

[0554] Synthesis of Compound 2-02

[0555] [ka] Compound 2-02 was synthesized in the same manner as in Example 1. LCMS (ESI): m / z [M+H] calculated for C 29 H 28 Cl2N5O4:580.14;found:580.3. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 9.12 (s, 1H), 8.81 (s, 1H), 8.40 (s, 1H), 7.59 (s, 2H), 7.41 (s, 1H), 6.98 (d, J = 16.8 Hz, 2H), 6.90-6.68 (m, 1H), 6.17-5.91 (m, 1H), 5.31 (s, 2H), 3.89 (s, 3H), 3.14 (s, 3H), 1.55 (s, 9H). Figure 9 shows the nuclear magnetic resonance of compound 2-02.

[0556] Synthesis of Compound 2-03

[0557] [ka] Compound 2-03 was synthesized in the same manner as in Example 1. LCMS (ESI): m / z [M+H] calculated for C 28 H 28 N5O5S 546.17;found:546.3. 1H NMR(400MHz,CHLOROFORM-d)δ=9.33-9.15(m,1H),8.89(s,1H),8.62(s,1H),7.72-7.41(m,3H),7.26(br s,1H),6.92(d,J=12.0Hz,2H),6.33-6.22(m,1H),5.31(s,2H),3.90(s,3H),3.84(br d,J=4.8Hz,2H),3.78(br d,J=4.8Hz,2H),3.49(s,2H),1.55(s,6H). Figure 10 shows the nuclear magnetic resonance of compound 2-03.

[0558] Synthesis of Compound 2-04

[0559] [ka] Compound 2-04 was synthesized in the same manner as in Example 1. LCMS (ESI): m / z [M+H] calculated for C 27 H 28 N5O4S:518.18;found:518.3. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 9.14 (br s, 1H), 8.86 (br s, 1H), 8.54 (s, 1H), 7.53-7.47 (m, 2H), 7.25 (br d, J = 4.8 Hz, 1H), 6.89 (d, J = 12.8 Hz, 2H), 5.29 (s, 2H), 3.88 (s, 3H), 3.15 (s, 3H), 1.54 (s, 9H). Figure 11 shows the nuclear magnetic resonance of compound 2-04.

[0560] Synthesis of Compound 2-06

[0561] [ka] Compound 2-06 was synthesized in the same manner as in Example 1. LCMS (ESI): m / z [M+H] calculated for C 27 H 28 Cl2N5O3:540.15;found:540.3. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.60 (s, 2H), 7.56-7.51 (m, 1H), 7.43 (s, 1H), 7.37 (br s, 1H), 6.91-6.83 (m, 1H), 6.61-6.52 (m, 1H), 5.28 (s, 2H), 3.98-3.90 (m, 6H), 3.14 (s, 3H), 1.56 (s, 9H). Figure 13 shows the nuclear magnetic resonance of compound 2-06.

[0562] Synthesis of compound 2-07

[0563] [ka] Compound 2-07 was synthesized in the same manner as in Example 1. LCMS (ESI): m / z [M+H] calculated for C 26 H 28 N5O4S:506.18;found:506.4. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.69-7.27 (m, 5H), 6.98-6.72 (m, 1H), 6.67-6.37 (m, 1H), 5.45-5.08 (m, 2H), 4.04-3.87 (m, 6H), 3.86 (br s, 2H), 3.77 (br d, J = 5.2 Hz, 2H), 3.52-3.47 (m, 2H), 1.56 (s, 6H). Figure 14 shows the nuclear magnetic resonance of compound 2-07.

[0564] Synthesis of compound 2-08

[0565] [ka] Compound 2-08 was synthesized in the same manner as in Example 1. LCMS (ESI): m / z [M+H] calculated for C 25 H 28 N5O3S:578.18;found:578.3. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.60 (s, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 3.2, 5.2 Hz, 1H), 7.36-7.31 (m, 2H), 6.83 (s, 1H), 6.60 (d, J = 2.0 Hz, 1H), 5.27 (s, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.14 (s, 3H), 1.54 (s, 9H). Figure 15 shows the nuclear magnetic resonance of compound 2-08.

[0566] Example 2 Reaction Scheme 2

[0567] [ka] Synthesis of 1-bromo-4-(bromomethyl)-2-methoxy-benzene

[0568] [ka] A mixture of 1-bromo-2-methoxy-4-methyl-benzene (25 g, 124.34 mmol, 1 equiv.), AIBN (2.04 g, 12.43 mmol, 0.1 equiv.), and NBS (24.34 g, 136.78 mmol, 1.1 equiv.) in CCl4 (300 mL) was degassed and purged with N2 three times, then the mixture was stirred at 80 °C under a N2 atmosphere for 16 h. The mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® silica flash column, eluent of 0–7% ethyl acetate / petroleum ether, 80 mL / min gradient). The compound 1-bromo-4-(bromomethyl)-2-methoxy-benzene (34 g, 121.45 mmol, 98% yield) was obtained as a colorless oil. 1 H NMR(400MHz,CHLOROFORM-d)δ=7.50(d,J=8.0Hz,1H),6.93(d,J=1.9Hz,1H),6.87(dd,J=1.8,8.1Hz,1H),4.45(s,2H),3.94-3.90(m,3H).

[0569] Synthesis of ethyl 2-[(4-bromo-3-methoxy-phenyl)methylsulfanyl]acetate To a solution of ethyl 2-sulfanylacetate (3.85 g, 32.04 mmol, 3.51 mL, 1.28 equiv.) in THF (70 mL), NaH (1.50 g, 37.51 mmol, 60% purity, 1.5 equiv.) was added dropwise at 0 °C. After the addition, the mixture was stirred at 0 °C for 0.5 h, and then 1-bromo-4-(bromomethyl)-2-methoxy-benzene (7 g, 25.00 mmol, 1 equiv.) in THF (30 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 2 h. The reaction was quenched with saturated NH4Cl (50 mL) at 0 °C. The mixture was poured into ice water (100 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent: 0–25% ethyl acetate / petroleum ether, 60 mL / min gradient). The compound 2-[(4-bromo-3-methoxy-phenyl)methylsulfanyl]ethyl acetate (5.9 g, 18.48 mmol, 74% yield) was obtained as a colorless oil. 1 H NMR(400MHz,CHLOROFORM-d)δ=7.46(d,J=8.0Hz,1H),6.92(d,J=1.4Hz,1H),6.81(dd,J=1.5,8 .0Hz,1H),4.18(q,J=7.1Hz,2H),3.90(s,3H),3.79(s,2H),3.06(s,2H),1.29(t,J=7.1Hz,3H).

[0570] Synthesis of 2-[(4-bromo-3-methoxy-phenyl)methylsulfanyl]acetic acid

[0571] [ka] A mixture of ethyl 2-[(4-bromo-3-methoxy-phenyl)methylsulfanyl]acetate (14.5 g, 45.42 mmol, 1 equiv.) and LiOH.HO (7.62 g, 181.70 mmol, 30 mL, 4 equiv.) in EtOH (150 mL) was stirred at 25 °C under a N atmosphere for 2 h. The mixture was poured into ice-water (200 mL). The reaction mixture was acidified to pH = 6 with 1 M aqueous HCl, and the aqueous phase was extracted with ethyl acetate (150 mL*3). The combined organic phases were washed with brine (500 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated to give the product. The crude product, 2-[(4-bromo-3-methoxy-phenyl)methylsulfanyl]acetic acid (12 g, crude), was obtained as a colorless oil and used directly without further purification. 1 H NMR(400MHz,METHANOL-d4)δ=7.44(d,J=8.0Hz,1H),7.02(s,1H),6.83(br d,J=7.8Hz,1H),3.87(s,3H),3.81(s,2H),3.12(s,2H).

[0572] Synthesis of 6-bromo-7-methoxy-isothiochroman-4-one

[0573] [ka] To a solution of 2-[(4-bromo-3-methoxy-phenyl)methylsulfanyl]acetic acid (12 g, 41.21 mmol, 1 equiv.) in DCM (100 mL) was added SOCl2 (151.20 g, 1.27 mol, 92.31 mL, 30.84 equiv.). The mixture was stirred at 50 °C for 2 h. The mixture was concentrated to give the crude product. The crude product, 2-[(4-bromo-3-methoxy-phenyl)methylsulfanyl]acetyl chloride (13 g, crude), was obtained as a yellow oil and used directly without further purification.

[0574] To a solution of 2-[(4-bromo-3-methoxy-phenyl)methylsulfanyl]acetyl chloride (13 g, 41.99 mmol, 1 equiv.) in chlorobenzene (100 mL) was added SnCl (1 M, 83.98 mL, 2 equiv.) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with saturated NaHCO (200 mL) and then filtered through a Celite pad. The filtrate was poured into ice-water (200 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (200 mL*3). The combined organic phase was washed with brine (500 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® silica flash column, eluent: 0–30% ethyl acetate / petroleum ether, 80 mL / min gradient). The compound 6-bromo-7-methoxy-isothiochroman-4-one (8 g, 29.29 mmol, 70% yield) was obtained as a red solid. 1 H NMR(400MHz,CHLOROFORM-d)δ=8.28(s,1H),6.66(s,1H),3.96(s,3H),3.86(s,2H),3.51(s,2H).

[0575] Synthesis of 2-(6-bromo-7-methoxy-4-oxo-isothiochroman-3-yl)-2-oxo-ethyl acetate

[0576] [ka] To a solution of 6-bromo-7-methoxy-isothiochroman-4-one (1.1 g, 4.03 mmol, 1 equiv.) in THF (15 mL), LiHMDS (1 M, 5.24 mL, 1.3 equiv.) was added dropwise at −70° C. for 10 minutes. After the addition, the mixture was stirred at −70° C. for 0.5 hours, and then diethyl oxalate (882.80 mg, 6.04 mmol, 825.04 μL, 1.5 equiv.) in THF (5 mL) was added dropwise at −70° C. The resulting mixture was stirred at 0° C. for 1 hour. The mixture was poured into ice water (20 mL), and the reaction mixture was acidified to pH=6 with 1 M aqueous HCl, resulting in the formation of a precipitate in the reaction mixture. The mixture was filtered, and the filter cake was collected and dried under vacuum. The compound 2-(6-bromo-7-methoxy-4-oxo-isothiochroman-3-yl)-2-oxo-ethyl acetate (1.2 g, 3.22 mmol, 80% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=7.93(s,1H),7.15(s,1H),4.24(q,J=7.0Hz,2H),3.94(s,3H),3.90(s,2H),1.28(t,J=7.1Hz,3H).

[0577] Synthesis of 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isothiochromeno[4,3-c]pyrazole-3-carboxylic acid

[0578] [ka] A mixture of ethyl 2-(6-bromo-7-methoxy-4-oxo-isothiochroman-3-yl)-2-oxoacetate (130 mg, 348.32 μmol, 1 equiv.), (3,5-dichlorophenyl)hydrazine hydrochloride (74.36 mg, 348.32 μmol, 1 equiv.), and AcOH (209.80 mg, 3.49 mmol, 0.2 mL, 10.03 equiv.) in 2 mL of EtOH was stirred at 80 °C under a N atmosphere for 5 h. The mixture was filtered, and the filter cake was collected and dried under vacuum to give the crude product. The crude product, ethyl 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isothiochromeno[4,3-c]pyrazole-3-carboxylate (0.17 g, crude), was obtained as a black solid and used directly without further purification. LCMS(ESI):m / z[M+H]calcd for C 20 H 16 BrCl2N2O3S:512.94;found:512.8. 1 H NMR(400MHz,DMSO-d6)δ=7.91-7.87(m,1H),7.77(d,J=1.6Hz,2H),7.33(s,1H),6 .88(s,1H),4.36-4.32(m,2H),4.08(s,2H),3.91-3.90(m,3H),1.34-1.30(m,3H).

[0579] Synthesis of 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isothiochromeno[4,3-c]pyrazole-3-carboxylic acid

[0580] [ka] A mixture of ethyl 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isothiochromeno[4,3-c]pyrazole-3-carboxylate (1.4 g, 2.72 mmol, 1 equiv.) and LiOH.HO (571.25 mg, 13.61 mmol, 6 mL, 5 equiv.) in THF (10 mL), EtOH (10 mL), and HO (2 mL) was stirred at 25 °C under a N atmosphere for 16 h. The residue was poured into ice water (20 mL), and the reaction mixture was acidified to pH = 6 with 1 M aqueous HCl. The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to give the crude product. The crude product, 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isothiochromeno[4,3-c]pyrazole-3-carboxylic acid (1.2 g, crude) was obtained as a red solid and used directly without further purification. LCMS (ESI): m / z [M+H] calculated for C 18 H 12 BrCl2N2O3S:484.91;found:484.7. 1 H NMR(400MHz,METHANOL-d4)δ=7.68-7.64(m,3H),7.16(s,1H),6.96(s,1H),4.01(s,2H),3.94(s,3H).

[0581] Synthesis of (8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,5-dihydroisothiochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone

[0582] [ka] To a solution of 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isothiochromeno[4,3-c]pyrazole-3-carboxylic acid (0.6 g, 1.23 mmol, 1 equiv.) in THF (10 mL), HATU (703.89 mg, 1.85 mmol, 1.5 equiv.) and DIEA (478.51 mg, 3.70 mmol, 644.90 μL, 3 equiv.) were added at 25 °C. After the addition, the mixture was stirred at this temperature for 0.5 h, and then 3,3-dimethylmorpholine (156.35 mg, 1.36 mmol, 1.1 equiv.) in THF (5 mL) was added at 25 °C. The resulting mixture was stirred at 25 °C for 16 h. The mixture was poured into ice water (30 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent: 0-20% ethyl acetate / petroleum ether, 40 mL / min gradient). The compound (8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,5-dihydroisothiochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone (0.6 g, 1.03 mmol, 83% yield) was obtained as a yellow oil. LCMS (ESI): m / z [M+H] calcd for C 24 H 23 BrCl2N3O3S:581.99;found:582.0.

[0583] Synthesis of 5-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,5-dihydroisothiochromeno[4,3-c]pyrazol-8-yl)nicotinonitrile

[0584] [ka] A mixture of (8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,5-dihydroisothiochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone (0.35 g, 600.01 μmol, 1 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (138.04 mg, 600.01 μmol, 1 equiv.), KCO (165.85 mg, 1.20 mmol, 2 equiv.), and Pd(dppf)Cl (43.90 mg, 60.00 μmol, 0.1 equiv.) in dioxane (5 mL) and HO (0.5 mL) was degassed and purged twice with N, then heated to 60 °C under N for 16 h. The mixture was diluted with EtOAc (40 mL) and then filtered. The filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent: 0-40% ethyl acetate / petroleum ether, 40 mL / min gradient). The compound 5-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,5-dihydroisothiochromeno[4,3-c]pyrazol-8-yl)nicotinonitrile (0.2 g, 329.75 μmol, 55% yield) was obtained as a yellow solid. LCMS (ESI): m / z [M+H] calcd for C 30 H 26 Cl2N5O3S:606.11;found:606.2.

[0585] Synthesis of 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-5H-isothiochromeno[4,3-c]pyrazol-8-yl]pyridine-3-carboxamide

[0586] [ka] To a solution of 5-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,5-dihydroisothiochromeno[4,3-c]pyrazol-8-yl)nicotinonitrile (0.2 g, 329.75 μmol, 1 equiv.) in DMSO (3 mL), KCO (136.72 mg, 989.25 μmol, 3 equiv.) and HO (0.420 g, 3.70 mmol, 355.93 μL, 30% purity, 11.23 equiv.) were added at 0 °C. The mixture was stirred at 0-25 °C for 2 h. The reaction was quenched with saturated NaSO (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 42% to 72% B / min). The compound 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-5H-isothiochromeno[4,3-c]pyrazol-8-yl]pyridine-3-carboxamide (160 mg, 216.64 μmol, 66% yield, TFA) was obtained as a white solid. LCMS (ESI): m / z [M+H] calculated for C 30 H 28 Cl2N5O4S:624.12.;found:624.2. 1 H NMR (400 MHz, METHANOL-d) δ = 8.44 (d, J = 1.1 Hz, 1H), 8.09 (s, 1H), 7.83 (s, 1H), 7.14-7.08 (m, 3H), 6.79 (s, 1H), 6.38 (s, 1H), 3.57 (s, 2H), 3.41 (s, 3H), 2.98 (s, 2H), 2.79-2.77 (m, 4H), 0.99 (s, 6H). Figure 16 shows the nuclear magnetic resonance spectrum of compound 3-01.

[0587] Synthesis of (1-(3,5-dichlorophenyl)-7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1,5-dihydroisothiochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone

[0588] [ka] A mixture of (8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,5-dihydroisothiochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone (0.25 g, 428.58 μmol, 1 equiv.), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (89.17 mg, 428.58 μmol, 1 equiv.), KCO (118.46 mg, 857.16 μmol, 2 equiv.), and Pd(dppf)Cl (31.36 mg, 42.86 μmol, 0.1 equiv.) in dioxane (5 mL) and HO (0.5 mL) was degassed and purged with N three times, then heated to 60 °C under N for 16 h. The residue was diluted with EtOAc (40 mL) and then filtered. The filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent of 0-40% ethyl acetate / petroleum ether, 40 mL / min gradient). The compound [1-(3,5-dichlorophenyl)-7-methoxy-8-(1-methylpyrazol-3-yl)-5H-isothiochromeno[4,3-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (220 mg, 376.38 μmol, 88% yield) was obtained as a white solid. LCMS (ESI): m / z [M+H] calcd for C 28 H 28 Cl2N5O3S:584.12.11;found:584.2. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.54-7.48 (m, 3H), 7.43 (s, 1H), 7.31 (d, J = 2.0 Hz, 1H), 6.92 (s, 1H), 6.55 (d, J = 2.1 Hz, 1H), 3.97-3.93 (m, 5H), 3.92-3.88 (m, 2H), 3.88-3.83 (m, 5H), 3.50 (s, 2H), 1.56 (s, 6H). Figure 18 shows the nuclear magnetic resonance spectrum of compound 3-03.

[0589] Reaction Scheme 3

[0590] [ka] Synthesis of 8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide

[0591] [ka] To a solution of 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isothiochromeno[4,3-c]pyrazole-3-carboxylic acid (598.53 mg, 1.23 mmol, 1 equiv.) in THF (10 mL) was added HATU (702.17 mg, 1.85 mmol, 1.5 equiv.) and DIEA (477.34 mg, 3.69 mmol, 643.32 μL, 3 equiv.) at 25° C. After the addition, the mixture was stirred at 25° C. for 0.5 h, and then N,2-dimethylpropan-2-amine (118.04 mg, 1.35 mmol, 162.37 μL, 1.1 equiv.) in THF (5 mL) was added at 25° C. The resulting mixture was stirred at 25° C. for 16 h. The mixture was poured into ice water (30 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent of 0-20% ethyl acetate / petroleum ether, 40 mL / min gradient). The compound 8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide (0.65 g, 1.17 mmol, 95% yield) was obtained as a yellow oil. LCMS (ESI): m / z [M+H] calcd for C 23 H 22 BrCl2N3O2S:554.00;found:554.1.

[0592] Synthesis of N-tert-butyl-8-(5-cyano-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide

[0593] [ka] A mixture of 8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)7-methoxy-N-methyl-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide (0.4 g, 720.31 μmol, 1 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (165.72 mg, 720.31 μmol, 1 equiv.), KCO (199.10 mg, 1.44 mmol, 2 equiv.), and Pd(dppf)Cl (52.71 mg, 72.03 μmol, 0.1 equiv.) in dioxane (5 mL) and HO (0.5 mL) was degassed and purged with N three times, then heated to 60 °C under N for 16 h. The mixture was diluted with EtOAc (40 mL) and then filtered. The filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent of 0-40% ethyl acetate / petroleum ether, 40 mL / min gradient). The compound N-tert-butyl-8-(5-cyano-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide (0.4 g, 691.43 μmol, 96% yield) was obtained as a yellow solid. LCMS (ESI): m / z [M+H] calcd for C 29 H 25 Cl2N5O2S:578.10;found:578.1.

[0594] Synthesis of N-tert-butyl-8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide

[0595] [ka] To a solution of N-tert-butyl-8-(5-cyano-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide (0.4 g, 691.43 μmol, 1 equiv.) in DMSO (5 mL), KCO (286.68 mg, 2.07 mmol, 3 equiv.) and HO (0.790 g, 6.97 mmol, 669.49 μL, 30% purity, 10.08 equiv.) were added at 0 °C. The mixture was stirred at 0–25 °C for 2 h. The reaction was quenched with saturated NaSO (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 50% to 80% B over ★ minutes). The compound N-tert-butyl-8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide (160 mg, 225.18 μmol, 33% yield, TFA) was obtained as a white solid. LCMS (ESI): m / z [M+H] calcd for C 29 H 27 Cl2N5O3S:596.12;found:596.2. 1 H NMR (400 MHz, METHANOL-d) δ = 8.94 (s, 1H), 8.59 (s, 1H), 8.32 (d, J = 1.0 Hz, 1H), 7.67-7.59 (m, 3H), 7.31 (s, 1H), 6.91 (s, 1H), 4.10 (s, 2H), 3.94 (s, 3H), 3.18 (s, 3H), 1.54 (s, 9H). Figure 17 shows the nuclear magnetic resonance of compound 3-02.

[0596] Synthesis of N-tert-butyl-8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-4-oxo-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide

[0597] [ka] To a solution of N-tert-butyl-8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide (20 mg, 33.53 μmol, 1 equiv.) in DCM (5 mL) was added oxone (82.45 mg, 134.11 μmol, 4 equiv.). The mixture was stirred at 25 °C for 16 h. The reaction was quenched with saturated NaSO (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL * 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 38% to 68% B over 9 min). The compound N-tert-butyl-8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-4-oxo-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide (10 mg, 13.76 μmol, 41% yield, TFA) was obtained as a white solid. LCMS (ESI): m / z [M+H] calculated for C 29 H 27 Cl2N5O4S:612.12;found:612.2. 1 H NMR(400MHz,CHLOROFORM-d)δ=8.92(s,1H),8.57(s,1H),8.02-7.97(m,1H),7.56(t,J=1.8Hz,1H),7.49(d,J=1.7Hz,2H),7.18(s, 1H),7.02(s,1H),4.58(d,J=15.4Hz,1H),4.03(d,J=15.3Hz,1H),3.89(s,3H),3.21(s,3H),1.57(s,9H). Figure 20 shows the nuclear magnetic resonance of compound 3-07.

[0598] Synthesis of N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(1-methylpyrazol-3-yl)-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide

[0599] [ka] A solution of 8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide (0.25 g, 450.20 μmol, 1 equiv.), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (93.67 mg, 450.20 μmol, 1 equiv.), KCO (124.44 mg, 900.39 μmol, 2 equiv.), and Pd(dppf)Cl (32.94 mg, 45.02 μmol, 0.1 equiv.) in dioxane (5 mL) and HO (0.5 mL) was degassed and purged with N three times, then heated to 60 °C under N for 16 h. The residue was diluted with EtOAc (40 mL) and then filtered. The filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent of 0-40% ethyl acetate / petroleum ether, 40 mL / min gradient). The compound N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(1-methylpyrazol-3-yl)-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide (0.2 g, 359.39 μmol, 80% yield) was obtained as a white solid. LCMS (ESI): m / z [M+H] calcd for C 27 H 27 Cl2N5O2S:556.13;found:556.3. 1H NMR(400MHz,CHLOROFORM-d)δ=7.52(d,J=1.7Hz,2H),7.45(s,1H),7.42(d,J=1.7Hz,1H),7.33(d,J=2.2Hz,1H),6.93(s,1H) ),6.50(d,J=2.1Hz,1H),3.96-3.95(m,2H),3.94(s,3H),3.88(s,3H),3.19(s,3H),1.54(s,9H). Figure 19 shows the nuclear magnetic resonance of compound 3-04.

[0600] Example 3 Reaction Scheme 4

[0601] [ka] Synthesis of 5-bromo-6-methoxy-benzofuran-3-one

[0602] [ka] To a mixture of 6-methoxybenzofuran-3(2H)-one (12.2 g, 74.32 mmol, 1 equiv.) in DMF (60 mL) was added NBS (15.87 g, 89.18 mmol, 1.2 equiv.) at 0° C. The mixture was stirred at 15° C. for 20 h. The mixture was poured into HO (600 mL), causing a precipitate to form in the reaction mixture. The resulting mixture was filtered, and the filter cake was dried under vacuum to give 5-bromo-6-methoxybenzofuran-3(2H)-one (16.5 g, 61.78 mmol, 83% yield, 91% purity) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ=7.81(s,1H),7.08-6.97(m,1H),4.83(s,2H),3.96(s,3H).

[0603] 4: Synthesis of ethyl 2-(5-bromo-6-methoxy-3-oxo-2,3-dihydrobenzofuran-2-yl)-2-oxoacetate

[0604] [ka] To a mixture of 5-bromo-6-methoxybenzofuran-3(2H)-one (19.1 g, 78.58 mmol, 1 equiv.) in THF (150 mL) was added LDA (2 M, 47.15 mL, 1.2 equiv.) at −78° C. under a N2 atmosphere. The mixture was stirred at −78° C. for 15 min, and then diethyl oxalate (18.37 g, 125.73 mmol, 17.17 mL, 1.6 equiv.) was added. The mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with 1 N HCl (100 mL) and then extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with brine (200 mL) and dried over Na2SO4. It was filtered and the filtrate was concentrated in vacuo to give ethyl 2-(5-bromo-6-methoxy-3-oxo-2,3-dihydrobenzofuran-2-yl)-2-oxoacetate (35 g, crude) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ=8.26(s,1H),7.38(s,1H),4.34(q,J=7.09Hz,2H),3.94(s,3H),1.30(t,J=7.09Hz,3H).

[0605] Synthesis of ethyl 7-bromo-6-methoxy-1-(4-methoxybenzyl)-1H-benzofuro[3,2-c]pyrazole-3-carboxylate

[0606] [ka] To a mixture of ethyl 2-(5-bromo-6-methoxy-3-oxo-2,3-dihydrobenzofuran-2-yl)-2-oxoacetate (300 mg, 874.31 μmol, 1 equiv.) in 2 mL of AcOH, (4-methoxyphenyl)methylhydrazine hydrochloride (164.94 mg, 874.31 μmol, 1 equiv.) was added, and the mixture was stirred at 110° C. for 1 hour. The reaction mixture was adjusted to pH 7 with saturated NaHCO3, and the resulting mixture was extracted with ethyl acetate (50 mL*3). The combined organic phase was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give ethyl 7-bromo-6-methoxy-1-(4-methoxybenzyl)-1H-benzofuro[3,2-c]pyrazole-3-carboxylate (150 mg, 326.59 μmol, 37% yield) as a brown solid.

[0607] Synthesis of ethyl 6-methoxy-7-(1-methylpyrazol-3-yl)-1H-benzofuro[3,2-c]pyrazole-3-carboxylate

[0608] [ka] To a mixture of ethyl 6-methoxy-1-[(4-methoxyphenyl)methyl]-7-(1-methylpyrazol-3-yl)benzofuro[3,2-c]pyrazole-3-carboxylate (650 mg, 1.41 mmol, 1 equiv.) in DCM (5 mL), TFA (160.95 mg, 1.41 mmol, 104.85 μL, 1 equiv.) was added, and the mixture was stirred at 70 °C for 16 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to give ethyl 6-methoxy-7-(1-methylpyrazol-3-yl)-1H-benzofuro[3,2-c]pyrazole-3-carboxylate (420 mg, 1.23 mmol, 87% yield) as a white solid.

[0609] Synthesis of ethyl 6-methoxy-7-(1-methylpyrazol-3-yl)-1-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylate and ethyl 6-methoxy-7-(1-methylpyrazol-3-yl)-2-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylate

[0610] [ka] To a mixture of ethyl 6-methoxy-7-(1-methylpyrazol-3-yl)-1H-benzofuro[3,2-c]pyrazole-3-carboxylate (320 mg, 940.26 μmol, 1 equiv.) and 3-thienylboronic acid (180.47 mg, 1.41 mmol, 1.5 equiv.) in DCM (10 mL) was added Cu(OAc) (170.78 mg, 940.26 mol, 1 equiv.), Py (148.75 mg, 1.88 mmol, 151.78 μL, 2 equiv.), and 4A MS (50 mg). The mixture was stirred at 25 °C under an O atmosphere (15 psi) for 16 h. HO (20 mL) and NH HO (1 mL) were added, and the resulting mixture was extracted with ethyl acetate (20 mL). The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography column (petroleum ether:ethyl acetate=2:1), and the residue was purified by preparative TLC (petroleum ether:ethyl acetate=2:1) ​​(third purification) to give ethyl 6-methoxy-7-(1-methylpyrazol-3-yl)-1-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylate (23 mg, 54.44 μmol, 6% yield) as a brown solid. 1H NMR(400MHz,DMSO-d6)δ=8.18(s,1H),7.63(dd,J=1.3,3.2Hz,1H),7.58(dd,J=3.2,5.1Hz,1H),7.49-7.41(m,1H) ,7.35(d,J=2.0Hz,1H),7.21(s,1H),6.74(d,J=2.0Hz,1H),4.47(q,J=7.2,2H),3.91(s,6H),1.42(t,J=7.2,3H).

[0611] Ethyl 6-methoxy-7-(1-methylpyrazol-3-yl)-2-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylate (180 mg, 426.08 μmol, 45% yield) was obtained as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ=8.43(s,1H),7.56(dd,J=1.3,3.2Hz,1H),7.49-7.44(m,1H),7.43-7.40(m,1H),7 .39-7.35(m,1H),7.21(s,1H),6.74(d,J=2.2Hz,1H),4.43(q,J=7.2,2H),3.98(s,6H),1.41(t,J=7.2,3H).

[0612] Synthesis of 6-methoxy-7-(1-methylpyrazol-3-yl)-1-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylic acid

[0613] [ka] To a mixture of ethyl 6-methoxy-7-(1-methylpyrazol-3-yl)-1-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylate (23 mg, 54.44 μmol, 1 equiv.) in HO (1 mL) and THF (2 mL), LiOH·HO (6.85 mg, 163.33 μmol, 3 equiv.) was added, and the mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo to remove THF. The reaction mixture was adjusted to pH 6 with 1 M aqueous HCl. A precipitate formed in the reaction mixture, and the resulting mixture was filtered. The filter cake was dried in vacuo to give 6-methoxy-7-(1-methylpyrazol-3-yl)-1-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylic acid (20 mg, 50.71 μmol, 93% yield) as a pale green solid.

[0614] Synthesis of (3,3-dimethylmorpholin-4-yl)-[6-methoxy-7-(1-methylpyrazol-3-yl)-1-(3-thienyl)benzofuro[3,2-c]pyrazol-3-yl]methanone

[0615] [ka] To a mixture of 6-methoxy-7-(1-methylpyrazol-3-yl)-1-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylic acid (20 mg, 50.71 μmol, 1 equiv.) in DMF (1 mL) was added HATU (28.92 mg, 76.06 μmol, 1.5 equiv.), DIEA (13.11 mg, 101.42 μmol, 17.66 μL, 2 equiv.), followed by 3,3-dimethylmorpholine (8.76 mg, 76.06 μmol, 1.5 equiv.), and the mixture was stirred at 25° C. for 1 hour. The mixture was filtered. The filtrate was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 52% to 82% B over 9 min) followed by lyophilization to give (3,3-dimethylmorpholin-4-yl)-[6-methoxy-7-(1-methylpyrazol-3-yl)-1-(3-thienyl)benzofuro[3,2-c]pyrazol-3-yl]methanone (5.69 mg, 9.40 μmol, 19% yield, TFA) as a yellow solid. LCMS (ESI): m / z [M+H] calculated for C 25 H 26 N5O4S:492.16;found:492.1. 1H NMR(400MHz,DMSO-d6)δ=7.81(s,1H),7.54(dd,J=1.3,3.2Hz,1H),7.48(dd,J=3.2,5.1Hz,1H),7.33(d,J=2. 1Hz,1H),7.19(dd,J=1.4,5.2Hz,1H),7.17(s,1H),6.30(d,J=2.2Hz,1H),3.56(s,3H),3.50(s,3H),3.47(br d,J=5.3Hz,2H),3.40(br d, J = 4.5 Hz, 2H), 3.06 (s, 2H), 1.06 (s, 6H). Figure 40 shows the nuclear magnetic resonance of compound 4-07.

[0616] Synthesis of (3,3-dimethylmorpholino)(6-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-2-(thiophen-3-yl)-2H-benzofuro[3,2-c]pyrazol-3-yl)methanone

[0617] [ka] The compound (3,3-dimethylmorpholino)(6-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-2-(thiophen-3-yl)-2H-benzofuro[3,2-c]pyrazol-3-yl)methanone was synthesized by the same procedure as compound 4-07. LCMS (ESI): m / z [M+H] calculated for C 25 H 26 N5O4S:492.16;found:492.1. 1H NMR(400MHz,DMSO-d6)δ=8.36-8.28(m,1H),7.75-7.71(m,2H),7.64(dd,J=1.4,3.2Hz,1H),7.53(s,1H), 7.33(dd,J=1.4,5.1Hz,1H),6.73(d,J=2.3Hz,1H),3.97(s,3H),3.92(s,3H),3.52-3.49(m,4H),3.36(br s,2H),1.43(s,6H). Figure 39 shows the nuclear magnetic resonance of compound 4-07A.

[0618] Example 4 Reaction Scheme 5

[0619] [ka] Synthesis of 7-bromo-6-methoxy-1H-benzofuro[3,2-c]pyrazole-3-carboxylic acid

[0620] [ka] A mixture of ethyl 7-bromo-6-methoxy-1-(4-methoxybenzyl)-1H-benzofuro[3,2-c]pyrazole-3-carboxylate (200 mg, 435.46 μmol, 1 equiv.) in TFA (49.65 mg, 435.46 μmol, 32.35 μL, 1 equiv.) was stirred at 70 °C for 16 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to give ethyl 7-bromo-6-methoxy-1H-benzofuro[3,2-c]pyrazole-3-carboxylate (145 mg, 427.55 μmol, 98% yield) as a white solid.

[0621] Synthesis of ethyl 7-bromo-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylate and ethyl 7-bromo-6-methoxy-2-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylate

[0622] [ka] To a mixture of ethyl 7-bromo-6-methoxy-1H-benzofuro[3,2-c]pyrazole-3-carboxylate (145 mg, 427.55 μmol, 1 equiv.) and 3-thienylboronic acid (82.06 mg, 641.33 μmol, 1.5 equiv.) in DCM (10 mL) was added Cu(OAc) (77.66 mg, 427.55 μmol, 1 equiv.), Py (67.64 mg, 855.10 μmol, 69.02 μL, 2 equiv.), and 4A MS (50 mg, 1.00 equiv.), and the mixture was stirred at 25 °C under an O atmosphere (15 psi) for 16 h. To the mixture, HO (10 mL) and 25% NH HO (0.5 mL) were added, and the resulting mixture was extracted with ethyl acetate (10 mL*3). The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate = 4:1) to give ethyl 7-bromo-6-methoxy-2-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylate (68 mg, 161.42 μmol, 38% yield) as a white solid and ethyl 7-bromo-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylate (40 mg, 94.95 μmol, 22% yield) as a yellow solid. 1H NMR(400MHz,CHLOROFORM-d)δ=8.10(s,1H),7.56(dd,J=1.3,3.1Hz,1H),7.39(dd,J=3.3,5.1Hz,1H ),7.32(dd,J=1.2,5.2Hz,1H),7.19(s,1H),4.42(q,J=7.2Hz,2H),4.00(s,3H),1.45-1.41(m,3H).

[0623] Ethyl 7-bromo-6-methoxy-2-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylate 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.95 (s, 1H), 7.63 (d, J = 3.2 Hz, 1H), 7.60-7.57 (m, 1H), 7.55-7.51 (m, 1H), 7.23 (s, 1H), 4.56 (s, 2H), 3.99 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H).

[0624] Synthesis of 7-bromo-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylic acid

[0625] [ka] To a mixture of ethyl 7-bromo-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylate (200 mg, 474.76 μmol, 1 equiv.) in THF (2 mL) and HO (1 mL) was added LiOH·HO (59.76 mg, 1.42 mmol, 3 equiv.), and the mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo to remove the organic phase, and the resulting mixture was adjusted to pH 6 with 1 N HCl. A precipitate formed in the reaction mixture. The resulting mixture was filtered, and the filter cake was dried in vacuo to give 7-bromo-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylic acid (160 mg, 406.91 μmol, 86% yield) as a brown solid.

[0626] Synthesis of [7-bromo-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone

[0627] [ka] To a mixture of 7-bromo-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazole-3-carboxylic acid (50 mg, 127.16 μmol, 1 equiv.) in DMF (1 mL), HATU (72.52 mg, 190.74 μmol, 1.5 equiv.), DIEA (32.87 mg, 254.32 μmol, 44.30 μL, 2 equiv.), and then 3,3-dimethylmorpholine (21.97 mg, 190.74 μmol, 1.5 equiv.) were added, and the mixture was stirred at 25 °C for 16 h. HO (5 mL) was added to the mixture, which was then extracted with ethyl acetate (10 mL * 3). The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography column (petroleum ether:ethyl acetate = 0~30%) to give [7-bromo-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (40 mg, 81.57 μmol, yield 64%) as a yellow solid.

[0628] Synthesis of 5-[3-(3,3-dimethylmorpholine-4-carbonyl)-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazol-7-yl]pyridine-3-carbonitrile

[0629] [ka] To a mixture of [7-bromo-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (40 mg, 81.57 μmol, 1 equiv.) in HO (0.5 mL) and dioxane (1 mL) was added Pd(dppf)Cl (5.97 mg, 8.16 μmol, 0.1 equiv.), KCO (33.82 mg, 244.71 μmol, 3 equiv.), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (22.52 mg, 97.89 μmol, 1.2 equiv.) was added, and the mixture was stirred at 80 °C under N for 16 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=3:1) to give 5-[3-(3,3-dimethylmorpholine-4-carbonyl)-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazol-7-yl]pyridine-3-carbonitrile (30 mg, 58.42 μmol, 72% yield) as a brown solid.

[0630] Synthesis of 5-[3-(3,3-dimethylmorpholine-4-carbonyl)-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazol-7-yl]pyridine-3-carbonitrile and 5-[3-(3,3-dimethylmorpholine-4-carbonyl)-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazol-7-yl]pyridine-3-carbonitrile

[0631] [ka] To a mixture of 5-[3-(3,3-dimethylmorpholine-4-carbonyl)-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazol-7-yl]pyridine-3-carbonitrile (30 mg, 58.42 μmol, 1 equiv.) in DMSO (1 mL), HO (66.22 mg, 584.15 μmol, 56.12 μL, 30% purity, 10 equiv.) and KCO (16.15 mg, 116.83 μmol, 2 equiv.) were added, and the mixture was stirred at 60 °C for 1 h. Saturated aqueous NaSO (20 mL) was added to the mixture. The mixture was adjusted to pH = 7 with 1 N HCl, and the resulting mixture was detected with KI paper (no blue color). The resulting mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 33% to 63% B over 9 min) followed by lyophilization to give 5-[3-(3,3-dimethylmorpholine-4-carbonyl)-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazol-7-yl]pyridine-3-carboxamide (8.55 mg, 13.11 μmol, 22% yield, 99% purity, TFA) as an off-white solid. LCMS (ESI): m / z [M+H] calculated for C 27 H 28 N5O5S: 532.16; found: 532.1. 1H NMR (400 MHz, DMSO-d6) δ = 9.02 (d, J = 1.7 Hz, 1H), 8.89 (d, J = 1.6 Hz, 1H), 8.39 (s, 1H), 8.21 (br s, 1H), 8.00 (br s, 1H), 7.90 (s, 1H), 7.83-7.77 (m, 1H), 7.69 (s, 1H), 7.67-7.62 (m, 2H), 3.91 (s, 5H), 3.82 (br d, J = 4.9 Hz, 2H), 3.48 (s, 2H), 1.48 (s, 6H). Figure 31 shows the nuclear magnetic resonance of compound 4-03A.

[0632] 5-[3-(3,3-dimethylmorpholine-4-carbonyl)-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazol-7-yl]pyridine-3-carbonitrile (9.42 mg, 14.86 μmol, 25% yield, 99% purity, TFA) was obtained as a brown solid. LCMS (ESI): m / z [M+H] calculated for C 27 H 24 NOS: 514.15; found: 514.2. 1H NMR (400 MHz, DMSO-d6) δ = 9.10 (s, 1H), 9.06 (s, 1H), 8.61-8.56 (m, 1H), 8.05 (br s, 1H), 7.98 (s, 1H), 7.85 (br s, 1H), 7.74 (s, 1H), 7.70-7.67 (m, 1H), 3.96 (br s, 5H), 3.86 (br s, 2H), 3.52 (br s, 2H), 1.52 (s, 6H). Figure 32 shows the nuclear magnetic resonance of compound 4-03.

[0633] Synthesis of Compound 4-04

[0634] [ka] Compound 4-04 was synthesized via the same procedure as in Example 4. LCMS (ESI): m / z [M+H] calculated for C 26 H 26 NOS: 504.16; found: 504.1 H NMR (400 MHz, DMSO-d) δ = 9.02 (s, 1H), 8.88 (d, J = 1.5 Hz, 1H), 8.38 (s, 1H), 8.23-8.17 (m, 1H), 7.98 (br s, 1H), 7.90 (s, 1H), 7.82-7.77 (m, 1H), 7.69 (s, 1H), 7.67-7.62 (m, 2H), 3.91 (s, 3H), 3.22 (s, 3H), 1.51 (s, 9H). Figure 34 shows the nuclear magnetic resonance of compound 4-04.

[0635] Synthesis of Compound 4-03A

[0636] [ka] Compound 4-03A was synthesized via the same procedure as in Example 4. LCMS (ESI): m / z [M+H] calculated for C 27 H 26 N5O5S 532.16;found:532.1. 1H NMR(400MHz,DMSO-d6)δ=9.02(d,J=1.8Hz,1H),8.93(d,J=1.8Hz,1H),8.44(br s,1H),8.25(br s,1H),8.07(s,1H),7.74(dd,J=3.2,5.0Hz,1H),7.70-7.64(m,3H),7.34(d,J=5.0Hz,1H),3.94(s,3H),3.53(br d,J=4.4Hz,2H),3.48(br d,J=4.4Hz,2H),3.39(s,2H),1.45(s,6H). Figure 31 shows the nuclear magnetic resonance of compound 4-03A.

[0637] Synthesis of Compound 4-04A

[0638] [ka] Compound 4-04A was synthesized via the same procedure as in Example 4. LCMS (ESI): m / z [M+H] calculated for C 26 H 26 NOS: 504.16; found: 504.1. 1H NMR (400 MHz, DMSO-d6) δ = 8.96 (s, 1H), 8.88 (s, 1H), 8.38 (br s, 1H), 8.19 (br s, 1H), 8.01 (s, 1H), 7.67 (dd, J = 3.4, 5.0 Hz, 1H), 7.64-7.58 (m, 2H), 7.55 (br d, J = 1.5 Hz, 1H), 7.28 (d, J = 4.0 Hz, 1H), 3.88 (s, 3H), 2.91 (s, 3H), 1.42 (s, 9H). Figure 33 shows the nuclear magnetic resonance of compound 4-04A.

[0639] Example 5 Reaction Scheme 6

[0640] [ka] Synthesis of 6-bromo-5-methoxy-indan-1-one

[0641] [ka] To a solution of 1-bromo-2-methoxy-benzene (2 g, 10.69 mmol, 1.33 mL, 1 equiv.) and 3-chloropropanoyl chloride (1.49 g, 11.76 mmol, 1.13 mL, 1.1 equiv.) in DCM (10 mL) was added AlCl (1.57 g, 11.76 mmol, 642.80 μL, 1.1 equiv.) at 0° C. The mixture was stirred at 0° C. for 0.5 h, and then HSO (10 mL) was added. The mixture was then concentrated under vacuum to remove DCM. The resulting mixture was stirred at 100° C. for 2 h. The mixture was slowly poured into water and allowed to stand overnight. A precipitate formed in the reaction mixture, which was filtered, and the filter cake was dried under vacuum to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent of 0-50% petroleum ether gradient / ethyl acetate, 60 mL / min) to give 6-bromo-5-methoxy-indan-1-one (900 mg, 3.73 mmol, 35% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=7.77(s,1H),7.30(s,1H),3.96(s,3H),3.08-3.00(m,2H),2.66-2.59(m,2H).

[0642] Synthesis of 2-(6-bromo-5-methoxy-1-oxo-indan-2-yl)-2-oxo-ethyl acetate

[0643] [ka] To a mixture of 6-bromo-5-methoxy-indan-1-one (400 mg, 1.66 mmol, 1 equiv.) in THF (6 mL) was added LDA (2 M, 1.24 mL, 1.5 equiv.) at −78° C. under a N atmosphere. The mixture was stirred at −78° C. for 15 minutes, and then diethyl oxalate (387.96 mg, 2.65 mmol, 362.58 μL, 1.6 equiv.) was added. The mixture was stirred at 0° C. for 1 hour. The reaction mixture was acidified to pH=6 with 1 M aqueous HCl, and a precipitate formed in the reaction mixture. It was filtered, and the filter cake was dried under vacuum to give 2-(6-bromo-5-methoxy-1-oxo-indan-2-yl)-2-oxo-ethyl acetate (470 mg, 1.38 mmol, 83% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=8.03-7.86(m,1H),7.42(br s,1H),4.36-4.23(m,2H),3.98(s,3H),3.89-3.76(m,2H),1.32(t,J=7.07Hz,3H).

[0644] Synthesis of ethyl 7-bromo-1-(3,5-dichlorophenyl)-6-methoxy-4H-indeno[1,2-c]pyrazole-3-carboxylate

[0645] [ka] To a mixture of ethyl 2-(6-bromo-5-methoxy-1-oxo-indan-2-yl)-2-oxoacetate (300 mg, 879.37 μmol, 1 equiv.) in t-BuOH (4 mL), AcOH (264.04 mg, 4.40 mmol, 251.71 μL, 5 equiv.) and (3,5-dichlorophenyl)hydrazine hydrochloride (187.74 mg, 879.37 μmol, 1 equiv.) were added. The mixture was stirred at 90° C. for 1 h. The mixture was concentrated in vacuo to give a residue. The residue was triturated with ethyl acetate (5 mL) at 15° C. for 0.5 h to give ethyl 7-bromo-1-(3,5-dichlorophenyl)-6-methoxy-4H-indeno[1,2-c]pyrazole-3-carboxylate (340 mg, 705.17 μmol, 80% yield) as a gray solid.

[0646] Synthesis of 7-bromo-1-(3,5-dichlorophenyl)-6-methoxy-4H-indeno[1,2-c]pyrazole-3-carboxylic acid

[0647] [ka] To a mixture of ethyl 7-bromo-1-(3,5-dichlorophenyl)-6-methoxy-4H-indeno[1,2-c]pyrazole-3-carboxylate (340 mg, 705.17 μmol, 1 equiv.) in THF (3 mL) and HO (3 mL) was added LiOH.HO (88.77 mg, 2.12 mmol, 3 equiv.). The mixture was stirred at 15 °C for 16 hours. The reaction mixture was acidified to pH = 3 with 1 M aqueous HCl, and a precipitate formed in the reaction mixture. This was filtered, and the filter cake was dried under vacuum to give 7-bromo-1-(3,5-dichlorophenyl)-6-methoxy-4H-indeno[1,2-c]pyrazole-3-carboxylic acid (270 mg, crude) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=7.88(d,J=1.63Hz,2H),7.84(d,J=1.75Hz,1H),7.50(d,J=6.38Hz,2H),3.92(s,3H),3.77(s,2H).

[0648] Synthesis of [7-bromo-1-(3,5-dichlorophenyl)-6-methoxy-4H-indeno[1,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone

[0649] [ka] To a mixture of 7-bromo-1-(3,5-dichlorophenyl)-6-methoxy-4H-indeno[1,2-c]pyrazole-3-carboxylic acid (270 mg, 594.58 μmol, 1 equiv.) in DMF (4 mL) was added HATU (226.08 mg, 594.58 μmol, 1 equiv.) and DIEA (230.53 mg, 1.78 mmol, 310.69 μL, 3 equiv.). The mixture was stirred at 15° C. for 15 minutes, and then 3,3-dimethylmorpholine (82.18 mg, 713.50 μmol, 1.2 equiv.) was added. The mixture was stirred at 25° C. for 16 hours. The mixture was poured into HO (20 mL), which caused a precipitate to form in the reaction mixture. This was filtered, and the filter cake was dried under vacuum to give the crude product. The crude product was triturated with 2-methoxy-2-methyl-propane (5 mL) at 15° C. for 15 min to give [7-bromo-1-(3,5-dichlorophenyl)-6-methoxy-4H-indeno[1,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (150 mg, 272.10 μmol, 46% yield) as a yellow solid.

[0650] Synthesis of [1-(3,5-dichlorophenyl)-6-methoxy-7-(1-methylpyrazol-3-yl)-4H-indeno[1,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone

[0651] [ka] To a mixture of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (67.94 mg, 326.53 μmol, 1.2 equiv.) in dioxane (2 mL) and HO (0.4 mL) was added Pd(dppf)Cl (39.82 mg, 54.42 μmol, 0.2 equiv.), [7-bromo-1-(3,5-dichlorophenyl)-6-methoxy-4H-indeno[1,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (150 mg, 272.10 μmol, 1 equiv.), and KCO (112.82 mg, 816.31 μmol, 3 equiv.). The mixture was stirred at 80 °C under a N atmosphere for 16 h. The mixture was filtered, and the filtrate was concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (TFA)-ACN]; gradient: 65% to 95% B over 9 min), followed by lyophilization to give [1-(3,5-dichlorophenyl)-6-methoxy-7-(1-methylpyrazol-3-yl)-4H-indeno[1,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (42.8 mg, 72.05 μmol, 26% yield, 93% purity) as a yellow solid. LCMS (ESI): m / z [M+H] calcd for C 28 H 28 N5O3Cl2:552.15;found:552.2. 1 H NMR(400MHz,DMSO-d6)δ=8.16(s,1H),7.89(d,J=1.75Hz,2H),7.82(t,J=1.81Hz,1H),7.70(d,J=2.13Hz,1H),7.42(s,1H),6.72(d,J=2.13 Hz, 1H), 3.94 (s, 3H), 3.89-3.86 (m, 2H), 3.86 (s, 3H), 3.78-3.75 (m, 2H), 3.74 (s, 2H), 3.44 (s, 2H), 1.45 (s, 6H). Figure 47 shows the nuclear magnetic resonance of compound 5-05.

[0652] Synthesis of N-tert-butyl-7-(5-cyano-3-pyridyl)-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide

[0653] [ka] To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (179.90 mg, 781.95 μmol, 1.2 equiv.) in dioxane (2.5 mL) and HO (0.5 mL) was added KCO (270.18 mg, 1.95 mmol, 3 equiv.), 7-bromo-N-tert-butyl-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide (300 mg, 651.63 μmol, 1 equiv.), and Pd(dppf)Cl (95.36 mg, 130.33 μmol, 0.2 equiv.). The mixture was stirred at 80 °C under a N atmosphere for 16 h. The reaction mixture was poured into HO (5 mL) and ethyl acetate (5 mL), and then the mixture was separated. The aqueous phase was extracted with ethyl acetate (5 mL * 3). The combined organic phases were dried over anhydrous NaSO and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent of 0-70% petroleum ether gradient / ethyl acetate, 30 mL / min) to give N-tert-butyl-7-(5-cyano-3-pyridyl)-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide (200 mg, 413.58 μmol, 63% yield) as a brown solid.

[0654] Synthesis of 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-6-methoxy-4H-indeno[1,2-c]pyrazol-7-yl]pyridine-3-carboxamide

[0655] [ka] To a mixture of [1-(3,5-dichlorophenyl)-7-(5-cyano-3-pyridyl)-6-methoxy-4H-indeno[1,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (70 mg, 121.85 μmol, 1 equiv.) in DMSO (2 mL) was added HO (290 mg, 2.56 mmol, 245.76 μL, 30% purity, 20.99 equiv.) and KCO (33.68 mg, 243.71 μmol, 2 equiv.). The mixture was stirred at 15 °C for 15 min. The mixture was poured into saturated aqueous NaSO (10 mL), and the whole was stirred at 15 °C for an additional 1 h. The resulting mixture was extracted with ethyl acetate (10 mL*3), and the combined organic phase was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 40% to 70% B over 9 min) followed by lyophilization to give 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-6-methoxy-4H-indeno[1,2-c]pyrazol-7-yl]pyridine-3-carboxamide (5.33 mg, 8.82 μmol, 7% yield, 98% purity) as an off-white solid. LCMS (ESI): m / z [M+H] calculated for C 30 H 28 N5O4Cl2:592.14;found:592.2. 1 H NMR(400MHz,DMSO-d6)δ=8.97(d,J=1.96Hz,1H),8.82(d,J=2.08Hz,1H),8.37-8.32(m,1H),8.18-8.12(m,1H) ,7.90(d,J=1.71Hz,2H),7.77-7.72(m,1H),7.65-7.59(m,1H),7.57-7.53(m,1H),7.44-7.39(m,1H),3.91(br s, 2H), 3.88 (s, 3H), 3.84-3.79 (m, 2H), 3.79-3.74 (m, 2H), 3.45 (s, 2H), 1.46 (s, 6H). Figure 43 shows the nuclear magnetic resonance of compound 5-01.

[0656] Reaction Scheme 7

[0657] [ka] Synthesis of 7-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-6-methoxy-N-methyl-4H-indeno[1,2-c]pyrazole-3-carboxamide

[0658] [ka] To a mixture of 7-bromo-1-(3,5-dichlorophenyl)-6-methoxy-4H-indeno[1,2-c]pyrazole-3-carboxylic acid (500 mg, 1.10 mmol, 1 equiv.) in DMF (5 mL) was added HATU (502.39 mg, 1.32 mmol, 1.2 equiv.) and DIEA (426.92 mg, 3.30 mmol, 575.36 μL, 3 equiv.). The mixture was stirred at 15 °C for 15 minutes, and then N-2-dimethylpropan-2-amine (143.96 mg, 1.65 mmol, 198.02 μL, 1.5 equiv.) was added to the mixture. The mixture was stirred at 15 °C for 16 hours and then poured into HO (20 mL), whereupon a precipitate was observed. The precipitate was collected by filtration, and the filter cake was dried under vacuum to give 7-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-6-methoxy-N-methyl-4H-indeno[1,2-c]pyrazole-3-carboxamide (520 mg, 993.79 μmol, 90% yield) as an off-white solid.

[0659] Synthesis of N-tert-butyl-1-(3,5-dichlorophenyl)-7-(5-cyano-3-pyridyl)-6-methoxy-N-methyl-4H-indeno[1,2-c]pyrazole-3-carboxamide

[0660] [ka] To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (158.29 mg, 688.01 μmol, 1.2 equiv.) in dioxane (2.5 mL) and HO (0.5 mL) was added KCO (237.72 mg, 1.72 mmol, 3 equiv.), 7-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-6-methoxy-N-methyl-4H-indeno[1,2-c]pyrazole-3-carboxamide (300 mg, 573.34 μmol, 1 equiv.), and Pd(dppf)Cl (83.90 mg, 114.67 μmol, 0.2 equiv.). The mixture was stirred at 80 °C under a N atmosphere for 16 h. The reaction mixture was poured into HO (5 mL) and ethyl acetate (5 mL), and then the mixture was separated. The aqueous phase was extracted with ethyl acetate (5 mL * 3). The combined organic phases were dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent: 0–70% petroleum ether gradient / ethyl acetate, 30 mL / min) to give N-tert-butyl-1-(3,5-dichlorophenyl)-7-(5-cyano-3-pyridyl)-6-methoxy-N-methyl-4H-indeno[1,2-c]pyrazole-3-carboxamide (140 mg, 256.20 μmol, 45% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ=9.00(dd,J=12.16,1.90Hz,2H),8.45(t,J=2.02Hz,1H),7.89(d,J=1.71Hz,2H) ,7.74(t,J=1.71Hz,1H),7.52(s,1H),7.43(s,1H),3.89(s,3H),3.78(s,2H),3.19(s,3H),1.48(s,9H).

[0661] Synthesis of N-tert-butyl-7-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-6-methoxy-N-methyl-4H-indeno[1,2-c]pyrazole-3-carboxamide

[0662] [ka] To a mixture of N-tert-butyl-1-(3,5-dichlorophenyl)-7-(5-cyano-3-pyridyl)-6-methoxy-N-methyl-4H-indeno[1,2-c]pyrazole-3-carboxamide (90 mg, 164.70 μmol, 1 equiv.) in DMSO (2 mL) was added HO (290 mg, 2.56 mmol, 245.76 μL, 30% purity, 15.53 equiv.) and KCO (45.53 mg, 329.40 μmol, 2 equiv.). The mixture was stirred at 15 °C for 15 min. The mixture was poured into saturated aqueous NaSO (10 mL), and the mixture was stirred at 15 °C for an additional 1 h. It was then extracted with ethyl acetate (10 mL*3), and the combined organic phase was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (TFA)-ACN]; gradient: 42% to 72% B) followed by lyophilization to give N-tert-butyl-7-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-6-methoxy-N-methyl-4H-indeno[1,2-c]pyrazole-3-carboxamide (2.66 mg, 3.80 μmol, 2% yield, 97% purity, TFA) as an off-white solid. LCMS (ESI): m / z [M+H] calculated for C 31 H 28 N5Cl2O5F3: 564.15; found: 564.2. 1H NMR (400 MHz, DMSO-d6) δ = 8.99-8.96 (m, 1H), 8.83 (d, J = 1.59 Hz, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 7.90 (s, 2H), 7.71-7.75 (m, 1H), 7.60-7.65 (m, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 3.88 (s, 3H), 3.78-3.81 (m, 2H), 3.19 (s, 3H), 1.48 (s, 9H). Figure 44 shows the nuclear magnetic resonance of compound 5-02.

[0663] Synthesis of N-tert-butyl-1-(3,5-dichlorophenyl)-6-methoxy-N-methyl-7-(1-methylpyrazol-3-yl)-4H-indeno[1,2-c]pyrazole-3-carboxamide

[0664] [ka] To a mixture of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (104.98 mg, 504.54 μmol, 1.2 equiv.) in dioxane (2.5 mL) and HO (0.5 mL) was added KCO (174.33 mg, 1.26 mmol, 3 equiv.), 7-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-6-methoxy-N-methyl-4H-indeno[1,2-c]pyrazole-3-carboxamide (220 mg, 420.45 μmol, 1 equiv.), and Pd(dppf)Cl (61.53 mg, 84.09 μmol, 0.2 equiv.). The mixture was stirred at 80 °C under a N atmosphere for 16 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue that was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 70% to 100% B over 9 min) followed by lyophilization to give N-tert-butyl-1-(3,5-dichlorophenyl)-6-methoxy-N-methyl-7-(1-methylpyrazol-3-yl)-4H-indeno[1,2-c]pyrazole-3-carboxamide (13.19 mg, 24.14 μmol, 5% yield, 96% purity) as an orange solid. LCMS (ESI): m / z [M+H] calculated for C 27 H 28N5Cl2O2: 524.15; found: 524.2. 1H NMR (400 MHz, DMSO-d6) δ = 8.17 (s, 1H), 7.87 (s, 2H), 7.80 (s, 1H), 7.70 (d, J = 1.47 Hz, 1H), 7.41 (s, 1H), 6.72 (d, J = 1.83 Hz, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.73 (s, 2H), 3.17 (s, 3H), 1.48 (s, 9H). Figure 48 shows the nuclear magnetic resonance of compound 5-06.

[0665] Example 6 Reaction 7

[0666] [ka] Synthesis of tert-butyl N-amino-N-(3-thienyl)carbamate (2)

[0667] [ka] A mixture of 3-bromothiophene (20 g, 122.67 mmol, 11.49 mL, 1 equiv.), tert-butyl N-aminocarbamate (32.42 g, 245.35 mmol, 2 equiv.), CsCO (79.94 g, 245.35 mmol, 2 equiv.), (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (3.22 g, 24.53 mmol, 0.2 equiv.), and CuI (2.34 g, 12.27 mmol, 0.1 equiv.) in DMSO (200 mL) was degassed and purged with N three times, then heated at 80 °C under N for 16 h. The resulting residue was poured into ice water (500 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (200 mL*3), and the combined organic phase was washed with brine (200 mL*3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to give a residue, which was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® silica flash column, eluent of 0-20% ethyl acetate / petroleum ether, 80 mL / min gradient). Compound tert-butyl N-amino-N-(3-thienyl)carbamate (7 g, 32.67 mmol, 27% yield) was obtained as a brown oil. 1H NMR(400MHz,CHLOROFORM-d)δ=7.36(br d,J=4.3Hz,1H),7.18(dd,J=3.4,5.3Hz,1H),7.14(br s,1H),4.58-4.17(m,2H),1.56(s,9H).

[0668] Synthesis of 3-thienylhydrazine

[0669] [ka] A mixture of tert-butyl N-amino-N-(3-thienyl)carbamate (1 g, 3.99 mmol, 1 equiv., HCl) in EtOAc (6 mL) and HCl / EtOAc (6 mL) was stirred for 1 h at 15° C. The mixture was concentrated in vacuo to give 3-thienylhydrazine (600 mg, crude, HCl) as a gray solid, which was used in the next step without further purification.

[0670] To a mixture of 3-thienylhydrazine (600 mg, 3.98 mmol, 6.79 e-1 equiv, HCl) in t-BuOH (20 mL) was added AcOH (1.76 g, 29.31 mmol, 1.68 mL, 5 equiv) and 2-(6-bromo-5-methoxy-1-oxo-indan-2-yl)-2-oxo-ethyl acetate (2 g, 5.86 mmol, 1 equiv), and the mixture was stirred at 90° C. for 16 h, then concentrated in vacuo to give the crude product. The crude product was triturated once with EtOH (4 mL) at 15° C. for 20 min, and then a second time with petroleum ether:ethyl acetate (3:1, 5 mL) at 15° C. for 20 min to give ethyl 7-bromo-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxylate (1.7 g, 4.05 mmol, 69% yield) as a black solid. 1 H NMR(400MHz,DMSO-d6)δ=8.04(dd,J=3.12,1.41Hz,1H),7.88-7.84(m,1H),7.54(s,1H), 7.53-7.48(m,2H),4.36-4.29(m,2H),3.91(s,3H),3.78(s,2H),1.34(t,J=7.15Hz,3H).

[0671] Synthesis of 7-bromo-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxylic acid

[0672] [ka] To a mixture of ethyl 7-bromo-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxylate (1.7 g, 4.05 mmol, 1 equiv.) in HO (8 mL) and THF (8 mL) was added LiOH.HO (510.42 mg, 12.16 mmol, 3 equiv.). The mixture was stirred at 15 °C for 16 h. The reaction mixture was acidified to pH = 6 with 1 M aqueous HCl. A precipitate formed in the reaction mixture, which was collected by filtration. The filter cake was dried under vacuum to give 7-bromo-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxylic acid (1.3 g, 3.32 mmol, 82% yield) as a brown solid.

[0673] Synthesis of [7-bromo-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone

[0674] [ka] To a mixture of 7-bromo-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxylic acid (500 mg, 1.28 mmol, 1 equiv.) in DMF (5 mL) was added HATU (583.12 mg, 1.53 mmol, 1.2 equiv.) and DIEA (495.51 mg, 3.83 mmol, 667.81 μL, 3 equiv.). The mixture was stirred at 15 °C for 15 minutes, and then 3,3-dimethylmorpholine (220.79 mg, 1.92 mmol, 1.5 equiv.) was added. The resulting mixture was stirred at 15 °C for 16 hours and then poured into HO (20 mL), resulting in the formation of a precipitate in the reaction mixture. The mixture was filtered, and the filter cake was collected and dried under vacuum to give [7-bromo-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (520 mg, 1.06 mmol, 83% yield) as a black solid.

[0675] Synthesis of (3,3-dimethylmorpholin-4-yl)-[6-methoxy-7-(1-methylpyrazol-3-yl)-1-(3-thienyl)-4H-indeno[1,2-c]pyrazol-3-yl]methanone

[0676] [ka] To a mixture of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (112.47 mg, 540.54 μmol, 1.2 equiv.) in dioxane (2.5 mL) and HO (0.5 mL) was added KCO (186.77 mg, 1.35 mmol, 3 equiv.), [7-bromo-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (220 mg, 450.45 μmol, 1 equiv.), and Pd(dppf)Cl (65.92 mg, 90.09 μmol, 0.2 equiv.). The mixture was stirred at 80 °C under N for 16 h. The mixture was filtered, and the filtrate was concentrated under vacuum to give a residue that was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 45% to 75% B), followed by lyophilization to give (3,3-dimethylmorpholin-4-yl)-[6-methoxy-7-(1-methylpyrazol-3-yl)-1-(3-thienyl)-4H-indeno[1,2-c]pyrazol-3-yl]methanone (26.4 mg, 39.36 μmol, 9% yield, 90% purity, TFA) as an orange solid. LCMS (ESI): m / z [M+H] calcd for C 28 H 28 N5O5SF3:490.18;found:490.2. 1H NMR(400MHz,DMSO-d6)δ=7.99(s,1H),7.69(d,J=2.08Hz,1H),7.52-7.47(m,1H),7.91(dd,J=3 .06,1.10Hz,1H),7.87-7.82(m,1H),7.40(s,1H),6.69(d,J=2.08Hz,1H),3.91(s,3H),3.89(br s,2H),3.85(s,3H),3.76-3.73(m,2H),3.72(s,2H),3.43(s,2H),1.44(s,6H). Figure 49 shows the nuclear magnetic resonance of compound 5-07.

[0677] Synthesis of (3,3-dimethylmorpholin-4-yl)-[7-(5-cyano-3-pyridyl)-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazol-3-yl]methanone

[0678] [ka] To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (169.59 mg, 737.11 μmol, 1.2 equiv.) in dioxane (2.5 mL) and HO (0.5 mL) was added KCO (254.68 mg, 1.84 mmol, 3 equiv.), [7-bromo-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (300 mg, 614.26 μmol, 1 equiv.), and Pd(dppf)Cl (89.89 mg, 122.85 μmol, 0.2 equiv.). The mixture was stirred at 80 °C under a N atmosphere for 16 h. The reaction mixture was poured into HO (5 mL) and extracted with ethyl acetate (5 mL*3). The combined organic phase was dried over anhydrous NaSO and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent of 0-70% petroleum ether gradient / ethyl acetate, 30 mL / min) to give (3,3-dimethylmorpholin-4-yl)-[7-(5-cyano-3-pyridyl)-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazol-3-yl]methanone (150 mg, 293.20 μmol, 48% yield) as a brown solid.

[0679] Synthesis of 5-[3-(3,3-dimethylmorpholine-4-carbonyl)-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazol-7-yl]pyridine-3-carboxamide

[0680] [ka] To a mixture of (3,3-dimethylmorpholin-4-yl)-[7-(5-cyano-3-pyridyl)-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazol-3-yl]methanone (100 mg, 195.47 μmol, 1 equiv.) in DMSO (2 mL) was added KCO (54.03 mg, 390.94 μmol, 2 equiv.) and HO (410 mg, 3.62 mmol, 347.46 μL, 30% purity, 18.50 equiv.). The mixture was stirred at 15 °C for 15 min. The mixture was poured into saturated aqueous NaSO (10 mL) and stirred at 15 °C for an additional 1 h, followed by extraction with ethyl acetate (10 mL). The combined organic phase was dried over anhydrous NaSO. It was filtered, and the filtrate was concentrated under vacuum to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 28% to 58% B over 9 min), followed by lyophilization to give 5-[3-(3,3-dimethylmorpholine-4-carbonyl)-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazol-7-yl]pyridine-3-carboxamide (99.06 mg, 153.91 μmol, 79% yield, 100% purity, TFA) as a yellow solid. LCMS (ESI): m / z [M+H] calculated for C 30 H 28 N5O6SF3:530.18;found:530.2. 1 H NMR(400MHz,DMSO-d6)δ=9.00(d,J=1.96Hz,1H),8.84(d,J=2.08Hz,1H),8.37-8.32(m,1H),8.21(s,1H),7.98 (dd,J=3.00,1.28Hz,1H),7.77(dd,J=5.01,3.18Hz,1H),7.67(s,1H),7.55-7.50(m,2H),7.44(s,1H),3.92(br s, 2H), 3.86 (s, 3H), 3.79 (s, 2H), 3.74-3.77 (m, 2H), 3.45-3.42 (m, 2H), 1.45 (s, 6H). Figure 45 shows the nuclear magnetic resonance of compound 5-03.

[0681] Synthesis of 7-bromo-N-tert-butyl-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide

[0682] [ka] To a mixture of 7-bromo-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxylic acid (500 mg, 1.28 mmol, 1 equiv.) in DMF (5 mL) was added HATU (583.12 mg, 1.53 mmol, 1.2 equiv.) and DIEA (495.51 mg, 3.83 mmol, 667.81 μL, 3 equiv.). The mixture was stirred at 15 °C for 15 min, and then N-2-dimethylpropan-2-amine (167.09 mg, 1.92 mmol, 229.84 μL, 1.5 equiv.) was added, and the mixture was stirred at 15 °C for an additional 16 h. The mixture was then poured into HO (20 mL), causing a precipitate to form in the reaction mixture, and the mixture was filtered, and the filter cake was collected and dried under vacuum to give 7-bromo-N-tert-butyl-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide (500 mg, 1.09 mmol, 84.98% yield) as a black solid.

[0683] Synthesis of N-tert-butyl-6-methoxy-N-methyl-7-(1-methylpyrazol-3-yl)-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide

[0684] [ka] To a mixture of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (108.46 mg, 521.30 μmol, 1.2 equiv.) in dioxane (2.5 mL) and HO (0.5 mL) was added KCO (180.12 mg, 1.30 mmol, 3 equiv.), 7-bromo-N-tert-butyl-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide (200 mg, 434.42 μmol, 1 equiv.), and Pd(dppf)Cl (63.57 mg, 86.88 μmol, 0.2 equiv.). The mixture was stirred at 80 °C under a N atmosphere for 16 h. The mixture was filtered, and the filtrate was concentrated under vacuum to give a residue that was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 52% to 82% B), followed by lyophilization to give N-tert-butyl-6-methoxy-N-methyl-7-(1-methylpyrazol-3-yl)-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide (56.24 mg, 93.80 μmol, 22% yield, 96% purity, TFA) as an off-white solid. LCMS (ESI): m / z [M+H] calcd for C 27 H 28 N5O4SF3:462.19;found:462.2. 1 H NMR(400MHz,DMSO-d6)δ=8.17(s,1H),7.87(s,2H),7.80(s,1H),7.70(d,J=1.47Hz,1H),7.41(s,1H),6.72(d ,J=1.83Hz,1H),3.94(s,3H),3.86(s,3H),3.73(s,2H),3.17(s,3H),1.48(s,9H). Figure 50 shows the nuclear magnetic resonance of compound 5-08.

[0685] Synthesis of N-tert-butyl-7-(5-cyano-3-pyridyl)-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide

[0686] [ka] To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (179.90 mg, 781.95 μmol, 1.2 equiv.) in dioxane (2.5 mL) and HO (0.5 mL) was added KCO (270.18 mg, 1.95 mmol, 3 equiv.), 7-bromo-N-tert-butyl-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide (300 mg, 651.63 μmol, 1 equiv.), and Pd(dppf)Cl (95.36 mg, 130.33 μmol, 0.2 equiv.). The mixture was stirred at 80 °C under a N atmosphere for 16 h. The reaction mixture was poured into HO (5 mL) and ethyl acetate (5 mL), and then the mixture was separated. The aqueous phase was extracted with ethyl acetate (5 mL * 3). The combined organic phase was dried over anhydrous NaSO. It was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent of 0-70% petroleum ether gradient / ethyl acetate, 30 mL / min) to give N-tert-butyl-7-(5-cyano-3-pyridyl)-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide (200 mg, 413.58 μmol, 63% yield) as a brown solid.

[0687] Synthesis of N-tert-butyl-7-(5-carbamoyl-3-pyridyl)-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide

[0688] [ka] To a mixture of N-tert-butyl-7-(5-cyano-3-pyridyl)-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide (150 mg, 310.18 μmol, 1 equiv.) in DMSO (2 mL) was added HO (140 mg, 1.23 mmol, 118.64 μL, 30% purity, 3.98 equiv.) and KCO (85.74 mg, 620.37 μmol, 2 equiv.). The mixture was stirred at 15 °C for 15 min. The mixture was poured into saturated aqueous NaSO (10 mL), and the mixture was stirred at 15 °C for an additional 1 h. The resulting mixture was extracted with ethyl acetate (10 mL*3), and the combined organic phase was concentrated under vacuum to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 35% to 65% B over 9 min), followed by lyophilization to give N-tert-butyl-7-(5-carbamoyl-3-pyridyl)-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide (94.35 mg, 147.13 μmol, 47% yield, 96% purity, TFA) as a yellow solid. LCMS (ESI): m / z (M+H) calculated for C 29 H 28 N5O5SF3:502.18;found:502.2. 1 H NMR(400MHz,DMSO-d6)δ=9.01(d,J=2.00Hz,1H),8.86(d,J=2.00Hz,1H),8.38(t,J=2.06Hz,1H),8.22(s,1H),7.97(dd,J=3.19,1.44Hz,1H),7.80- 7.74(m,1H),7.69(s,1H),7.52(dt,J=3.38,1.56Hz,2H),7.45(s,1H),3.8 6(s,3H),3.78(s,2H)3.18(s,3H),1.47(s,9H). Figure 46 shows the nuclear magnetic resonance of compound 5-04.

[0689] Example 7 Reaction Scheme 8

[0690] [ka] Synthesis of 7-bromo-6-methoxy-tetralin-1-one

[0691] [ka] To a mixture of 6-methoxytetralin-1-one (20 g, 113.50 mmol, 1 equiv.) and NBS (20.20 g, 113.50 mmol, 1 equiv.) in HO (200 mL) was added HSO (55.66 g, 227.00 mmol, 30.25 mL, 40% purity, 2 equiv.) at 0 °C. The mixture was then stirred at 60 °C for 5 h. The mixture was cooled to room temperature, filtered, and the filter cake was collected to obtain the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® silica flash column, eluent of 0–18% ethyl acetate / petroleum ether, 60 mL / min gradient). The compound 7-bromo-6-methoxy-tetralin-1-one (4.2 g, 16.46 mmol, 15% yield) was obtained as a white solid. 1 H NMR(400MHz,CHLOROFORM-d)δ=8.27-8.16(m,1H),6.70(br s,1H),3.99-3.91(m,3H),2.96-2.86(m,2H),2.66-2.55(m,2H),2.19-2.07(m,2H).

[0692] Synthesis of 2-(7-bromo-6-methoxy-1-oxo-tetralin-2-yl)-2-oxo-ethyl acetate

[0693] [ka] To a solution of 7-bromo-6-methoxy-tetralin-1-one (4 g, 15.68 mmol, 1 equiv.) in THF (60 mL) was added LDA (2 M, 10.19 mL, 1.3 equiv.) dropwise over 10 min at −70° C. After the addition, the mixture was stirred at −70° C. for 0.5 h, and then diethyl oxalate (3.44 g, 23.52 mmol, 3.21 mL, 1.5 equiv.) in THF (10 mL) was added dropwise over 10 min at −70° C. The resulting mixture was stirred at 0° C. for 16 h. The mixture was poured into ice water (200 mL), and the reaction mixture was acidified to pH=6 with 1 M aqueous HCl. The aqueous phase was extracted with ethyl acetate (200 mL*3), and the combined organic phase was washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 (250*70 mm, 10 μm); mobile phase: [water (FA)-ACN]; gradient: 55% to 85% B over 20 min). The compound 2-(7-bromo-6-methoxy-1-oxo-tetralin-2-yl)-2-oxo-ethyl acetate (3.6 g, 10.14 mmol, 65% yield) was obtained as a yellow solid. 1 H NMR(400MHz,CHLOROFORM-d)δ=8.19(s,1H),6.72(s,1H),4.38(q,J=7.1Hz,2 H),3.97(s,3H),3.00-2.93(m,2H),2.89-2.82(m,2H),1.41(t,J=7.1Hz,3H).

[0694] Synthesis of ethyl 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylate

[0695] [ka] A mixture of ethyl 2-(7-bromo-6-methoxy-1-oxo-tetralin-2-yl)-2-oxoacetate (3.5 g, 9.85 mmol, 1 equiv.), (3,5-dichlorophenyl)hydrazine hydrochloride (2.31 g, 10.84 mmol, 1.1 equiv.) in 40 mL of EtOH and 5.92 g of AcOH (5.64 mL, 10 equiv.) was stirred at 80° C. under a N atmosphere for 5 hours. The mixture was cooled to room temperature, filtered, and the filter cake was collected and dried under vacuum to give ethyl 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylate (4.5 g, crude) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=7.94-7.88(m,1H),7.74(d,J=1.8Hz,2H),7.23(s,1H),6.84(s,1H),4.32(q,J=7.0Hz,2H),3.88(s,3H),2.96(br s,4H),1.32(t,J=7.1Hz,3H).

[0696] Synthesis of 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylic acid

[0697] [ka] A mixture of ethyl 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylate (4.5 g, 9.07 mmol, 1 equiv.) and LiOH.HO (1.52 g, 36.28 mmol, 10 mL, 4 equiv.) in EtOH (40 mL) was stirred at 25 °C under a N atmosphere for 16 h. The reaction mixture was acidified to pH = 6 with 1 M aqueous HCl. A precipitate formed in the reaction mixture, and the mixture was filtered. The filter cake was collected and dried under vacuum to give 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylic acid (4 g, crude) as a white solid. LCMS (ESI): m / z [M+H] calcd for C 19 H14 BrCl2N2O3:466.95;found:467.0 / 468.9.

[0698] Synthesis of [8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone

[0699] [ka] To a solution of 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylic acid (1 g, 2.14 mmol, 1 equiv.) in DMF (10 mL), HATU (1.22 g, 3.20 mmol, 1.5 equiv.) and DIEA (828.25 mg, 6.41 mmol, 1.12 mL, 3 equiv.) were added at 25 °C. After the addition, the mixture was stirred at this temperature for 0.5 h, and then 3,3-dimethylmorpholine (246.03 mg, 2.14 mmol, 1 equiv.) was added, and the resulting mixture was stirred at 25 °C for 2 h. The mixture was then poured into ice water (30 mL) and stirred for 3 min. The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (50 mL) and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was concentrated under vacuum to give a residue that was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether, 45 mL / min gradient) to give the crude product. The crude product was further purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 70% to 100% B over 9 min). The compound [8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (1.05 g, 1.55 mmol, 72% yield, TFA salt) was obtained as a white solid. LCMS (ESI): m / z [M+H] calcd for C25 H 25 BrCl2N3O3:564.04;found:564.2. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.52-7.37 (m, 3H), 7.06 (s, 1H), 6.88 (s, 1H), 3.93 (s, 3H), 3.87-3.77 (m, 4H), 3.49 (s, 2H), 3.00-2.93 (m, 2H), 2.91-2.84 (m, 2H), 1.55 (s, 6H). Figure 51 shows the nuclear magnetic resonance of compound 6-01A.

[0700] Synthesis of [1-(3,5-dichlorophenyl)-7-methoxy-8-(1-methylpyrazol-3-yl)-4,5-dihydrobenzo[g]indazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone

[0701] [ka] A mixture of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (40.49 mg, 194.59 μmol, 1.1 equiv.), [8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (0.1 g, 176.90 μmol, 1 equiv.), KCO (48.90 mg, 353.80 μmol, 2 equiv.), and Pd(dppf)Cl (12.94 mg, 17.69 μmol, 0.1 equiv.) in dioxane (2 mL) and HO (0.2 mL) was degassed and purged with N three times, then heated at 80 °C under N for 16 h. The residue was diluted with EtOAc (10 mL) and filtered through a Celite pad. The filtrate was concentrated to give a residue, which was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent: 0-35% ethyl acetate / petroleum ether, 45 mL / min gradient) to give the crude product. The crude product was further purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 62% to 92% B over 9 min). The compound [1-(3,5-dichlorophenyl)-7-methoxy-8-(1-methylpyrazol-3-yl)-4,5-dihydrobenzo[g]indazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (30 mg, 44.09 μmol, 25% yield, TFA) was obtained as a white solid. LCMS(ESI):m / z[M+H]calcd for C 29 H 30 Cl2N5O3:566.16;found:566.3. 1H NMR(400MHz,CHLOROFORM-d)δ=7.50(d,J=1.4Hz,3H),7.47-7.43(m,1H),7.32(d,J =1.9Hz,1H),6.92(s,1H),6.53(d,J=2.1Hz,1H),3.92(s,3H),3.88(s,3H),3.84(br d,J=3.6Hz,2H),3.82-3.78(m,2H),3.49(s,2H),3.06-2.97(m,2H),2.94-2.86(m,2H),1.56(s,6H). Figure 57 shows the nuclear magnetic resonance of compound 6-03.

[0702] Synthesis of [1-(3,5-dichlorophenyl)-7-methoxy-8-(1-methylpyrazol-3-yl)benzo[g]indazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone

[0703] [ka] A mixture of [1-(3,5-dichlorophenyl)-7-methoxy-8-(1-methylpyrazol-3-yl)-4,5-dihydrobenzo[g]indazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (90 mg, 158.88 μmol, 1 equiv.) and DDQ (144.26 mg, 635.51 μmol, 4 equiv.) in dioxane (2 mL) was stirred at 80 °C under a N atmosphere for 16 h. The product was poured into ice water (20 mL) and quenched with saturated aqueous NaSO (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3), and the combined organic phase was washed with brine (20 mL) and dried over anhydrous NaSO. The mixture was filtered, and the filtrate was concentrated under vacuum to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (TFA)-ACN]; gradient: 66% to 96% B over 9 min). The compound [1-(3,5-dichlorophenyl)-7-methoxy-8-(1-methylpyrazol-3-yl)benzo[g]indazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (50 mg, 73.69μmol, 46% yield, TFA) was obtained as a white solid. LCMS (ESI): m / z [M+H] calculated for C 29 H 28 Cl2N5O3:564.15;found:564.1. 1 H NMR(400MHz,CHLOROFORM-d)δ=8.32(s,1H),7.85(d,J=8.9Hz,1H),7.55(d,J=1.8Hz,2H),7.53-7.49(m,2H),7.30(s,2 H),6.64(d,J=2.1Hz,1H),3.96(s,3H),3.87(s,3H),3.80(s,4H),3.47(s,2H),1.55(s,6H). Figure 57 shows the nuclear magnetic resonance of compound 6-07.

[0704] Reaction Scheme 9

[0705] [ka] Synthesis of 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carbonitrile

[0706] [ka] A solution of [8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone (0.5 g, 884.51 μmol, 1 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (223.85 mg, 972.96 μmol, 1.1 equiv.), KCO (244.49 mg, 1.77 mmol, 2 equiv.), and Pd(dppf)Cl (129.44 mg, 176.90 μmol, 0.2 equiv.) in dioxane (5 mL) and HO (0.5 mL) was degassed and purged with N three times, then heated at 80 °C under N for 16 h. The mixture was diluted with EtOAc (40 mL) and then filtered. The filtrate was concentrated to give a residue, which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-40% ethyl acetate / petroleum ether, 40 mL / min gradient) to give the crude product. The crude product was further purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 65% to 95% B over 9 min). The compound 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carbonitrile (340 mg, 483.98 μmol, 55% yield, TFA) was obtained as a white solid. LCMS(ESI):m / z[M+H]calcd for C31H28Cl2N5O3:588.15;found:588.2. 1H NMR(400MHz,CHLOROFORM-d)δ=8.78(d,J=1.9Hz,1H),8.72(d,J=2.1Hz,1H),7.97(t,J=2.0Hz,1H),7.51(s,3H),7.02(s,1H),6. 87(s,1H),3.90(s,3H),3.84(s,4H),3.50(s,2H),3.11-3.04(m,2H),2.98-2.91(m,2H),1.56(s,6H). Figure 52 shows the nuclear magnetic resonance of compound 6-01B.

[0707] Synthesis of 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide

[0708] [ka] To a solution of 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carbonitrile (0.3 g, 509.79 μmol, 1 equiv.) in MeOH (5 mL) was added KCO (3 M, 339.86 μL, 2 equiv.) and HO (0.39 g, 3.44 mmol, 330.51 μL, 30% purity, 6.75 equiv.). The mixture was stirred at 25 °C for 16 h. The reaction was quenched with saturated Na2SO3 (10 mL), the mixture was extracted with EtOAc (10 mL*3), and the combined organic phase was washed with brine (15 mL) and concentrated to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 150*40 mm*15 μm; mobile phase: [water (TFA)-ACN]; gradient: 40% to 70% B over 15 min). The compound 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide (120 mg, 166.55 μmol, 33% yield, TFA) was obtained as a white solid. LCMS(ESI):m / z[M+H]calcd for C31H30Cl2N5O4:606.16;found:606.2. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 9.19 (s, 1H), 8.80 (s, 1H), 8.40 (s, 1H), 7.53-7.47 (m, 3H), 7.05 (s, 1H), 6.89 (s, 1H), 6.12-5.95 (m, 2H), 3.91 (s, 3H), 3.84 (s, 4H), 3.50 (s, 2H), 3.12-3.05 (m, 2H), 2.98-2.91 (m, 2H), 1.56 (s, 6H). Figure 53 shows the nuclear magnetic resonance of compound 6-01.

[0709] Synthesis of 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-benzo[g]indazol-8-yl]pyridine-3-carboxamide

[0710] [ka] A mixture of 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide (33 mg, 54.41 μmol, 1 equiv.) and DDQ (49.41 mg, 217.64 μmol, 4 equiv.) in dioxane (2 mL) was degassed and purged with N three times, then the mixture was stirred at 80 °C under N atmosphere for 16 h. The product was poured into ice water (20 mL) and quenched with saturated NaSO (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL*3), and the combined organic phase was washed with brine (50 mL) and dried over anhydrous NaSO. The mixture was filtered, and the filtrate was concentrated under vacuum to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 42% to 72% B). The compound 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-benzo[g]indazol-8-yl]pyridine-3-carboxamide (15 mg, 20.88 μmol, yield 38%, TFA) was obtained as a white solid. LCMS(ESI):m / z[M+H]calcd for C31H28Cl2N5O4:604.14;found:604.1. 1H NMR(400MHz,METHANOL-d4)δ=8.87(br s,1H),8.62(br s,1H),8.29(s,1H),7.83(d,J=8.9Hz,1H),7.70(d,J=1.8Hz,2H),7.69-7.60(m,3H),7.5 3(s,1H), 3.91(s,3H), 3.74(s,4H), 3.47(s,2H), 1.51(s,6H). Figure 59 shows the nuclear magnetic resonance of compound 6-05.

[0711] Reaction Scheme 10

[0712] [ka] Synthesis of 8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-4,5-dihydrobenzo[g]indazole-3-carboxamide

[0713] [ka] To a solution of 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylic acid (1 g, 2.14 mmol, 1 equiv.) in DMF (10 mL), HATU (1.22 g, 3.20 mmol, 1.5 equiv.) and DIEA (828.25 mg, 6.41 mmol, 1.12 mL, 3 equiv.) were added at 25 °C. After the addition, the mixture was stirred at 25 °C for 0.5 h, and then N-2-dimethylpropan-2-amine (186.19 mg, 2.14 mmol, 256.11 μL, 1 equiv.) was added. The resulting mixture was stirred at 25 °C for 2 h, then poured into ice water (30 mL) and stirred for 3 min. The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0-30% ethyl acetate / petroleum ether, 60 mL / min gradient) to give the crude product. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 75% to 100% B over 9 min). The compound 8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-4,5-dihydrobenzo[g]indazole-3-carboxamide (1.1 g, 1.69 mmol, 79% yield, TFA) was obtained as a white solid. LCMS(ESI):m / z[M+H]calcd for C 24 H 25 BrCl2N3O2:536.04;found:535.9. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.45 (s, 3H), 7.07 (s, 1H), 6.88 (s, 1H), 3.93 (s, 3H), 3.12 (s, 3H), 3.00-2.93 (m, 2H), 2.91-2.83 (m, 2H), 1.54 (s, 9H). Figure 54 shows the nuclear magnetic resonance of compound 6-02A.

[0714] Synthesis of N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(1-methylpyrazol-3-yl)-4,5-dihydrobenzo[g]indazole-3-carboxamide

[0715] [ka] A mixture of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (63.90 mg, 307.11 μmol, 1.1 equiv), 8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-4,5-dihydrobenzo[g]indazole-3-carboxamide (150 mg, 279.19 μmol, 1 equiv), KCO (77.17 mg, 558.37 μmol, 2 equiv), and Pd(dppf)Cl (20.43 mg, 27.92 μmol, 0.1 equiv) in dioxane (3 mL) and HO (0.3 mL) was degassed and purged with N three times, then heated to 80 °C under N for 16 h. The mixture was cooled, diluted with EtOAc (20 mL), and then filtered through a Celite pad. The filtrate was concentrated to give a residue that was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent: 0-30% ethyl acetate / petroleum ether, 40 mL / min gradient). The compound N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(1-methylpyrazol-3-yl)-4,5-dihydrobenzo[g]indazole-3-carboxamide (0.1 g, 185.71 μmol, 67% yield) was obtained as a colorless oil. LCMS (ESI): m / z [M+H] calcd for C 28 H 30 Cl2N5O2: 538.17; found: 538.3. Figure 58 shows the nuclear magnetic resonance of compound 6-04.

[0716] Synthesis of N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(1-methylpyrazol-3-yl)benzo[g]indazole-3-carboxamide

[0717] [ka] A mixture of N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(1-methylpyrazol-3-yl)-4,5-dihydrobenzo[g]indazole-3-carboxamide (0.1 g, 185.71 μmol, 1 equiv.) and DDQ (168.63 mg, 742.85 μmol, 4 equiv.) in dioxane (2 mL) was degassed and purged with N three times, then the mixture was stirred at 80 °C under N atmosphere for 16 h. The reaction was quenched with saturated NaSO (5 mL), and the mixture was extracted with EtOAc (10 mL * 2). The combined organic phase was washed with brine (10 mL) and dried over NaSO. The mixture was filtered, and the filtrate was concentrated to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (TFA)-ACN]; gradient: 68% to 98% B). The compound N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(1-methylpyrazol-3-yl)benzo[g]indazole-3-carboxamide (25 mg, 38.43 μmol, yield 21%, TFA) was obtained as a white solid. LCMS (ESI): m / z [M+H] calculated for C 28 H 28 Cl2N5O2:536.15;found:536.3. 1 H NMR(400MHz,CHLOROFORM-d)δ=8.45(s,1H),7.91(d,J=8.8Hz,1H),7.66(d,J=1.9Hz,2H),7.60-7.55(m,2H),7.39- 7.37(m,2H),6.73(d,J=2.1Hz,1H),4.04(s,3H),3.96(s,3H),3.20(s,3H),1.61(s,9H). Figure 62 shows the nuclear magnetic resonance of compound 6-08.

[0718] Reaction Scheme 11

[0719] [ka] Synthesis of N-tert-butyl-8-(5-cyano-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-4,5-dihydrobenzo[g]indazole-3-carboxamide

[0720] [ka] A mixture of 8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-4,5-dihydrobenzo[g]indazole-3-carboxamide (0.5 g, 930.62 μmol, 1 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (235.52 mg, 1.02 mmol, 1.1 equiv.), KCO (257.24 mg, 1.86 mmol, 2 equiv.), and Pd(dppf)Cl (136.19 mg, 186.12 μmol, 0.2 equiv.) in dioxane (5 mL) and HO (0.5 mL) was degassed and purged with N three times, then heated at 80 °C under N for 16 h. The mixture was diluted with EtOAc (40 mL) and then filtered. The filtrate was concentrated to give a residue, which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0-40% ethyl acetate / petroleum ether, 40 mL / min gradient) to give the crude product. The crude product was further purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 70% to 100% B over 9 min). The compound N-tert-butyl-8-(5-cyano-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-4,5-dihydrobenzo[g]indazole-3-carboxamide (390 mg, 578.21 μmol, 62% yield, TFA) was obtained as a white solid. LCMS(ESI):m / z[M+H]calcd for C30H28Cl2N5O2:560.15;found:560.2. 1H NMR(400MHz,CHLOROFORM-d)δ=8.78(d,J=1.8Hz,1H),8.72(d,J=2.0Hz,1H),7.98(t,J=2.0Hz,1H),7.53(d,J=1.8Hz,2H),7.48(d,J=1.8H) z,1H),7.02(s,1H),6.89(s,1H),3.90(s,3H),3.14(s,3H),3.10-3.04(m,2H),2.96-2.89(m,2H),1.55(s,9H). Figure 55 shows the nuclear magnetic resonance of compound 6-02B.

[0721] Synthesis of N-tert-butyl-8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-4,5-dihydrobenzo[g]indazole-3-carboxamide

[0722] [ka] To a solution of N-tert-butyl-8-(5-cyano-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-4,5-dihydrobenzo[g]indazole-3-carboxamide (0.3 g, 535.26 μmol, 1 equiv.) in MeOH (5 mL) was added KCO (3 M, 356.84 μL, 2 equiv.) and HO (0.45 g, 3.97 mmol, 381.36 μL, 30% purity, 7.41 equiv.). The mixture was stirred at 25 °C for 16 h and then quenched with saturated NaSO (5 mL). The aqueous phase was extracted with ethyl acetate (10 mL). The combined organic phase was washed with brine (20 mL) and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was concentrated to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 150*40 mm*15 μm; mobile phase: [water (TFA)-ACN]; gradient: 45% to 75% B over 15 min). The compound N-tert-butyl-8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-4,5-dihydrobenzo[g]indazole-3-carboxamide (150 mg, 216.60 μmol, 40% yield, TFA) was obtained as a white solid. LCMS (ESI): m / z [M+H] calculated for C30H30Cl2N5O3: 578.16; found: 578.2. 1 H NMR (400 MHz, DMSO-d6) δ = 8.93 (s, 1H), 8.52 (br s, 1H), 8.21-8.08 (m, 2H), 7.76 (s, 1H), 7.71 (d, J = 1.8 Hz, 2H), 7.64 (br s, 1H), 7.30 (s, 1H), 6.85 (s, 1H), 3.85 (s, 3H), 3.07-3.00 (m, 5H), 2.75 (br t, J = 7.4 Hz, 2H), 1.46 (s, 9H). Figure 56 shows the nuclear magnetic resonance of compound 6-02.

[0723] Synthesis of N-tert-butyl-8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-benzo[g]indazole-3-carboxamide

[0724] [ka] A mixture of N-tert-butyl-8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-4,5-dihydrobenzo[g]indazole-3-carboxamide (0.1 g, 172.86 μmol, 1 equiv.) and DDQ (156.96 mg, 691.46 μmol, 4 equiv.) in dioxane (2 mL) was stirred at 80 °C under a N atmosphere for 5 h. The residue was then poured into ice water (20 mL) and quenched with saturated NaSO (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (20 mL) and dried over anhydrous NaSO. The mixture was filtered, and the filtrate was concentrated under vacuum to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 50% to 80% B / min). The compound N-tert-butyl-8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-benzo[g]indazole-3-carboxamide (10 mg, 14.48 μmol, yield 8%, TFA) was obtained as a white solid. LCMS (ESI): m / z [M+H] calculated for C30H28Cl2N5O3: 576.15; found: 576.2. 1 H NMR (400 MHz, METHANOL-d4) δ = 9.02 (s, 1H), 8.80 (s, 1H), 8.51 (br s, 1H), 7.86 (br d, J = 8.6 Hz, 1H), 7.80 (s, 2H), 7.76 (br d, J = 9.2 Hz, 1H), 7.72 (br d, J = 3.8 Hz, 2H), 7.68 (s, 1H), 4.02 (s, 3H), 3.17 (s, 3H), 1.63 (s, 9H). Figure 60 shows the nuclear magnetic resonance of compound 6-06.

[0725] Example 8 Reaction Scheme 12

[0726] [ka] Synthesis of 8-(5-cyanopyridin-3-yl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid

[0727] [ka] To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (1.46 g, 6.36 mmol, 1.2 equiv.) in dioxane (20 mL) and HO (4 mL), KCO (2.20 g, 15.89 mmol, 3 equiv.), 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid (2.48 g, 5.30 mmol, 1 equiv.), and Pd(dppf)Cl (775.27 mg, 1.06 mmol, 0.2 equiv.) were added. The mixture was stirred at 60 °C under a N atmosphere for 16 h. The reaction mixture was poured into HO (100 mL) and ethyl acetate (100 mL) and extracted with ethyl acetate (100 mL*3). The combined organic phase was dried over anhydrous NaSO and filtered. The filtrate was concentrated in vacuo to give a residue. The crude product was triturated with MTBE (20 mL) at 15 °C for 15 minutes to give 8-(5-cyanopyridin-3-yl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid (4 g, crude) as a black solid. 1 H NMR(400MHz,DMSO-d6)δ=8.96-8.87(m,1H),8.70(s,1H),8.15(s,1H),7.68(s,1H),7.63(s,2H),7.26(s,1H),6.90(br s,1H),3.84(s,3H),2.99-2.89(m,4H).

[0728] Synthesis of 8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylic acid

[0729] [ka] To a mixture of 8-(5-cyanopyridin-3-yl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid (200 mg, 407.06 μmol, 1 equiv.) in DMSO (2 mL) was added KCO (112.52 mg, 814.13 μmol, 2 equiv.) and HO (461.54 mg, 4.07 mmol, 391.13 μL, 30% purity, 10 equiv.). The mixture was stirred at 15 °C for 15 min. Saturated aqueous NaSO (10 mL) was added, and the mixture was stirred at 15 °C for 1 h. The reaction mixture was adjusted to pH 7 with 1 M aqueous HCl. The mixture was extracted with ethyl acetate (10 mL*3). The combined organic phase was dried over anhydrous NaSO and filtered. The mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 30% to 60% B over 9 min). The compound 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid (30 mg, 58.90 μmol, 14% yield) was obtained as an off-white solid.

[0730] Synthesis of tert-butyl 4-[8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carbonyl]-1,4-diazepane-1-carboxylic acid

[0731] [ka] To a mixture of 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid (30 mg, 58.90 μmol, 1 equiv.) in DMF (2 mL) was added DIEA (22.84 mg, 176.70 μmol, 30.78 μL, 3 equiv.) and HATU (33.59 mg, 88.35 μmol, 1.5 equiv.). The mixture was stirred at 25 °C for 0.5 h. Then, tert-butyl 1,4-diazepane-1-carboxylate (21.23 mg, 106.02 μmol, 20.90 μL, 1.8 equiv.) was added to the reaction mixture. The mixture was stirred at 25 °C for 16 h. The mixture was poured into HO (2 mL). A precipitate formed in the reaction mixture, and the mixture was filtered, and the filter cake was collected and dried under vacuum to obtain a residue, which gave the compound tert-butyl 4-[8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carbonyl]-1,4-diazepane-1-carboxylic acid (30 mg, crude) as a black solid.

[0732] Synthesis of 5-[3-(1,4-diazepane-1-carbonyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide

[0733] [ka] A mixture of tert-butyl 4-[8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carbonyl]-1,4-diazepane-1-carboxylate (30 mg, 43.38 μmol, 1 equiv) in 4 N HCl / EtOAc (1 mL) was stirred for 1 h at 15° C. The mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 18% to 48% B over 9 min) followed by lyophilization to give 5-[3-(1,4-diazepane-1-carbonyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide (4.29 mg, 5.84 μmol, 13% yield, 96% purity, TFA) as a brown gum. LCMS (ESI): m / z [M+H] calculated for C 32 H 29 N6O5Cl2F3:591.16;found:591.2. 1H NMR(400MHz,DMSO-d6)δ=8.91(d,J=1.9Hz,1H),8.81-8.66(m,2H),8.48(d,J=2.0Hz,1H),8.12 (t,J=1.9Hz,2H),7.82-7.73(m,3H),7.62(s,1H),7.30(s,1H),6.82(d,J=3.6Hz,1H),4.03(br d,J=4.5Hz,1H),3.94(br t,J=6.0Hz,1H),3.85(s,3H),3.70(br t, J = 6.0 Hz, 1H), 3.33-3.19 (m, 4H), 3.08-3.00 (m, 2H), 2.88 (q, J = 7.4 Hz, 2H), 2.06 (br d, J = 0.8 Hz, 2H). Figure 65 shows the nuclear magnetic resonance of compound 8-03.

[0734] Reaction Scheme 13

[0735] [ka] Synthesis of tert-butyl 4-[8-(5-cyano-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carbonyl]-3-methyl-piperazine-1-carboxylic acid

[0736] [ka] To a solution of 8-(5-cyano-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylic acid (250 mg, 508.83 μmol, 1 equiv.) in DMF (3 mL) was added HATU (290.21 mg, 763.24 μmol, 1.5 equiv.) and DIEA (197.29 mg, 1.53 mmol, 265.89 μL, 3 equiv.). The mixture was stirred at 25° C. for 30 minutes. Then, a mixture of tert-butyl 3-methylpiperazine-1-carboxylate (183.43 mg, 915.89 μmol, 1.8 equiv.) in DMF (1.5 mL) was added. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was diluted with water (10 mL) and filtered to obtain a filter cake. The filter cake was collected and dried under vacuum to obtain the compound tert-butyl 4-[8-(5-cyano-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carbonyl]-3-methylpiperazine-1-carboxylic acid (200 mg, crude) as a brown solid. 1 H NMR(400MHz,CHLOROFORM-d)δ=8.83-8.67(m,2H),8.04-7.96(m,1H),7.51(s,3H),7.02(s,1H),6.92-6.83(m,1H),4.93(br d,J=8.0Hz,1H),4.60-4.38(m,1H),3.90(s,4H),3.21-3.03(m,3H),3.00-2.95(m,3H),2.89(s,2H),1.49(s,9H),1.32(br d,J=4.4Hz,3H).

[0737] Synthesis of tert-butyl 4-[8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carbonyl]-3-methylpiperazine-1-carboxylic acid

[0738] [ka] To a solution of tert-butyl 4-[8-(5-cyano-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carbonyl]-3-methyl-piperazine-1-carboxylate (180 mg, 267.23 μmol, 1 equiv.) in DMSO (2 mL) was added KCO (3 M, 178.15 μL, 2 equiv.) and HO (50 mg, 440.99 μmol, 42.37 μL, 30% purity, 1.65 equiv.). The mixture was stirred at 20-60 °C for 18 h. The reaction mixture was diluted with saturated aqueous NaSO (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The compound tert-butyl 4-[8-(5-carbamoyl-3-pyridyl-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carbonyl]-3-methyl-piperazine-1-carboxylic acid (184 mg, 266.05 μmol, 99% yield) was obtained as a yellow oil.

[0739] Synthesis of 5-[1-(3,5-dichlorophenyl)-7-methoxy-3-(2-methylpiperazine-1-carbonyl)-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide

[0740] [ka] A mixture of tert-butyl 4-[8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carbonyl]-3-methyl-piperazine-1-carboxylate (130 mg, 187.97 μmol, 1 equiv) in 4 N HCl / EtOAc (2 mL) was stirred for 1 h at 15° C. The mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (TFA)-ACN]; gradient: 20% to 50% B / min (over min)), followed by lyophilization to give 5-[1-(3,5-dichlorophenyl)-7-methoxy-3-(2-methylpiperazine-1-carbonyl)-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide (50 mg, 70.87 μmol, 38% yield, 100% purity, TFA) as an off-white solid. LCMS (ESI): m / z [M+H] calculated for C 32 H 29 N6Cl2O5F3:591.16;found:591.2 1H NMR(400MHz,DMSO-d6)δ=9.19-9.05(m,1H),8.92(d,J=2.0Hz,1H),8.78-8.61(m,1H),8.48(d,J=2.1Hz,1H),8.17-8.08(m,2H),7.82-7.79(m,1 H),7.77(d,J=1.9Hz,2H),7.62(s,1H),7.30(s,1H),6.81(s,1H),5.13- 4.89(m,1H),4.71-4.51(m,1H),3.85(s,3H),3.37-3.15(m,4H),3.04(br d, J = 7.0 Hz, 2H), 2.87 (br d, J = 7.1 Hz, 2H), 1.36 (br d, J = 5.9 Hz, 3H). Figure 63 shows the nuclear magnetic resonance of compound 8-01.

[0741] Synthesis of 5-[1-(3,5-dichlorophenyl)-3-(2,4-dimethylpiperazine-1-carbonyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide

[0742] [ka] To a mixture of 5-[1-(3,5-dichlorophenyl)-7-methoxy-3-(2-methylpiperazine-1-carbonyl)-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide (40 mg, 67.63 μmol, 1 equiv.) in DCM (3 mL) was added AcOH (812.22 μg, 13.53 μmol, 7.74 e-1 μL, 0.2 equiv.) and HCHO (6.59 mg, 81.15 μmol, 6.04 μL, 1.2 equiv., 37% in HO). The mixture was stirred at 15° C. for 1 hour, and then NaBH(OAc) (43.00 mg, 202.88 μmol, 3 equiv.) was added. The mixture was stirred at 15° C. for 16 hours. The mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 18%-48% B over 9 min) followed by lyophilization to give 5-[1-(3,5-dichlorophenyl)-3-(2,4-dimethylpiperazine-1-carbonyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide (22.94 mg, 31.88 μmol, 47% yield, 100% purity, TFA) as an off-white solid. LCMS (ESI): m / z [M+H] calculated for C 33 H 31 N6Cl2O5F3:605.18;found:605.2. 1 H NMR(400MHz,METHANOL-d4)δ=8.94-8.89(m,1H),8.61-8.55(m,1H),8.31-8.26(m,1H),7. 69-7.63(m,3H),7.24(s,1H),6.87(s,1H),5.49-4.91(m,2H),3.94-3.88(m,3H),3.57(br Figure 66 shows the nuclear magnetic resonance of compound 8-05.

[0743] Synthesis of 5-[3-(4-cyano-2-methylpiperazine-1-carbonyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide

[0744] [ka] To a solution of 5-[1-(3,5-dichlorophenyl)-7-methoxy-3-(2-methylpiperazine-1-carbonyl)-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide (100 mg, 159.25 μmol, 1 equiv., HCl) in DCM (2 mL) was added TEA (80.57 mg, 796.24 μmol, 110.83 μL, 5 equiv.) and BrCN (230 mg, 2.17 mmol, 159.39 μL, 13.64 equiv.) at 0° C. The mixture was stirred at 0° C. for 0.25 h. The reaction mixture was diluted with ice water (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL*3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 32% to 62% B over 10 min) followed by lyophilization. The compound 5-[3-(4-cyano-2-methyl-piperazine-1-carbonyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide (10.78 mg, 16.79 μmol, 11% yield, 96% purity) was obtained as an off-white solid. LCMS (ESI): m / z [M+H] calculated for C 31 H 28 Cl2N7O3:616.16;found:616.3. 1H NMR(400MHz,METHANOL-d4)δ=8.88(d,J=2.0Hz,1H),8.54(d,J=2.0Hz,1H),8.22(t,J=2. 0Hz,1H),7.69-7.59(m,3H),7.23(s,1H),6.87-6.83(m,1H),4.96-4.91(m,2H),4.52(br s,1H),3.91(s,3H),3.71-3.36(m,3H),3.28-3.22(m,1H),3.14-3.07(m,2H),2.93-2.86(m,2H),1.48(d,J=6.8Hz,3H). Figure 70 shows the nuclear magnetic resonance of compound 8-09.

[0745] Reaction Scheme 14

[0746] [ka] Synthesis of 5-(1-(3,5-dichlorophenyl)-7-methoxy-3-(4-methyl-1,4-diazepane-1-carbonyl)-4,5-dihydro-1H-benzo[g]indazol-8-yl)nicotinonitrile

[0747] [ka] To a mixture of 8-(5-cyano-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylic acid (150 mg, 305.30 μmol, 1 equiv.) in DMF (3 mL) was added HATU (174.12 mg, 457.95 μmol, 1.5 equiv.) and DIEA (118.37 mg, 915.89 μmol, 159.53 μL, 3 equiv.). The mixture was stirred at 15 °C for 15 minutes, and then 1-methyl-1,4-diazepane (62.75 mg, 549.53 μmol, 68.36 μL, 1.8 equiv.) was added. The mixture was stirred at 15 °C for 16 hours. The mixture was poured into HO (10 mL). A precipitate formed in the reaction mixture, and the mixture was filtered. The filter cake was collected and dried under vacuum to a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent of 0-10% ethyl acetate:methanol, 18 mL / min) to afford 5-(1-(3,5-dichlorophenyl)-7-methoxy-3-(4-methyl-1,4-diazepane-1-carbonyl)-4,5-dihydro-1H-benzo[g]indazol-8-yl)nicotinonitrile (90 mg, 153.19 μmol, 50.18% yield) as a yellow solid. LCMS (ESI): m / z [M+H] calculated for C 33 H 29 N6O4Cl2F3:587.17;found:587.2. 1 H NMR(400MHz,METHANOL-d4)δ=8.80(d,J=1.8Hz,1H),8.68(s,1H),8.08(br s,1H),7.75-7.61(m,3H),7.24(s,1H),6.86(d,J=13.9Hz,1H),4.33-3.96(m,2H),3.92(s,3H),3.87-3.72(m,2H),3.7 1-3.49(m,2H), 3.48-3.32(m,2H), 3.14-3.07(m,2H), 3.02-2.91(m,5H), 2.39-2.20(m,2H). Figure 68 shows the nuclear magnetic resonance of compound 8-07A.

[0748] Synthesis of 5-[1-(3,5-dichlorophenyl)-7-methoxy-3-(4-methyl-1,4-diazepane-1-carbonyl)-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide

[0749] [ka] To a mixture of 5-(1-(3,5-dichlorophenyl)-7-methoxy-3-(4-methyl-1,4-diazepane-1-carbonyl)-4,5-dihydro-1H-benzo[g]indazol-8-yl)nicotinonitrile (90 mg, 153.19 μmol, 1 equiv.) in THF (1 mL) and HO (1 mL) was added LiOH·HO (6.43 mg, 153.19 μmol, 1 equiv.). The mixture was stirred at 60 °C for 16 h. The reaction mixture was adjusted to pH 5 with 1 M aqueous HCl. The resulting mixture was extracted with ethyl acetate (3 mL*3). The combined organic phases were dried over anhydrous NaSO and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 18% to 48% B over 9 min), followed by lyophilization to give 5-[1-(3,5-dichlorophenyl)-7-methoxy-3-(4-methyl-1,4-diazepane-1-carbonyl)-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide (24.6 mg, 34.19 μmol, 22% yield, 100% purity, TFA) as a white solid. LCMS (ESI): m / z [M+H] calculated for C 33 H 31 N6O5Cl2F3:605.18;found:605.2. 1H NMR(400MHz,METHANOL-d4)δ=8.91(d,J=1.5Hz,1H),8.57(br s,1H),8.27(br s,1H),7.70-7.61(m,3H),7.24(s,1H),6.86(d,J=13.8Hz,1H),4.10(br s,2H),3.91(s,3H),3.86-3.72(m,2H),3.70-3.49(m,2H),3.49-3.32(m,2H),3. 14-3.07(m,2H), 3.02-2.92(m,5H), 2.37-2.23(m,2H). Figure 69 shows the nuclear magnetic resonance of compound 8-07.

[0750] Synthesis of compound 8-02

[0751] [ka] Compound 8-02 was synthesized via the same procedure as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 31 H 31 Cl2N6O3:605.18;found:605.3. 1 H NMR(400MHz,METHANOL-d4)δ=8.93(d,J=1.6Hz,1H),8.60(d,J=1.6Hz,1H),8.31(s,1H),7.69-7.60(m,3H),7.24(s,1H),6.87(s,1H),4.07(br t,J=5.4Hz,2H),3.91(s,3H),3.43(br t,J=5.4Hz,2H),3.30(br Figure 64 shows the nuclear magnetic resonance of compound 8-02.

[0752] Synthesis of compound 8-06

[0753] [ka] Compound 8-06 was synthesized via the same procedure as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 32 H33 Cl2N6O3619.19;found:619.3. 1 H NMR (400 MHz, METHANOL-d4) δ = 8.92 (br s, 1H), 8.58 (br s, 1H), 8.27 (s, 1H), 7.69-7.61 (m, 3H), 7.23 (s, 1H), 6.84 (s, 1H), 3.90 (s, 3H), 3.67-3.31 (m, 6H), 3.13-3.06 (m, 2H), 2.97 (s, 3H), 2.91 (br d, J = 7.2 Hz, 2H), 1.69 (s, 6H). Figure 67 shows the nuclear magnetic resonance of compound 8-06.

[0754] Synthesis of compounds 8-10

[0755] [ka] Compounds 8-10 were synthesized via the same procedure as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 30 H 30 ClNO: 594.16; found: 594.2. H NMR (400 MHz, METHANOL-d) δ = 8.92 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.24 (t, J = 2.0 Hz, 1H), 7.79 (t, J = 1.8 Hz, 1H), 7.74 (d, J = 1.9 Hz, 2H), 7.25 (s, 1H), 6.80 (s, 1H), 4.44 (s, 2H), 3.92 (s, 3H), 3.17-3.10 (m, 4H), 2.71 (s, 3H), 1.46 (s, 6H). Figure 71 shows the nuclear magnetic resonance spectra of compounds 8-10.

[0756] Synthesis of compounds 8-14

[0757] [ka] Compounds 8-14 were synthesized via the same procedure as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 33 H 30 N5O5Cl2F3:590.16;found:590.2.1 H NMR(400MHz,METHANOL-d4)δ=8.96(br s,1H),8.67(br s,1H),8.42-8.38(m,1H),7.65-7.59(m,3H),7.25(s,1H),6.91(s,1H),3.92(s,3H),3.90-3.83(m,2H),3.10(br t, J = 7.2 Hz, 2H), 2.91 (t, J = 7.3 Hz, 2H), 1.96-1.85 (m, 4H), 1.60 (s, 6H). Figure 72 shows the nuclear magnetic resonance of compound 8-14.

[0758] Synthesis of compounds 8-15

[0759] [ka] Compounds 8-15 were synthesized via the same procedure as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 32 H 31 Cl2N6O3:617.18;found:617.3. 1H NMR(400MHz,METHANOL-d4)δ=8.93-8.86(m,1H),8.56(br d,J=9.3Hz,1H),8.26(dd,J=1.9,4.8Hz,1H),7.70-7.68(m,1H),7.67(d,J=1.6Hz,2H),7.24(s,1H),6.84(d,J=1.5Hz,1H),5.60(br d,J=5.4Hz,1H),5.05(br d,J=4.1Hz,1H),4.90(s,1H),3.93-3.90(m,3H),3.62(br d, J = 12.4 Hz, 2H), 3.56-3.46 (m, 1H), 3.40-3.34 (m, 1H), 3.10 (br s, 3H), 3.03-2.96 (m, 1H), 2.92 (s, 3H), 2.36-2.18 (m, 2H), 2.11-2.02 (m, 2H). Figure 73 shows the nuclear magnetic resonance of compounds 8-15.

[0760] Synthesis of compounds 8-17

[0761] [ka] Compounds 8-17 were synthesized via the same procedure as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 32 H 31 Cl2N6O3:617.18;found:617.2. 1 H NMR(400MHz,METHANOL-d4)δ=8.91-8.83(m,1H),8.57-8.50(m,1H),8.23(q,J=2. 2Hz,1H),7.67-7.58(m,3H),7.22(s,1H),6.89-6.81(m,1H),4.77-4.54(m,1H),4 .33-3.95(m,1H),3.90(s,3H),3.56(dd,J=1.8,13.2Hz,1H),3.15-2.84(m,7H),2 .51-2.40(m,3H), 2.23-2.00(m,2H), 1.94-1.68(m,2H). Figure 76 shows the nuclear magnetic resonance of compound 8-17.

[0762] Synthesis of compounds 8-20

[0763] [ka] Compound 8-20 was synthesized via the same procedure as in Example 8. LCMS (ESI): m / z [M+H] calculated for C31H29Cl2N6O3: 603.16; found: 603.1. 1H NMR (400MHz, METHANOL-d4) δ = 8.94 (d, J = 1.8 Hz, 1H), 8.61 (s, 1H), 8.33-8.28 (m, 1H), 7.70 (d, J = 1.0 Hz, 1H), 7.68 (s, 2H), 7.26 (s, 1H), 6.91 (s, 1H), 4.93 (s, 2H), 4.57 (br s, 1H), 4.55 (s, 1H), 4.44 (s, 1H), 4.38 (s, 1H), 4.33-4.24 (m, 2H), 3.94 (s, 3H), 3.14-3.06 (m, 4H), 2.95 (br d, J = 6.5 Hz, 3H). Figure 77 shows the nuclear magnetic resonance of compounds 8-20.

[0764] Synthesis of compounds 8-21

[0765] [ka] Compound 8-21 was synthesized via the same procedure as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 33 H 31 N6O5Cl2F3:605.18;found:605.2. 1 H NMR(400MHz,DMSO-d6)δ=9.42(brdd,J=1.6,7.4Hz,1H),8.93(d,J=2.0Hz,2H),8.50(d,J=2.1Hz,1H),8.1 6-8.10(m,2H),7.84-7.79(m,1H),7.77(d,J=1.8Hz,2H),7.63(s,1H),7.31(s,1H),6.85(s,1H),4.95(br s,2H),3.86(s,3H),3.33-3.20(m,4H),3.09-3.02(m,2H),2.85(br t, J = 6.9 Hz, 2H), 1.43 (d, J = 7.1 Hz, 6H). Figure 78 shows the nuclear magnetic resonance of compound 8-21.

[0766] Synthesis of compounds 8-22

[0767] [ka] Compound 8-22 was synthesized via a similar procedure to Example 8. LCMS (ESI): m / z [M+H] calculated for C31H31Cl2N6O3: 605.18; found: 605.2. 1H NMR(400MHz,METHANOL-d4)δ=8.92(d,J=2.0Hz,1H),8.60(d,J=2.0Hz,1H),8.30(t,J=2.0Hz,1H),7.70-7.60(m,3H),7.25(s,1H),6.89(s,1H),3.92(s, 3H),3.70(dd,J=3.9,13.6Hz,2H),3.38(dd,J=3.2,13.6Hz,2H),3.15-3.06 (m,2H),3.01-2.89(m,2H),1.52(d,J=6.9Hz,6H). Figure 79 shows the nuclear magnetic resonance of compound 8-22.

[0768] Synthesis of compounds 8-24

[0769] [ka] Compound 8-24 was synthesized via the same procedure as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 31 H 29 Cl2N6O3:603.16;found:603.3. 1 H NMR(400MHz,METHANOL-d4)δ=8.92(s,1H),8.59(d,J=1.9Hz,1H),8.35-8.26(m,1H),7.69-7.60(m,3H),7.24(s,1H),6.90-6.82(m,1H),5.27(br s,1H),4.55-4.19(m,1H),3.91(s,4H),3.87-3.78(m,1H),3.67-3.44(m,2H),3. 17-3.06(m,2H), 3.05-2.92(m,2H), 2.33-1.97(m,4H). Figure 81 shows the nuclear magnetic resonance of compound 8-24.

[0770] Synthesis of Compound 8-26A

[0771] [ka] Compound 8-26A was synthesized via a procedure similar to that of Example 8. LCMS (ESI): m / z [M+H] calculated for C31H27Cl2N6O3: 601.14; found: 601.1. 1H NMR (400 MHz, METHANOL-d4) δ = 8.60 (s, 1H), 8.52-8.46 (m, 1H), 7.90 (s, 1H), 7.46 (s, 3H), 7.04 (s, 1H), 6.67 (s, 1H), 3.72 (s, 5H), 3.26-3.19 (m, 2H), 2.94-2.89 (m, 2H), 2.67 (br t, J = 7.2 Hz, 2H), 2.46 (s, 1H), 1.64 (s, 6H). Figure 83 shows the NMR spectrum of compound 8-26A.

[0772] Synthesis of Compounds 8-26

[0773] [ka] Compound 8-26 was synthesized via a procedure similar to that of Example 8. LCMS (ESI): m / z [M+H] calculated for C31H29Cl2N6O4: 619.15; found: 619.2. 1H NMR (400 MHz, METHANOL-d4) δ = 8.60 (s, 1H), 8.52-8.46 (m, 1H), 7.90 (s, 1H), 7.46 (s, 3H), 7.04 (s, 1H), 6.67 (s, 1H), 3.72 (s, 5H), 3.26-3.19 (m, 2H), 2.94-2.89 (m, 2H), 2.67 (br t, J = 7.2 Hz, 2H), 2.46 (s, 1H), 1.64 (s, 6H). Figure 84 shows the NMR spectrum of compound 8-26.

[0774] Synthesis of compounds 8-28

[0775] [ka] Compound 8-28 was synthesized via the same procedure as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 31 H 30 N6O3Cl2:605.18;found:605.2. 1 H NMR(400MHz,METHANOL-d4)δ=8.88(d,J=2.0Hz,1H),8.54(d,J=2.1Hz,1H),8.23(t,J=2.1Hz,1H),7.64(s,3 H),7.23(s,1H),6.86(s,1H),5.31-5.13(m,1H),4.90-4.87(m,1H),3.91(s,3H),3.13-3.07(m,4H),2.81(br d,J=9.0Hz,4H),2.70(br d, J = 5.9 Hz, 1H), 2.61-2.53 (m, 1H), 2.42-2.33 (m, 3H), 2.29-2.14 (m, 1H), 2.07-1.97 (m, 1H). Figure 86 shows the nuclear magnetic resonance of compound 8-28.

[0776] Synthesis of compounds 8-29

[0777] [ka] Compound 8-29 was synthesized via the same procedure as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 32 H 26 N5O6Cl2F3:590.13;found:590.2. 1H NMR(400MHz,METHANOL-d4)δ=8.94(d,J=1.9Hz,1H),8.63(s,1H),8.35(q,J=2.0Hz,1H),7. 73-7.61(m,3H),7.25(s,1H),6.89(d,J=4.6Hz,1H),5.60(s,0.5H),5.06(s,0.5H),4.70(br d,J=12.0Hz,1H),4.01-3.86(m,6H),3.64-3.52(m,1H),3.16-3.08(m,2H),3.08-2.91(m,2H),1.98(br d, J=4.1 Hz, 2H). Figure 81 shows the nuclear magnetic resonance of compound 8-24.

[0778] Synthesis of Compounds 8-30

[0779] [ka] Compound 8-30 was synthesized via the same procedure as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 32 H 31Cl2N6O3:617.18;found:617.1. 1H NMR (400 MHz, DMSO-d6) δ = 8.90 (d, J = 2.0 Hz, 1H), 8.54-8.38 (m, 1H), 8.20-8.01 (m, 2H), 7.85-7.70 (m, 3H), 7.60 (s, 1H), 7.28 (s, 1H), 6.90-6.72 (m, 1H), 5.13-4.39 (m, 1H), 4.21-3.58 (m, 5H), 3.09-2.52 (m, 8H), 2.44-2.36 (m, 1H), 2.20 (s, 2H), 2.15 (s, 1H), 2.03-1.86 (m, 1H), 1.84-1.67 (m, 1H). Figure 88 shows the nuclear magnetic resonance of compound 8-30.

[0780] Synthesis of Compounds 8-32

[0781] [ka] Compound 8-32 was synthesized via a procedure similar to that of Example 8. LCMS (ESI): m / z [M+H] calculated for C 30 H 28 Cl2N5O4:592.14;found:592.3. 1 H NMR(400MHz,METHANOL-d4)δ=8.95(br s,1H),8.65(br s,1H),8.42-8.34(m,1H),7.65-7.59(m,3H),7.25(s,1H),6.89(s,1H), 5.39(s,2H),3.95-3.89(m,3H),3.83(s,2H),3.13-3.06(m,2H),3.03(br d,J=7.2Hz,2H),1.60(s,6H). Figure 90 shows the nuclear magnetic resonance of compound 8-32.

[0782] Reaction Scheme 15

[0783] [ka] Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide

[0784] [ka] To a mixture of 5-bromopyridine-3-carboxamide (2 g, 9.95 mmol, 1 equiv.) in dioxane (20 mL), Pd(dppf)Cl (727.99 mg, 994.92 μmol, 0.1 equiv.), KOAc (1.95 g, 19.90 mmol, 2 equiv.), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.79 g, 14.92 mmol, 1.5 equiv.) were added, and the mixture was stirred at 100 °C under a N atmosphere for 3 h. 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (1.65 g, crude) in dioxane as a brown liquid was used directly in the next step.

[0785] Synthesis of ethyl 8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylate

[0786] [ka] To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (1.34 g, 5.4 mmol, 1.3.5 equiv.) and ethyl 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylate (2 g, 4.03 mmol, 1 equiv.) in dioxane (10 mL) and HO (4 mL) was added KCO (1.11 g, 8.06 mmol, 2 equiv.) and Pd(dppf)Cl (589.87 mg, 806.16 μmol, 0.2 equiv.). The mixture was stirred at 60 °C under a N atmosphere for 16 h. The reaction mixture was poured into HO (20 mL) and ethyl acetate (20 mL), and then the mixture was separated. The aqueous phase was extracted with ethyl acetate (10 mL). The combined organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a 0–80% petroleum ether gradient / ethyl acetate at 45 mL / min) to give ethyl 8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylate (1.2 g, 2.23 mmol, 55% yield) as a gray solid.

[0787] Synthesis of 8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylic acid

[0788] [ka] To a mixture of ethyl 8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylate (1.2 g, 2.23 mmol, 1 equiv.) in THF (10 mL) and HO (10 mL) was added LiOH·HO (281.11 mg, 6.70 mmol, 3 equiv.). The mixture was stirred at 15 °C for 16 h. The mixture was concentrated in vacuo to remove THF, and the resulting mixture was then filtered. The filter cake was dried in vacuo to give 8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylic acid (1 g, 1.96 mmol, 88% yield) as a gray solid. 1H NMR(400MHz,DMSO-d6)δ=8.90(d,J=2.1Hz,1H),8.47(d,J=2.0Hz,1H),8.14-8.02(m,2H),7.79(d,J=1.8Hz,1H),7.73(d,J=1.8Hz,2H),7.60(br s,1H),7.28(s,1H),6.78(s,1H),3.84(s,3H),3.04-2.92(m,4H).

[0789] Synthesis of tert-butyl 1-[8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carbonyl]-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridine-5-carboxylic acid

[0790] [ka] To a mixture of 8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylic acid (80 mg, 157.07 μmol, 1 equiv.) in DMF (2 mL) was added HATU (89.58 mg, 235.60 μmol, 1.5 equiv.) and DIEA (60.90 mg, 471.20 μmol, 82.07 μL, 3 equiv.). The mixture was stirred at 15° C. for 15 minutes, and then tert-butyl 1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,2-c]pyridine-5-carboxylate (35.55 mg, 157.07 μmol, 1 equiv.) was added. The mixture was stirred at 15° C. for 16 hours. The pH of the mixture was adjusted to 6 with TFA. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 52% to 82% B over 9 min), followed by lyophilization to give tert-butyl 1-[8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carbonyl]-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridine-5-carboxylic acid (20 mg, 23.33 μmol, 15% yield, 97% purity, TFA) as a white solid. NMR(400MHz,METHANOL-d4)δ=8.97(d,J=1.6Hz,1H),8.68(s,1H),8.42(s,1H),7.63(d,J=5.8Hz,3H),7. 25(s,1H),6.92(d,J=6.9Hz,1H),4.84-4.75(m,0.5H),4.49-4.38(m,0.5H),4.18-4.05(m,1H),4.03-3. 88(m,5H),3.78-3.66(m,1H),3.12-3.06(m,2H),3.04-2.85(m,3H),2.70(s,1H),2.48-2.30(m,1H),2.2 8-2.14(m,1H),2.04-1.90(m,2H),1.69-1.47(m,2H),1.46(d,J=1.6Hz,9H).LCMS(ESI):m / z[M+H]calcd for C 39 H 39N6O7Cl2F3:717.23;found:717.2.

[0791] Synthesis of 5-[3-(2,3,3a,4,5,6,7,7a-octahydropyrrolo[3,2-c]pyridine-1-carbonyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide

[0792] [ka]

[0793] A mixture of tert-butyl 1-[8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carbonyl]-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridine-5-carboxylate (20 mg, 27.87 μmol, 1 equiv) in 4 N HCl / dioxane (2 mL) was stirred for 1 hour at 15° C. The mixture was concentrated in vacuo to provide a residue. The residue was purified by preparative HPLC (TFA or neutral or basic conditions) followed by lyophilization to give 5-[3-(2,3,3a,4,5,6,7,7a-octahydropyrrolo[3,2-c]pyridine-1-carbonyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide (11.9 mg, 16.27 μmol, 58% yield, 100% purity, TFA) as a white solid. NMR(400MHz,METHANOL-d4)δ=8.91(d,J=1.8Hz,1H),8.58(s,1H),8.28(d,J=1.8Hz,1H),7.7 0-7.60(m,3H),7.23(s,1H),6.87(d,J=5.3Hz,1H),5.00-4.87(m,1H),4.51-4.17(m,1H),4.0 9-3.92(m,1H),3.91(s,3H),3.82-3.72(m,1H),3.33(brs,3H),3.19-3.06(m,3H),3.05-2.93 (m,2H),2.76-2.36(m,2H),2.28-2.08(m,2H),2.07-1.69(m,1H).LCMS(ESI):m / z[M+H]calcd for C 34 H 31 N6O5Cl2F3: 617.18; found: 617.2. Figure 80 shows the nuclear magnetic resonance of compound 8-23.

[0794] Reaction Scheme 16

[0795] [ka]

[0796] Synthesis of Compounds 8-16A

[0797] [ka]

[0798] Compound 8-16A was synthesized via a similar method to Example 8. LCMS (ESI): m / z [M+H] calculated for C 35 H 34 Cl2N6O5:689.20;found:689.2. 1H NMR(400MHz,METHANOL-d4)δ=8.96-8.79(m,1H),8.62-8.44(m,1H),8.22(brs,1H),7 .67-7.60(m,3H),7.21(brs,1H),6.82(brd,J=9.4Hz,1H),5.12(brd,J=15.8Hz,1H),4 .65-4.52(m,1H),4.04-3.91(m,2H),3.90-3.87(m,3H),3.68-3.51(m,2H),3.06(brd, J=5.0Hz,4H),2.85-2.77(m,1H),1.65(dd,J=5.9,8.8Hz,1H),1.46(d,J=13.2Hz,9H).

[0799] Synthesis of Compound 8-16B

[0800] [ka]

[0801] Compound 8-16B was synthesized via a similar method to Example 8. LCMS (ESI): m / z [M+H] calculated for C 30 H 27Cl2N6O3:589.14;found:589.1. 1H NMR(400MHz,METHANOL-d4)δ=9.05-8.80(m,1H),8.78-8.44(m,1H),8.27(s,1H),7.68(d,J=1. 7Hz,1H),7.64(d,J=1.6Hz,2H),7.24(s,1H),6.83(s,1H),5.22(brd,J=1.5Hz,1H),4.69(brd, J = 3.1 Hz, 1H), 3.95 (brd, J = 12.8 Hz, 1H), 3.91 (s, 3H), 3.86 (brd, J = 12.3 Hz, 1H), 3.67-3.55 (m, 2H), 3.15-3.07 (m, 3H), 3.06-2.99 (m, 2H), 1.92 (d, J = 10.0 Hz, 1H). Figure 74 shows the nuclear magnetic resonance of compound 8-16B.

[0802] Synthesis of compounds 8-16

[0803] [ka]

[0804] Compounds 8-16 were synthesized via the same method as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 31 H 29 Cl2N6O3:603.16;found:603.1. 1H NMR(400MHz,METHANOL-d4)δ=8.93(d,J=1.0Hz,1H),8.58(s,1H),8.31(t,J=2.0Hz,1H),7.68-7.66(m,1H),7.64(d,J=1.8Hz,2H),7.23(s,1H),6 .83(s,1H),5.25(brs,1H),4.70(brs,1H),4.10-3.66(m,7H),3.17-3.06 (m,3H), 3.05-2.96(m,5H), 2.07-1.97(m,1H). Figure 75 shows the nuclear magnetic resonance of compound 8-16.

[0805] Synthesis of Compound 8-25A

[0806] [ka]

[0807] Compound 8-25A was synthesized via a similar method to Example 8. LCMS (ESI): m / z [M+H] calculated for C 39 H 41 N6O7Cl2F3:719.24;found:719.4. 1 H NMR(400MHz,METHANOL-d4)δ=9.61(d,J=1.7Hz,1H),9.30(brs,1H),9.03(brs,1H),8.31(brs,3H),7.91(s,1H),7.66-7.50(m,1H),5.24-4.90(m,3H),4 .89-4.63(m,1H),4.58(s,3H),3.88-3.37(m,7H),2.86-2.71(m,1H),2.14( s,9H),1.82(brd,J=5.7Hz,2H),1.70-1.59(m,3H),1.54(brd,J=6.8Hz,1H).

[0808] Synthesis of Compounds 8-25

[0809] [ka]

[0810] Compound 8-25 was synthesized via the same method as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 34 H 33 N6O5Cl2F3:619.19;found:619.2. 1H NMR(400MHz,METHANOL-d4)δ=8.91(s,1H),8.58(brs,1H),8.28(t,J=1.9Hz,1H ),7.70-7.56(m,3H),7.24(s,1H),6.87(brs,1H),4.98-4.87(m,1H),4.73-4.57 (m,1H),3.91(s,3H),3.76-3.32(m,3H),3.29-3.17(m,2H),3.16-3.05(m,2H), 2.93 (brs, 2H), 2.51-2.18 (m, 1H), 1.26-0.76 (m, 6H). Figure 82 shows the nuclear magnetic resonance of compound 8-25.

[0811] Synthesis of compounds 8-27

[0812] [ka]

[0813] Compound 8-27 was synthesized via the same method as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 33 H 28 N5O6Cl2F3:604.1;found:604.2. 1 H NMR(400MHz,METHANOL-d4)δ=8.98(s,1H),8.71(s,1H),8.46(s,1H),7.63(s,3H),7.27(s,1H),6.93(s,1H),5.65(d,J=5.4Hz,2H),4.49(d,J= 5.5Hz, 2H), 3.96-3.86 (m, 5H), 3.14-3.06 (m, 2H), 3.04-2.95 (m, 2H), 2.40 (t, J = 6.7 Hz, 2H), 1.83 (brt, J = 6.4 Hz, 2H). Figure 85 shows the nuclear magnetic resonance of compound 8-27.

[0814] Synthesis of compound 8-31A

[0815] [ka]

[0816] Compound 8-31A was synthesized via a similar method to Example 8. LCMS (ESI): m / z [M+H] calculated for C 38 H 37 N6O7Cl2F3:703.21;found:703.2. 1 H NMR(400MHz,METHANOL-d4)δ=8.95(d,J=1.7Hz,1H),8.66(s,1H),8.40(s,1H),7. 63(s,3H),7.25(s,1H),6.96-6.86(m,1H),5.31(brd,J=5.9Hz,0.25H),4.83-4.7 2(m,0.75H),4.52-4.35(m,1H),4.30-4.02(m,1H),3.92(s,3H),3.70(brt,J=9.2 Hz,2H),3.28-3.18(m,1H),3.13-2.84(m,4H),2.34-1.97(m,4H),1.49(brs,9H).

[0817] Synthesis of Compounds 8-31

[0818] [ka]

[0819] Compound 8-31 was synthesized via the same method as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 34 H 31 N6O5Cl2F3:617.18;found:617.2. 1 H NMR(400MHz,METHANOL-d4)δ=8.93-8.87(m,1H),8.60-8.49(m,1H),8.34-8.22(m ,1H),7.77-7.49(m,3H),7.29-7.18(m,1H),6.89-6.75(m,1H),5.72-4.98(m,1H), 4.55-4.28(m,1H),4.26-3.96(m,2H),3.91(d,J=1.8Hz,3H),3.86-3.45(m,2H),3 .10-2.85(m,8H),2.43-2.29(m,2H),2.19-1.93(m,1H). Figure 89 shows the nuclear magnetic resonance of compound 8-31.

[0820] Synthesis of compound 8-33A

[0821] [ka]

[0822] Compound 8-33A was synthesized via a similar method to Example 8. LCMS (ESI): m / z [M+H] calculated for C 37 H 35 N6O7Cl2F3:689.2;found:689.2. 1 H NMR(400MHz,METHANOL-d4)δ=8.95(s,1H),8.65(s,1H),8.39(brs,1H),7.70-7.60(m,3H),7.25(d,J=2.3Hz,1H),6.95-6.85(m,1H),5.55-4.98(m, 1H),4.61-4.52(m,1H),4.04-3.96(m,1H),3.92(s,3H),3.66-3.44(m,3H ),3.15-2.94(m,4H),1.98(brd,J=10.5Hz,2H),1.48(brd,J=17.1Hz,9H).

[0823] Synthesis of Compounds 8-33

[0824] [ka]

[0825] Compound 8-33 was synthesized via the same method as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 32 H 27 N6O5Cl2F3:589.14;found:589.2. 1H NMR (400 MHz, METHANOL-d) δ = 8.93 (s, 1H), 8.59 (brs, 1H), 8.31 (d, J = 1.5 Hz, 1H), 7.69-7.57 (m, 3H), 7.23 (s, 1H), 6.92-6.77 (m, 1H), 5.76-5.10 (m, 1H), 4.58-4.48 (m, 1H), 4.32-4.14 (m, 1H), 3.91 (s, 3H), 3.85-3.70 (m, 1H), 3.68-3.39 (m, 2H), 3.14-2.84 (m, 4H), 2.32-2.17 (m, 1H), 2.06 (brd, J = 11.4 Hz, 1H). Figure 91 shows the nuclear magnetic resonance of compound 8-33.

[0826] Synthesis of Compounds 8-34

[0827] [ka]

[0828] Compound 8-34 was synthesized via the same method as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 28 H 26 Cl2N5O3:550.13;found:550.2. 1H NMR(400MHz,METHANOL-d4)δ=9.27(s,1H),9.08(s,1H),8.89(brs,1H),7.82(brd,J=2.6Hz,3H),7.50(s,1H),7.22(d,J=7.0Hz,1H),4.15(s,3H),3. 95-3.86(m,1H),3.81(q,J=7.1Hz,1H),3.51(s,3H),3.48(s,1H),3.35-3. 32(m, 1H), 3.07(brs, 2H), 1.46(q, J=6.5Hz, 3H). Figure 92 shows the nuclear magnetic resonance of compound 8-34.

[0829] Synthesis of compounds 8-39

[0830] [ka]

[0831] Compound 8-39 was synthesized via the same method as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 29 H 26 Cl2N5O3: 562.13; found: 562.2. 1H NMR (400 MHz, METHANOL-d4) δ = 9.02 (s, 1H), 8.78 (brs, 1H), 8.56 (brs, 1H), 7.66-7.60 (m, 3H), 7.28 (s, 1H), 6.97 (s, 1H), 3.94 (s, 3H), 3.26-3.07 (m, 6H), 2.86 (brs, 2H), 0.82-0.51 (m, 4H). Figure 93 shows the nuclear magnetic resonance of compound 8-39.

[0832] Synthesis of Compounds 8-44

[0833] [ka]

[0834] Compound 8-44 was synthesized via a similar method to Example 8. LCMS (ESI): m / z [M+H] calculated for C 31 H 29 Cl2N5O4:606.16;found:606.2. 1H NMR(400MHz,METHANOL-d4)δ=8.90(d,J=2.0Hz,1H),8.57(d,J=2.0Hz,1H),8.22(t, J=2.1Hz,1H),7.65-7.59(m,3H),7.23(s,1H),6.88(s,1H),4.44-4.26(m,4H),3.92 (s, 3H), 3.89-3.80 (m, 1H), 3.73-3.66 (m, 1H), 3.60-3.53 (m, 1H), 3.17-3.09 (m, 2H), 2.94-2.86 (m, 2H), 2.06-1.81 (m, 2H), 1.08-0.84 (m, 3H). Figure 94 shows the nuclear magnetic resonance of compound 8-44.

[0835] Reaction Scheme 17

[0836] [ka]

[0837] Synthesis of ethyl 8-bromo-1-(pyridin-2-yl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate

[0838] [ka]

[0839] A mixture of ethyl 2-(7-bromo-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-2-oxoacetate (1.9 g, 6.39 mmol, 1 equiv.), 2-pyridylhydrazine (697.79 mg, 6.39 mmol, 1 equiv.), AcOH (3.84 g, 63.94 mmol, 3.66 mL, 10 equiv.) in EtOH (20 mL) was degassed and purged with N three times, then the mixture was stirred at 80 °C under N atmosphere for 16 h. The mixture was poured into water (80 mL) and extracted with ethyl acetate (3 * 40 mL). The organic phase was separated, washed with saturated sodium chloride solution (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® silica flash column, eluent: 60–40% petroleum ether / ethyl acetate, 60 mL / min gradient) to give the compound ethyl 8-bromo-1-(pyridin-2-yl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate (1.1 g, 2.73 mmol, 42.76% yield, 99% purity) as a brown solid. 1H NMR(400MHz,DMSO-d6)δ=8.57(d,J=4.0Hz,1H),8.19(dt,J=1.6,8.0Hz,1H),7.84(d,J=8.0Hz,1H),7.66(m,J=5.1,1H),7. 45-7.38(m,1H),7.37-7.31(m,1H),6.79(d,J=1.6Hz,1H),4.34(q,J=7.2Hz,2H),3.03-2.88(m,4H),1.33(t,J=7.2Hz,3H).

[0840] Synthesis of ethyl 8-bromo-1-(2-pyridyl)-4,5-dihydrobenzo[g]indazole-3-carboxylate

[0841] [ka]

[0842] A mixture of ethyl 8-bromo-1-(2-pyridyl)-4,5-dihydrobenzo[g]indazole-3-carboxylate (900 mg, 2.26 mmol, 1 equiv.), 3-pyridylboronic acid (333.33 mg, 2.71 mmol, 1.2 equiv.), Pd(dppf)Cl (165.36 mg, 225.99 μmol, 0.1 equiv.), KCO (936.98 mg, 6.78 mmol, 3 equiv.) in dioxane (10 mL) and HO (1 mL) was degassed and purged with N three times, then the mixture was stirred at 60 °C under a N atmosphere for 16 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® silica flash column, eluent: 100–95% petroleum ether / ethyl acetate, 60 mL / min gradient). The compound ethyl 8-bromo-1-(2-pyridyl)-4,5-dihydrobenzo[g]indazole-3-carboxylate (530 mg, 1.33 mmol, 58.89% yield) was obtained as a gray solid. LCMS (ESI): m / z [M+H] calculated for C19H16N3O2Br: 398.25; found: 397.1.

[0843] Synthesis of 1-(pyridin-2-yl)-8-(pyridin-3-yl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid

[0844] [ka]

[0845] To a solution of ethyl 1-(2-pyridyl)-8-(3-pyridyl)-4,5-dihydrobenzo[g]indazole-3-carboxylate (360 mg, 908.08 μmol, 1 equiv.) in THF (2 mL) and HO (2 mL) was added LiOH.HO (152.43 mg, 3.63 mmol, 4 equiv.). The mixture was stirred at 25 °C for 2 h. The mixture was poured into water (40 mL) and extracted with ethyl acetate (3 * 20 mL). The organic phase was separated, washed with saturated sodium chloride solution (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The compound 1-(2-pyridyl)-8-(3-pyridyl)-4,5-dihydrobenzo[g]indazole-3-carboxylic acid (240 mg, 651.49 μmol, 71.74% yield) was obtained as a gray solid.

[0846] Synthesis of Compounds 8-77

[0847] [ka]

[0848] To a solution of 1-(2-pyridyl)-8-(3-pyridyl)-4,5-dihydrobenzo[g]indazole-3-carboxylic acid (40 mg, 108.58 μmol, 1 equiv.) in DMF (1 mL) was added HATU (61.93 mg, 162.87 μmol, 1.5 equiv.) and DIEA (42.10 mg, 325.74 μmol, 56.74 μL, 3 equiv.). The mixture was stirred at 25° C. for 0.5 hours. Then, piperidin-3-one (12.92 mg, 130.30 μmol, 1.2 equiv.) was added. The mixture was stirred at 25° C. for 1.5 hours. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 18% to 48% B over 15 min). The compound 1-[1-(2-pyridyl)-8-(3-pyridyl)-4,5-dihydrobenzo[g]indazole-3-carbonyl]piperidin-3-one (38.29 mg, 84.33 μmol, 77.67% yield, 99% purity) was obtained as a brown oil. LCMS (ESI): m / z [M+H] calculated for C27H24O2N5: 450.19; found: 450.3. 1 H NMR(400MHz,DMSO-d6)δ=8.63-8.57(m,1H),8.56-8.48(m,2H),8.19-8.11(m,1H),7.85-7.7 9(m,1H),7.77-7.69(m,1H),7.65-7.53(m,2H),7.52-7.47(m,1H),7.39(m,1H),7.19-7.09(m , 1H), 5.31 (s, 1H), 4.56-4.24 (m, 1H), 4.06-3.85 (m, 1H), 3.60 (s, 1H), 3.05-2.99 (m, 2H), 2.93-2.77 (m, 2H), 2.52 (s, 2H), 2.09-1.98 (m, 1H), 1.75-1.59 (m, 1H). Figure 95 shows the nuclear magnetic resonance of compound 8-77.

[0849] Synthesis of Compounds 8-75

[0850] [ka]

[0851] Compound 8-75 was synthesized via a similar method to Example 8. LCMS (ESI): m / z [M+H] calculated for C 31 H 29 N7O5F3:522.22;found:522.2. 1 H NMR(400MHz,DMSO-d6)δ=8.95(d,J=1.5Hz,1H),8.66(d,J=1.7Hz,1H),8.62-8.58(m,1H) ,8.27-8.19(m,2H),8.18-8.10(m,2H),7.86(d,J=8.1Hz,1H),7.70-7.63(m,2H),7.59(dd , J = 5.0, 7.4 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 1.1 Hz, 1H), 3.83-3.76 (m, 2H), 3.29 (brs, 2H), 3.06-2.98 (m, 2H), 2.86-2.78 (m, 2H), 1.72 (s, 6H). Figure 96 shows the nuclear magnetic resonance of compound 8-75.

[0852] Synthesis of Compounds 8-76

[0853] [ka]

[0854] Compound 8-76 was synthesized via a similar method to Example 8. LCMS (ESI): m / z [M+H] calculated for C 28 H 24 N6O4F3:451.18;found:451.1. 1H NMR(400MHz,DMSO-d6)δ=8.67(d,J=1.3Hz,1H),8.63(brd,J=4.8Hz,1H),8.59(brd,J=3.4Hz,1H) ,8.22-8.12(m,2H),8.02(brd,J=7.4Hz,1H),7.92-7.85(m,1H),7.68-7.60(m,3H),7.55(d,J=8.0 Hz, 1H), 7.14 (brd, J = 3.1 Hz, 1H), 4.52 (s, 1H), 4.17 (s, 1H), 4.11 (brt, J = 4.7 Hz, 1H), 3.84 (brd, J = 5.5 Hz, 1H), 3.30 (brs, 2H), 3.06-2.98 (m, 2H), 2.90 (brd, J = 4.9 Hz, 2H). Figure 97 shows the nuclear magnetic resonance spectra of compound 8-76.

[0855] Synthesis of compounds 8-78

[0856] [ka]

[0857] Compound 8-78 was synthesized via a similar method to Example 8. LCMS (ESI): m / z [M+H] calculated for C 28 H 26 N6O2479.21;found:479.3. 1 H NMR(400MHz,METHANOL-d4)δ=8.59(d,J=4.4Hz,1H),8.45(d,J=4.4Hz,2H),8.18-8.10(m,1H),7.88- 7.75(m,2H),7.67-7.58(m,1H),7.55-7.38(m,3H),7.08-7.00(m,1H),5.42(t,J=7.2Hz,1H),5.07(dd , J = 4.8, 9.2 Hz, 1H), 4.83-4.54 (m, 1H), 3.70-3.42 (m, 2H), 3.38 (d, J = 14.0 Hz, 1H), 3.28 (s, 1H), 3.06 (d, J = 6.8 Hz, 2H), 2.97-2.83 (m, 2H), 2.22-1.88 (m, 2H), 1.15-0.90 (m, 3H). Figure 98 shows the nuclear magnetic resonance of compound 8-78.

[0858] Synthesis of compounds 8-81

[0859] [ka]

[0860] Compound 8-81 was synthesized via the same method as in Example 8. LCMS (ESI): m / z [M+H] calculated for C28H24N6O2: 477.2; found: 477.2. 1 H NMR(400MHz,METHANOL-d4)δ=8.61-8.53(m,1H),8.50-8.41(m,2H),8.13(dt,J=1.6 ,8.0Hz,1H),7.88-7.78(m,2H),7.61(dd,J=4.8,7.6Hz,1H),7.56-7.46(m,2H),7.43 (dd, J = 5.2, 8.0 Hz, 1H), 7.08 (s, 1H), 4.25 (t, J = 4.8 Hz, 2H), 3.50 (s, 2H), 3.11-3.01 (m, 2H), 2.95-2.83 (m, 2H), 1.57 (s, 2H), 1.38-1.12 (m, 2H). Figure 99 shows the nuclear magnetic resonance of compound 8-81.

[0861] Reaction Scheme 18

[0862] [ka]

[0863] Synthesis of tert-butyl 4-(8-(5-carbamoylpyridin-3-yl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazole-3-carbonyl)-3,3-dimethylpiperazine-1-carboxylate

[0864] [ka]

[0865] To a solution of 8-(5-carbamoylpyridin-3-yl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid (500 mg, 981.66 μmol, 1 equiv.) in DMF (5 mL), DIEA (380.62 mg, 2.94 mmol, 512.96 μL, 3 equiv.) and HATU (559.89 mg, 1.47 mmol, 1.5 equiv.) were added at 25° C. After the addition, the mixture was stirred at this temperature for 0.5 hours, and then tert-butyl 3,3-dimethylpiperazine-1-carboxylate (252.45 mg, 1.18 mmol, 1.2 equiv.) was added dropwise at 25° C. The mixture was stirred at 25° C. for 15.5 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL). The organic phase was separated, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® silica flash column, eluent of 85% ethyl acetate / petroleum ether, 30 mL / min gradient). The compound tert-butyl 4-(8-(5-carbamoylpyridin-3-yl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazole-3-carbonyl)-3,3-dimethylpiperazine-1-carboxylate (160 mg, 226.75 μmol, 23.10% yield) was obtained as a yellow oil. LCMS(ESI):m / z[M+H]calcd for C36H39N6O5Cl2:705.23;found:705.4.

[0866] Synthesis of 5-(1-(3,5-dichlorophenyl)-3-(2,2-dimethylpiperazine-1-carbonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazol-8-yl)nicotinamide

[0867] [ka]

[0868] To a solution of tert-butyl 4-(8-(5-carbamoylpyridin-3-yl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazole-3-carbonyl)-3,3-dimethylpiperazine-1-carboxylate (160 mg, 226.75 μmol, 1 equiv.) in dioxane (2 mL) was added HCl / dioxane (4 M, 2 mL, 35.28 equiv.). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated in vacuo to give a residue. The compound 5-(1-(3,5-dichlorophenyl)-3-(2,2-dimethylpiperazine-1-carbonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazol-8-yl)nicotinamide (145 mg, 225.87 μmol, 99.61% yield, HCl) was obtained as a yellow solid. LCMS (ESI): m / z [M+H] calculated for C 31 H 32 Cl3N6O3:605.18;found:605.2 1 H NMR(400MHz,DMSO-d6)δ=9.98-9.88(m,1H),9.73-9.59(m,1H),9.43-9.31( m,1H),8.96(d,J=1.8Hz,1H),8.57-8.51(m,1H),8.22-8.14(m,1H),7.82-7. 66(m,2H),7.32(s,1H),6.84(s,1H),3.95-3.89(m,2H),3.86(s,3H),3.32- 3.18(m,6H),3.08-3.00(m,1H),2.86-2.79(m,1H),1.59(s,3H),1.45(s,3H)

[0869] Synthesis of Compounds 8-61

[0870] [ka]

[0871] To a solution of the compound 5-(1-(3,5-dichlorophenyl)-3-(2,2-dimethylpiperazine-1-carbonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazol-8-yl)nicotinamide (40 mg, 62.31 μmol, 1 equiv., HCl) in DCM (3 mL), AcOH (37.42 mg, 623.08 μmol, 35.67 μL, 10 equiv.) and 2,2-dimethoxypropane (7.79 mg, 74.77 μmol, 9.16 μL, 1.2 equiv.) were added dropwise at 25° C. After the addition, the mixture was stirred at this temperature for 30 min, and then NaBH(OAc) (26.41 mg, 124.62 μmol, 2 equiv.) was added dropwise at 25° C. The resulting mixture was stirred at 50° C. for 16 h. The reaction mixture was concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 45% to 75% B over 10 minutes), followed by lyophilization. The compound 5-(1-(3,5-dichlorophenyl)-3-(4-isopropyl-2,2-dimethylpiperazine-1-carbonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazol-8-yl)nicotinamide (0.99 mg, 1.45 μmol, yield 2.33%, purity 95%) was obtained as an off-white solid. LCMS (ESI): m / z [M+H] calculated for C34H37Cl2N6O3: 647.22; found: 647.2. 1 H NMR(400MHz,METHANOL-d4)δ=8.89(d,J=2.0Hz,1H),8.55(d,J=2.1Hz,1H),8.23(t,J=2. 1Hz,1H),7.70-7.59(m,3H),7.24(s,1H),6.86(s,1H),3.91(s,3H),3.67(brt,J=5.4Hz, 2H), 3.16-3.08 (m, 2H), 2.83 (t, J = 7.4 Hz, 2H), 2.72 (td, J = 6.3, 13.1 Hz, 1H), 2.64 (brt, J = 4.9 Hz, 2H), 2.47 (s, 2H), 1.59 (s, 6H), 1.07 (d, J = 6.5 Hz, 6H). Figure 100 shows the nuclear magnetic resonance spectra of compounds 8-61.

[0872] Synthesis of compounds 8-60

[0873] [ka]

[0874] Compound 8-60 was synthesized via the same method as in Example 8. LCMS (ESI): m / z [M+H] calculated for C 34 H 37 Cl2N6O5:633.21;found:633.2. 1 H NMR(400MHz,METHANOL-d4)δ=8.88(d,J=2.0Hz,1H),8.55-8.51(m,1H),8.22(t,J=2.1Hz,1 H),7.66-7.63(m,1H),7.62(d,J=1.8Hz,2H),7.22(s,1H),6.84(s,1H),3.90(s,3H),3.77- 3.70(m,2H),3.14-3.07(m,2H),2.83(t,J=7.3Hz,2H),2.64(brt,J=4.6Hz,2H),2.53(brd, J=7.3Hz, 2H), 2.50(s, 2H), 1.60(s, 6H), 1.14(t, J=7.2Hz, 3H). Figure 101 shows the nuclear magnetic resonance of compound 8-60.

[0875] Synthesis of Compounds 8-63

[0876] [ka]

[0877] Compound 8-63 was synthesized via a similar method to Example 8. LCMS (ESI): m / z [M+H] calculated for C 36 H 37 Cl2N6O5F3:647.22;found:647.2. 1H NMR(400MHz,METHANOL-d4)δ=8.90(d,J=2.0Hz,1H),8.55(d,J=2.0Hz,1H),8.25(t,J=2.0Hz,1H), 7.69-7.66(m,1H),7.63(d,J=1.8Hz,2H),7.23(s,1H),6.84(s,1H),3.91(s,3H),3.85-3.52(m,2H) ,3.50-3.33(m,2H),3.30-3.23(m,2H),3.17(brdd,J=6.8,9.9Hz,2H),3.13-3.07(m,2H),2.91(br d,J=1.6Hz,2H),1.89-1.76(m,2H),1.70(s,6H),1.04(t,J=7.4Hz,3H). The nuclear magnetic resonance of 102 and compound 8-63 is shown.

[0878] Synthesis of compound 8-58

[0879]

change

[0880] To a solution of 5-(1-(3,5-dichlorophenyl)-3-(2,2-dimethylpiperazine-1-carbonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazol-8-yl)nicotinamide (80 mg, 132.12 μmol, 1 equiv.) and TFA (53.48 mg, 528.48 μmol, 73.56 μL, 4 equiv.) in THF (1 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (30.67 mg, 132.12 μmol, 1 equiv.). The mixture was stirred at 40 °C for 5 h. The pH of the reaction mixture was adjusted to 5 with 1 M aqueous HCl, then diluted with 20 mL of HO and extracted with 20 mL of EtOAc (10 mL*2). The combined organic layers were washed with 20 mL (10 mL * 2) of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 150 * 30 mm * 7 um; mobile phase: [water (FA)-ACN]; gradient: 60% to 90% B over 10 min) followed by lyophilization. The compound 5-(1-(3,5-dichlorophenyl)-3-(2,2-dimethyl-4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazol-8-yl)nicotinamide (27.2 mg, 35.60 μmol, 26.94% yield, 96% purity, FA) was obtained as a white solid. LCMS(ESI):m / z[M+H]calcd for C34H34Cl2N6O5F3:687.18;found:687.1. 1 H NMR(400MHz,METHANOL-d4)δ=8.93(d,J=1.8Hz,1H),8.61(d,J=2.0Hz,1H),8.32(t,J=1.9Hz,1H),7.66-7.60(m,3H),7.24(s,1H),6.88 (s,1H),3.92(s,3H),3.72(t,J=5.1Hz,2H),3.15-3.07(m,4H),2.87-2.78(m,4H),2.64(s,2H),1.59(s,6H). Figure 103 shows the nuclear magnetic resonance of compound 8-58.

[0881] Reaction Scheme 19

[0882] [ka]

[0883] Synthesis of 2,2-dimethyloxazolidine

[0884] [ka]

[0885] A mixture of 2-aminoethan-1-ol (50 mg, 818.56 μmol, 49.41 μL, 1 equiv.) in propan-2-one (395.00 mg, 6.80 mmol, 0.5 mL, 8.31 equiv.) was stirred at 60 °C for 16 h. The reaction mixture was concentrated in vacuo. The 2,2-dimethyloxazolidine product (80 mg, 522.02 μmol, 63.77% yield, 66% purity) (a 2:1 mixture of SM and DP) was obtained as a yellow oil. LCMS (ESI): m / z [M+H] calculated for C5H13NO: 102.08; found: 102.1.

[0886] Synthesis of Compounds 8-51

[0887] [ka] 【...

Claims

1. Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein R １ is unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C １６ Heteroaryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ６ Aryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkynyl, unsubstituted or R ５ heterocycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ is alkynyl, Y is -OC(R ４ ) ２ - and Z is -OR ４ , -N(R ４ ) ２ , -SR ４ , —OH, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C ６ fluoroalkyl, unsubstituted or R ５ -O-(C １ -C ６ fluoroalkyl), unsubstituted or ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Heteroalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkynyl, unsubstituted or R ５ heterocycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C １６ is alkynyl, R ２ is unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C ６ fluoroalkyl, unsubstituted or R ５ O—(C) substituted with one, two, three, four, or five groups selected from １ -C ６ fluoroalkyl), or —OCH ２ CH ３ and R ３ is hydrogen, halogen, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C ６ fluoroalkyl, unsubstituted or R ５ -O-(C １ -C ６ fluoroalkyl), —OH, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Heteroalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C １６ Heteroaryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ６ Aryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkynyl, unsubstituted or R ５ heterocycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ is alkynyl, Each R ４ are independently hydrogen, halogen, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C ６ fluoroalkyl, unsubstituted or R ５ -O-(C １ -C ６ fluoroalkyl), —OH, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Heteroalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C １６ Heteroaryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ６ Aryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkynyl, unsubstituted or R ５ heterocycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ is alkynyl, Each R ５ are independently deuterium, halogen, —OH, —NO ２ , -CN, -SR ６ , -S(=O)R ６ , -S(=O) ２ R ６ , -N(R ６ ) ２ , -C(=O)R ６ , —OC(═O)R ６ , -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C ２ -C ６ Alkynyl, substituted or unsubstituted C １ -C ６ Alkoxy, substituted or unsubstituted C ３ -C ７ Cycloalkyl, substituted or unsubstituted C ２ -C ７ heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Each R ６ are independently hydrogen, deuterium, substituted or unsubstituted C １ -C ４ Alkyl, -CD ３ , substituted or unsubstituted C １ -C ４ Haloalkyl, substituted or unsubstituted C １ -C ４ Heteroalkyl, substituted or unsubstituted C ３ -C ６ Cycloalkyl, substituted or unsubstituted C ２ -C ５ A compound, or a pharmaceutically acceptable salt thereof, which is heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

2. Formula (I): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, wherein R １ is unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C １６ Heteroaryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ６ Aryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkynyl, unsubstituted or R ５ heterocycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ is alkynyl, Y is -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR ４ -, -SC(R ４ ) ２ -, -C(R ４ ) ２ O-, -C(R ４ ) ２ S-, -C(R ４ ) ２ NR ４ -, -C(R ４ ) ２ -, -S(=O)C(R ４ ) ２ -, -C(R ４ ) ２ S(=O)-, -S(=O) ２ C (R ４ ) ２ -, -C(R ４ ) ２ S (= O) ２ - or -CR ４ =CR ４ - and Z is -OR ４ , -N(R ４ ) ２ , -SR ４ , unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C ６ fluoroalkyl, unsubstituted or R ５ -O-(C １ -C ６ fluoroalkyl), —OH, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Heteroalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkynyl, unsubstituted or R ５ heterocycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C １６ is alkynyl, R is hydrogen, halogen, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C ６ fluoroalkyl, unsubstituted or R ５ -O-(C １ -C ６ fluoroalkyl), —OH, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Heteroalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C １６ Heteroaryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ６ Aryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkynyl, unsubstituted or R ５ heterocycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ is alkynyl, R ２ is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO ２ , -CF ３ , -OCF ３、 -SO ２ R, -SOR, -C(O)R, -CO ２ R, -C(O)N(R) ２ , -NRC(O)R, -NRC(O)N(R) ２ , -NRSO ２ R, or -N(R) ２ and R ３ is hydrogen, halogen, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C ６ fluoroalkyl, unsubstituted or R ５ -O-(C １ -C ６ fluoroalkyl), —OH, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Heteroalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C １６ Heteroaryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ６ Aryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkynyl, unsubstituted or R ５ heterocycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ is alkynyl, Each R ４ are independently hydrogen, halogen, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C ６ fluoroalkyl, unsubstituted or R ５ -O-(C １ -C ６ fluoroalkyl), —OH, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Heteroalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C １６ Heteroaryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ６ Aryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkynyl, unsubstituted or R ５ heterocycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ is alkynyl, Each R ５ are independently deuterium, halogen, —OH, —NO ２ , -CN, -SR ６ , -S(=O)R ６ , -S(=O) ２ R ６ , -N(R ６ ) ２ , -C(=O)R ６ , —OC(═O)R ６ , -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , unsubstituted C １ -C ６ Alkyl, unsubstituted C ２ -C ６ Alkenyl, unsubstituted C ２ -C ６ Alkynyl, unsubstituted C １ -C ６ Alkoxy, unsubstituted C ３ -C ７ Cycloalkyl, unsubstituted C ２ -C ７ heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl; Each R ６ are independently hydrogen, halogen, deuterium, unsubstituted C １ -C ４ Alkyl, -CD ３ , unsubstituted C １ -C ４ Haloalkyl, unsubstituted C １ -C ４ Heteroalkyl, unsubstituted C ３ -C ６ Cycloalkyl, unsubstituted C ２ -C ５ A compound, or a pharmaceutically acceptable salt thereof, which is heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

3. Formula (I): 【Chemistry 3】 or a pharmaceutically acceptable salt thereof, wherein R １ is unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from alkyl １ -C １６ , unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from alkenyl １ -C １６ , unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from heteroaryl ３ -C １６ , unsubstituted or R ５ C ６ aryl, unsubstituted or substituted with one, two, three, four, or five groups selected from R ５ C ３ -C ８ cycloalkyl, unsubstituted or substituted with one, two, three, four, or five groups selected from R ５ C ３ -C ８ cycloalkenyl, unsubstituted, or substituted with one, two, three, four, or five groups selected from R ５ C ３ -C ８ cycloalkynyl, unsubstituted or substituted with one, two, three, four, or five groups selected from R ５ heterocycloalkyl, unsubstituted or substituted with one, two, three, four, or five groups selected from R ５ heterocycloalkenyl, unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R ５ heterocycloalkynyl, or unsubstituted with 1, 2, 3, 4, or 5 groups selected from R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from alkynyl １ -C １６ and Y is -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR ４ -, -OC(R ４ ) ２ -, -SC(R ４ ) ２ -, -C(R ４ ) ２ O-, -C(R ４ ) ２ S-, -C(R ４ ) ２ NR ４ -, -C(R ４ ) ２ -, -S(=O)C(R ４ ) ２ -, -C(R ４ ) ２ S(=O)-, -S(=O) ２ C (R ４ ) ２ -, -C(R ４ ) ２ S (= O) ２ -, -C(R ４ ) ２ -C(R ４ ) ２ - or -CR ４ =CR ４ - and Z is —Ot-butyl; R is hydrogen, halogen, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C ６ fluoroalkyl, unsubstituted or R ５ -O-(C １ -C ６ fluoroalkyl), —OH, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Heteroalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C １６ Heteroaryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ６ Aryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkynyl, unsubstituted or R ５ heterocycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ is alkynyl, R ２ is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO ２ , -CF ３ , -OCF ３、 -SO ２ R, -SOR, -C(O)R, -CO ２ R, -C(O)N(R) ２ , -NRC(O)R, -NRC(O)N(R) ２ , -NRSO ２ R, or -N(R) ２ and R ３ is hydrogen, halogen, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C ６ fluoroalkyl, unsubstituted or R ５ -O-(C １ -C ６ fluoroalkyl), —OH, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Heteroalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C １６ Heteroaryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ６ Aryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkynyl, unsubstituted or R ５ heterocycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ is alkynyl, Each R ４ are independently hydrogen, halogen, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C ６ fluoroalkyl, unsubstituted or R ５ -O-(C １ -C ６ fluoroalkyl), —OH, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Heteroalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ Alkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C １６ Heteroaryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ６ Aryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkynyl, unsubstituted or R ５ heterocycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ C substituted with 1, 2, 3, 4, or 5 groups selected from １ -C １６ is alkynyl, Each R ５ are independently deuterium, halogen, —OH, —NO ２ , -CN, -SR ６ , -S(=O)R ６ , -S(=O) ２ R ６ , -N(R ６ ) ２ , -C(=O)R ６ , —OC(═O)R ６ , -C(=O)OR ６ , -C(=O)N(R ６ ) ２ , unsubstituted C １ -C ６ Alkyl, unsubstituted C ２ -C ６ Alkenyl, unsubstituted C ２ -C ６ Alkynyl, unsubstituted C １ -C ６ Alkoxy, unsubstituted C ３ -C ７ Cycloalkyl, unsubstituted C ２ -C ７ heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl; Each R ６ are independently hydrogen, halogen, deuterium, unsubstituted C １ -C ４ Alkyl, -CD ３ , unsubstituted C １ -C ４ Haloalkyl, unsubstituted C １ -C ４ Heteroalkyl, unsubstituted C ３ -C ６ Cycloalkyl, unsubstituted C ２ -C ５ A compound, or a pharmaceutically acceptable salt thereof, which is heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

4. R ３ is unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C １６ Heteroaryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ６ Aryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkynyl, unsubstituted or R ５ heterocycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ or a pharmaceutically acceptable salt thereof.

5. R ３ is unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C １６ 305. The compound of any one of claims 302 to 304, or a pharmaceutically acceptable salt thereof, which is heteroaryl.

6. R ３ but, 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 302. The compound of any one of claims 302-5, or a pharmaceutically acceptable salt thereof, selected from:

7. R ３ but, 【Chemistry 5】 302. The compound of any one of claims 302-6, or a pharmaceutically acceptable salt thereof, selected from:

8. R ３ but, 【Chemistry 6】 302. The compound of claim 302, or a pharmaceutically acceptable salt thereof, selected from:

9. R ３ but 【Chemistry 7】 302-308. The compound of claim 302, wherein:

10. R ３ but 【Chemistry 8】 302-308. The compound of claim 302, wherein:

11. R ３ but 【Chemistry 9】 302-308. The compound of claim 302, wherein:

12. R ３ but 【Chemistry 10】 302-308. The compound of claim 302, wherein:

13. R ３ but 【Chemistry 11】 302-308. The compound of claim 302, wherein:

14. R ３ but 【Chemistry 12】 302-308. The compound of claim 302, wherein:

15. R ３ but 【Chemistry 13】 302-308. The compound of claim 302, wherein:

16. R ３ but 【Chemistry 14】 302-308. The compound of claim 302, wherein:

17. R ３ but 【Chemistry 15】 302-308. The compound of claim 302, wherein:

18. R ３ but 【Chemistry 16】 302-308. The compound of claim 302, wherein:

19. R ２ -Halogen, -OR, -SR, -CN, -NO ２ , -CF ３ , -OCF ３ , or —C(═O)CH ３ 19. The compound of any one of claims 2 to 18, wherein:

20. R ２ But, -OCH ３ , -SCH ３ , -CN, -NO ２ , -CF ３ , or -OCF ３ 19. The compound of any one of claims 2 to 18, wherein:

21. R ２ But, -OCH ３ , -SCH ３ , or -OCF ３ 20. The compound of any one of claims 2 to 19, wherein:

22. R ２ Ga-SCH ３ 22. The compound of any one of claims 2 to 21, wherein:

23. R ２ Ga-OCF ３ 302-22. The compound of any one of claims 302-21, wherein:

24. R ２ Ga-CF ３ 20. The compound of any one of claims 302 to 19, wherein:

25. R ２ Ga-OCH ２ CH ３ 20. The compound of any one of claims 302 to 19, wherein:

26. R ２ Ga-OCH ３ 22. The compound of any one of claims 2 to 21, wherein:

27. R １ is unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C １６ Heteroaryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ６ Aryl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkynyl, unsubstituted or R ５ heterocycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ or a pharmaceutically acceptable salt thereof.

28. R １ is unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ６ 302. The compound of any one of claims 302 to 27, or a pharmaceutically acceptable salt thereof, which is aryl.

29. R １ is unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C １６ 30. The compound of any one of claims 302 to 27, or a pharmaceutically acceptable salt thereof, which is heteroaryl.

30. R １ but 【Chemistry 17-1】 【Chemistry 17-2】 【Chemistry 17-3】 302-27, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

31. R １ but 【Chemistry 18】 31. The compound of any one of claims 302-28 or 30, or a pharmaceutically acceptable salt thereof, selected from:

32. R １ but 【Chemistry 19】 30. The compound of any one of claims 2-28 or 30-31, wherein:

33. R １ but 【Chemistry 20】 30. The compound of any one of claims 2-28 or 30-31, wherein:

34. R １ but 【Chemical 21】 30. The compound of any one of claims 2-28 or 30-31, wherein:

35. R １ but 【Chemical 22】 30. The compound of any one of claims 2-28 or 30-31, wherein:

36. R １ but 【Chemical 23】 30. The compound of any one of claims 2-28 or 30-31, wherein:

37. R １ but 【Chemistry 24】 30. The compound of any one of claims 2-28 or 30-31, wherein:

38. R １ but 【Chemistry 25】 30. The compound of any one of claims 2-28 or 30-31, wherein:

39. R １ but 【Chemical Formula 26】 30. The compound of any one of claims 2-28 or 30-31, wherein:

40. R １ but 【Chemical 27】 30. The compound of any one of claims 2-28 or 30-31, wherein:

41. R １ but 【Chemical Formula 28】 30. The compound of any one of claims 2-28 or 30-31, wherein:

42. Y is —O—, —S—, or —NR ４ -, -OC(R ４ ) ２ -, -SC(R ４ ) ２ -, -C(R ４ ) ２ O-, -C(R ４ ) ２ S-, -C(R ４ ) ２ NR ４ -, -C(R ４ ) ２ -, -S(=O)C(R ４ ) ２ -, -C(R ４ ) ２ S(=O)-, -S(=O) ２ C (R ４ ) ２ -, -C(R ４ ) ２ S (= O) ２ - or -CR ４ =CR ４ 42. The compound of any one of claims 3 to 41, or a pharmaceutically acceptable salt thereof, wherein:

43. Y is —O—, —S—, or —NR ４ -, -OC(R ４ ) ２ -, -SC(R ４ ) ２ -, -C(R ４ ) ２ O-, -C(R ４ ) ２ S-, -C(R ４ ) ２ 43. The compound of any one of claims 3 to 42, or a pharmaceutically acceptable salt thereof, wherein:

44. Y is -O-, -S-, -NH-, -OCH ２ -, -SCH ２ -, -CH ２ O-, -CH ２ S-, -CH ２ -, -S(=O)CH ２ -, -CH ２ S(=O)-, -S(=O) ２ CH ２ -, -CH ２ S (= O) ２ 44. The compound of any one of claims 3 to 43, or a pharmaceutically acceptable salt thereof, wherein:

45. 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein Y is -O-.

46. 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein Y is -S-.

47. 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein Y is -S(=O)-.

48. Y is -S(=O) ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

49. Y is -S(=O)C(R ４ ) ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

50. Y is -C(R ４ ) ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein S(=O)-.

51. Y is -S(=O) ２ C (R ４ ) ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

52. Y is -C(R ４ ) ２ S (= O) ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

53. Y is -S(=O)CH ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

54. Y is -CH ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein S(=O)-.

55. Y is -S(=O) ２ CH ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

56. Y is -CH ２ S (= O) ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

57. Y is -NR ４ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

58. Y is -OC(R ４ ) ２ 45. The compound of any one of claims 3 to 44, or a pharmaceutically acceptable salt thereof, wherein:

59. Y is -SC(R ４ ) ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

60. Y is -C(R ４ ) ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, which is O-.

61. Y is -C(R ４ ) ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, which is S-.

62. Y is -C(R ４ ) ２ NR ４ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

63. Y is -C(R ４ ) ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

64. Y is -C(R ４ ) ２ -C(R ４ ) ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

65. Y is -CR ４ =CR ４ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

66. 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein Y is -NH-.

67. Y is -OCH ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

68. Y is -SCH ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

69. Y is -CH ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, which is O-.

70. Y is -CH ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, which is S-.

71. Y is -CH ２ NR ４ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

72. Y is -CH ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

73. Y is -CH ２ -CH ２ 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein:

74. 45. The compound of any one of claims 2 to 44, or a pharmaceutically acceptable salt thereof, wherein Y is -CH=CH-.

75. Z is -OR ４ , -N(R ４ ) ２ , -SR ４ , -CF ３ , -OCF ３ , —OH, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkenyl, unsubstituted or R ５ C substituted with 1, 2, 3, 4, or 5 groups selected from ３ -C ８ Cycloalkynyl, unsubstituted or R ５ heterocycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from ５ or a pharmaceutically acceptable salt thereof.

76. Z is -OR ４ , -N(R ４ ) ２ , -SR ４ , -CF ３ , -OCF ３ or ​ 302. The compound of any one of claims 2 to 2 or 4 to 75, or a pharmaceutically acceptable salt thereof, selected from:

77. Z is -OR ４ , -N(R ４ ) ２ , -SR ４ 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

78. Z is -OR ４ , -N(R ４ ) ２ , -SR ４ and at least one R of Z ４ but 【Chemistry 30】 302. The compound of any one of claims 2 or 4 to 74 or 77, or a pharmaceutically acceptable salt thereof, selected from:

79. Z is -OR ４ or -SR ４ and Z's R ４ but 【Chemical 31】 302. The compound of any one of claims 2 to 2, 4 to 74, or 77 to 78, or a pharmaceutically acceptable salt thereof.

80. Z is 【Chemical 32】 302. The compound of any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, selected from:

81. Z is 【Chemical 33】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

82. Z is 【Chemical 34】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

83. Z is 【Chemistry 35】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

84. Z is 【Chemical 36】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

85. Z is 【Chemical 37】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

86. Z is 【Chemical Formula 38】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

87. Z is 【Chemical 39】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

88. Z is 【Chemistry 40】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

89. Z is 【Chemistry 41】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

90. Z is 【Chemistry 42】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

91. Z is 【Chemistry 43】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

92. Z is 【Chemical 44】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

93. Z is 【Chemistry 45】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

94. Z is 【Chemistry 46】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

95. Z is 【Chemistry 47】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

96. Z is 【Chemistry 48】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

97. Z is 【Chemistry 49】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

98. Z is 【Chemistry 50】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

99. Z is 【Chemistry 51】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

100. Z is 【Chemistry 52】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

101. Z is 【Chemistry 53】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

102. Z is 【Chemical 54】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

103. Z is 【Chemistry 55】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

104. Z is 【Chemical Formula 56】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

105. Z is 【Chemical 57】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

106. Z is 【Chemistry 58】 302. The compound of any one of claims 2 to 4, or 4 to 74, wherein:

107. R １ or R ３ is substituted with halogen, or a pharmaceutically acceptable salt thereof.

108. R １ or R ３ is substituted with chlorine, or a pharmaceutically acceptable salt thereof.

109. R １ or R ３ is substituted with fluorine, or a pharmaceutically acceptable salt thereof.

110. R １ or R ３ But C １ -C ４ 110. The compound of any one of claims 302 to 109, or a pharmaceutically acceptable salt thereof, which is substituted with heteroalkyl.

111. At least one R in Z ４ but, 【Chemical 59】 111. The compound of any one of claims 302 to 110, or a pharmaceutically acceptable salt thereof, selected from:

112. 112. The compound of any one of claims 1 to 111, or a pharmaceutically acceptable salt thereof, which selectively modulates FSH and does not substantially modulate thyroid stimulating hormone (TSH) following administration of the compound to a subject.

113. 113. The compound of any one of claims 1 to 112, or a pharmaceutically acceptable salt thereof, which is an FSH agonist.

114. 114. The compound of any one of claims 1 to 113, or a pharmaceutically acceptable salt thereof, which is at least 3-fold selective for FSH over TSH (e.g., at least 3-fold, 5-fold, 10-fold, 20-fold, 50-fold, or 100-fold).

115. ECs in vitro or in vivo in response to FSH agonism ５０ is about 100 nM or less (e.g., 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, or 500 pM or less), or a pharmaceutically acceptable salt thereof.

116. Compound 1-01, compound 1-02A, compound 1-02, compound 1-03, compound 1-04, compound 1-05, compound 1-06, compound 2-01, compound 2-02, compound 2-03, compound 2-04, compound 2-05, compound 2-06, compound 2-07, compound 2-08, compound 3-01, compound 3-02, compound 3-03, compound 3-04, compound 3-07, compound 3-08, compound 3-09, compound 3-10A, compound 3-10, compound 3-11, compound 3-12, compound 4-01A, compound 4-01, compound 4-02A, compound 4-02, compound 4- 03A, compound 4-03, compound 4-04A, compound 4-04, compound 4-05A, compound 4-05, compound 4-06A, compound 4-06, compound 4-07A, compound 4-07, compound 4-08A, compound 4-08, compound 5-01, compound 5-02, compound 5-03, compound 5-04, compound 5-05, compound 5-06, compound 5-07, compound 5-08, compound 6-01A, compound 6-01B, compound 6-01, compound 6-02A, compound 6-02B, compound 6-02, compound 6-03, compound 6-04, compound 6-05, compound 6-06, compound 6- 07, compound 6-08, compound 8-01, compound 8-02, compound 8-03, compound 8-05, compound 8-06, compound 8-07A, compound 8-07, compound 8-09, compound 8-10, compound 8-14, compound 8-15, compound 8-16B, compound 8-16, compound 8-17, compound 8-20, compound 8-21, compound 8-22, compound 8-23, compound 8-24, compound 8-25, compound 8-26A, compound 8-26, compound 8-27, compound 8-28, compound 8-29, compound 8-30, compound 8-31, compound 8-32, compound 8-33, compound 8 -34, compound 8-39, compound 8-44, compound 8-77, compound 8-75, compound 8-76, compound 8-78, compound 8-81, compound 8-61, compound 8-60, compound 8-63, compound 8-58, compound 8-51, compound 8-67, compound 8-74, compound 8-4, compound 8-8, compound 8-4a, compound 8-13, compound 8-57, compound 8-18, compound 8-35, compound 8-36, compound 8-37, compound 8-38, compound 8-41, compound 8-42, compound 8-43, compound 8-45, compound 8-46, compound 8-47, compound 8-49,Compound 8-50, Compound 8-52A, Compound 8-54A, Compound 8-55, Compound 8-56, Compound 8-62, Compound 8-64, Compound 8-65, Compound 8-69, Compound 8-70, Compound 8-71, Compound 8-79, Compound 8-82, Compound 8 -83, Compound 8-84, Compound 8-86, Compound 8-87, Compound 8-89, Compound 9-13, Compound 9-21, Compound 9-4, Compound 9-5, Compound 9-11, Compound 9-14, Compound 9-9, Compound 9-15, Compound 9-2, Compound 9-7 , Compound 9-12, Compound 9-16, Compound 9-17, Compound 9-18, Compound 9-19, Compound 9-20, Compound 10-1, Compound 10-2, Compound 10-3, Compound 10-6, Compound 10-7, Compound 10-8, Compound 10-9, Compound 10 -10, Compound 11-1A, Compound 11-2, Compound 11-1, Compound 11-3, Compound 12-2, Compound 12-23, Compound 12-13, Compound 12-15, Compound 12-16, Compound 12-1, Compound 12-4, Compound 12-18, Compound 1 2-19, compound 13-1, compound 13-4, compound 13-9, compound 13-7, compound 13-8, compound 13-2, compound 13-5, compound 15-1, compound 15-3, compound 15-4, compound 15-5, compound 15-9, compound 15-2, compound Compound 15-6, Compound 15-10, Compound 12-05, Compound 12-07, Compound 12-11, Compound 12-12, Compound 14-03, Compound 15-08, Compound 15-10, Compound 3-05, Compound 3-06, Compound 4-03B, Compound 8-0 4A, Compound 8-16A, Compound 8-23A, Compound 8-25A, Compound 8-26B, Compound 8-31A, Compound 8-33A, Compound 8-44, Compound 8-66, Compound 8-72, Compound 8-90, Compound 8-90A, Compound 9-01, Compound 9-03, Compound 9-06, Compound 9-08, Compound 9-08A, Compound 9-10, Compound 9-19A, and Compound 9-24, or a pharmaceutically acceptable salt thereof.

117. 117. A method of treating a disease or disorder, comprising administering to a subject in need thereof a compound of any one of claims 1 to 116.

118. 118. The method of claim 117, wherein the disease or condition is polycystic ovary syndrome (PCOS).

119. 118. The method of claim 117, wherein the disease or condition is Turner syndrome.

120. 118. The method of claim 117, wherein the disease or condition is Klinefelter's syndrome.

121. 118. The method of claim 117, wherein the disease or condition is premature ovarian insufficiency (POI).

122. 118. The method of claim 117, wherein the disease or condition is a fertility disorder or male hypogonadism.

123. 117. A pharmaceutical composition comprising a compound of any one of claims 1 to 116, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient or carrier.

124. A pharmaceutically acceptable lipid nanoparticle formulation comprising a compound according to any one of claims 1 to 116 or a pharmaceutically acceptable composition according to claim 123.

125. 123. A method of treating a disease or disorder, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 116, a pharmaceutical composition according to claim 123, a pharmaceutically acceptable lipid nanoparticle formulation according to claim 124, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

126. 124. Use of a compound according to any one of claims 1 to 116, a pharmaceutical composition according to claim 123, a pharmaceutically acceptable lipid nanoparticle formulation according to claim 124, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder.

127. a. a compound according to any one of claims 1 to 116, a pharmaceutical composition according to claim 123, a pharmaceutically acceptable lipid nanoparticle formulation according to claim 124, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; b. Instructions for use Kit including:

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