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 novel FSH modulator compounds.

Description

[0001] Cross-reference

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 401,441, filed Aug. 26, 2022, and U.S. Provisional Application No. 63 / 522,983, filed Jun. 23, 2023, each of which is hereby incorporated by reference in its entirety. Background of the Invention

[0003] Glycoprotein hormones (such as gonadotropins and / or TSH) play important roles in a variety of bodily functions including metabolism, thermoregulation, and reproductive processes. Gonadotropins act on specific gonadal cell types to initiate ovarian and testicular differentiation and steroidogenesis. Follicle-stimulating hormone (FSH), a gonadotropin, is released from the anterior pituitary under the influence of gonadotropin-releasing hormone and estrogen and is also released from the placenta during pregnancy. FSH is a heterodimeric glycoprotein hormone that shares structural similarities with both luteinizing hormone (LH), which is also produced in the pituitary, and thyroid-stimulating hormone (TSH), as well as chorionic gonadotropin (CG), which is produced in the placenta. In females, FSH plays a key role in stimulating follicular development and maturation. In addition, it is the primary hormone regulating estrogen synthesis, while LH induces ovulation. In males, FSH is responsible for the integrity of the seminiferous tubules and acts on Sertoli cells to support gametogenesis.

[0004] These hormones are relatively large (28 - 38 kDa) and consist of a common α subunit non-covalently associated with a unique β subunit that confers receptor-binding specificity. The cellular receptors for these hormones are expressed on testicular Sertoli cells and ovarian granulosa cells. The FSH receptor is known to be a member of the membrane-bound receptor class of G-protein coupled receptors, which upon activation stimulates an increase in adenylate cyclase activity. This results in an increase in the level of the intracellular second messenger adenosine 3’,5’-monophosphate (cAMP), which in turn leads to an increase in steroid synthesis and secretion. Recent studies on the FSH receptor have shown that intracellular signaling is not limited to the classical Gs-mediated adenylate cyclase (cAMP), but also includes Gi, Gq proteins, and changes in intracellular calcium, as well as serine / threonine kinases (such as MAPK, Akt). Hydrophilicity plots of the amino acid sequences of these receptors reveal three common domains: a hydrophilic amino-terminal region, regarded as the amino-terminal extracellular domain, which includes a hinge domain that serves as a tethered inverse agonist; a hydrophobic segment of seven transmembrane lengths, regarded as the transmembrane domain; and a carboxyl-terminal region containing potential phosphorylation sites (serine, threonine, and tyrosine residues), regarded as the carboxyl-terminal intracellular or cytoplasmic domain. The glycoprotein hormone receptor family differs from other G-protein coupled receptors (such as the β-2 adrenergic receptor, rhodopsin receptor, and substance K receptor) in that its hydrophilic amino-terminal domain involved in hormone binding is larger.

[0005] In the United States, millions of infertile couples seek treatment each year. FSH, extracted from urine or produced by recombinant DNA technology, is a parenterally administered protein product used by specialists to induce ovulation and control ovarian hyperstimulation. The aim of inducing ovulation is to achieve single follicle ovulation, while the aim of controlling ovarian hyperstimulation is to harvest multiple oocytes for use in various in vitro assisted reproductive techniques, such as in vitro fertilization (IVF). FSH is also used clinically to treat male hypogonadism and male non-obstructive infertility, such as some types of spermatogenic disorders.

[0006] The FSHR is a highly specific target during follicular growth and is expressed only in the ovary. 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 a non-peptide small molecule FSH substitute that can be developed for oral administration. There remains a need for low molecular weight hormone mimics that selectively modulate the FSHR. SUMMARY OF THE INVENTION

[0007] In one aspect, the present disclosure describes FSH modulator compounds of formula (I):

[0008]

[0009] or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, R 1 is an unsubstituted or C1-C 5 alkyl substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; an unsubstituted or C1-C 5 alkenyl substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; an unsubstituted or C3-C 5 heteroaryl substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; an unsubstituted or C6 aryl substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; an unsubstituted or C3-C8 cycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; an unsubstituted or C3-C8 cycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; an unsubstituted or C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; a heterocycloalkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; a heterocycloalkenyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; a heterocycloalkynyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; or an unsubstituted or C1-C 5 alkynyl substituted with 1, 2, 3, 4, or 5 groups selected from R 16 .

[0011] In some embodiments, Y is -OC(R 4 )2-.

[0012] In some embodiments, Z is -OR 4 ; -N(R 4 )2; -SR 4 ; -CF3; -OCF3; -OH; an unsubstituted or C1-C 5 heteroalkyl substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; an unsubstituted or C1-C 5 alkyl substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; an unsubstituted or C1-C 5 alkenyl substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; an unsubstituted or C3-C8 cycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; an unsubstituted or C3-C8 cycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from R5 a C3-C8 cycloalkenyl group substituted with a group; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 a C3-C8 cycloalkynyl group substituted with a group; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 a heterocycloalkyl group substituted with a group; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 a heterocycloalkenyl group substituted with a group; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 a heterocycloalkynyl group substituted with a group; or unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 a C3-C 16 alkynyl group.

[0013] In some embodiments, R 2 is -CF3, -OCF3 or -OCH2CH3.

[0014] In some embodiments, R 3 is hydrogen; halogen; -CF3; -OCF3; -OH; a C1-C 5 heteroalkyl group unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 16 a C1-C 5 alkyl group unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 16 a C1-C 5 alkenyl group unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 16 a C3-C 5 heteroaryl group unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 16 a C6 aryl group unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 a C3-C8 cycloalkyl group unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 a C3-C8 cycloalkenyl group unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 a C3-C8 cycloalkynyl group unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 a heterocycloalkyl group unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 a heterocycloalkenyl group unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 a heterocycloalkynyl group unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 or a C1-C 5 alkynyl group unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 16 alkynyl group.

[0015] In some embodiments, each R 4 is independently hydrogen; a halogen; -CF3; -OCF3; -OH; C1-C 5 heteroalkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; C1-C 5 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; C1-C 5 alkenyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; C3-C 5 heteroaryl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; C6 aryl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; C3-C8 cycloalkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; C3-C8 cycloalkenyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; C3-C8 cycloalkynyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; heterocycloalkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; heterocycloalkenyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; heterocycloalkynyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; or C1-C 5 alkynyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 16 .

[0016] In some embodiments, each R 5 is independently deuterium, a 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)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.

[0017] In some embodiments, each R 6 is 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.

[0018] 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 -.

[0019] In some embodiments, Z is -OR 4 ; -N(R 4 )2; -SR 4 ; -CF3; -OCF3; -OH; C1-C 5 heteroalkyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkenyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 16 ; C3-C8 cycloalkyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkenyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ;5 a C3-C8 cycloalkynyl group substituted with a group; an unsubstituted or 1-, 2-, 3-, 4- or 5-substituted heterocycloalkyl group selected from R 5 ; an unsubstituted or 1-, 2-, 3-, 4- or 5-substituted heterocycloalkenyl group selected from R 5 ; an unsubstituted or 1-, 2-, 3-, 4- or 5-substituted heterocycloalkynyl group selected from R 5 ; or an unsubstituted or 1-, 2-, 3-, 4- or 5-substituted C3-C 5 alkynyl group. 16

[0020] In some embodiments, R 2 is -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -CF3, -OCF 3、 -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R or -N(R)2;

[0021] 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 -.

[0022] In some embodiments, R is hydrogen; halogen; -CF3; -OCF3; -OH; an unsubstituted or 1-, 2-, 3-, 4- or 5-substituted C1-C 5 heteroalkyl group selected from R 16 ; an unsubstituted or 1-, 2-, 3-, 4- or 5-substituted C1-C 5 alkyl group selected from R 16 ; an unsubstituted or 1-, 2-, 3-, 4- or 5-substituted C1-C 5 alkenyl group selected from R 16 ; an unsubstituted or 1-, 2-, 3-, 4- or 5-substituted C3-C 5 heteroaryl group selected from R 16 ; an unsubstituted or 1-, 2-, 3-, 4- or 5-substituted C1-C 5 ​a C6 aryl group substituted with a group; an unsubstituted or C3-C8 cycloalkyl group substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; an unsubstituted or C3-C8 cycloalkenyl group substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; an unsubstituted or C3-C8 cycloalkynyl group substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkyl group substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkenyl group substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkynyl group substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; or an unsubstituted or C1-C 5 alkynyl group substituted with 1, 2, 3, 4 or 5 groups selected from R 16 .

[0023] In some embodiments, Z is -O-tert-butyl.

[0024] In some embodiments, R 3 is an unsubstituted or C3-C 5 heteroaryl group substituted with 1, 2, 3, 4 or 5 groups selected from R 16 ; an unsubstituted or C6 aryl group substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; an unsubstituted or C3-C8 cycloalkyl group substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; an unsubstituted or C3-C8 cycloalkenyl group substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; an unsubstituted or C3-C8 cycloalkynyl group substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkyl group substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkenyl group substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; or a heterocycloalkynyl group substituted with 1, 2, 3, 4 or 5 groups selected from R 5 .

[0025] In some embodiments, R 3 is an unsubstituted or C3-C 5 heteroaryl group substituted with 1, 2, 3, 4 or 5 groups selected from R 16 .

[0026] In some embodiments, R 3 is selected from

[0027]

[0028]

[0029]

[0030] and their substituents.

[0031] In some embodiments, R 3 is selected from

[0032] and their substituents.

[0033] In some embodiments, R 3 is selected from

[0034] In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is

[0035] In some embodiments, R 3 is

[0036] In some embodiments, R 3 is

[0037] In some embodiments, R 2 is -halogen, -OR, -SR, -CN, -NO2, -CF3, -OCF3 or -C(=O)CH3.

[0038] In some embodiments, R 2is -OCH3, -SCH3, -CN, -NO2, -CF3 or -OCF3.

[0039] In some embodiments, R 2 is -OCH3, -SCH3 or -OCF3.

[0040] In some embodiments, R 2 is -SCH3.

[0041] In some embodiments, R 2 is -OCF3.

[0042] In some embodiments, R 2 is -CF3.

[0043] In some embodiments, R 2 is -OCH2CH3.

[0044] In some embodiments, R 2 is -OCH3.

[0045] In some embodiments, R 1 is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 of C3-C 16 heteroaryl; unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 of C6 aryl; unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 of C3-C8 cycloalkyl; unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 of C3-C8 cycloalkenyl; unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 of C3-C8 cycloalkynyl; unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 of heterocycloalkyl; unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 of heterocycloalkenyl; or unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 of heterocycloalkynyl.

[0046] In some embodiments, R 1 is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 of C6 aryl.

[0047] In some embodiments, R 1 is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 of C3-C 16 heteroaryl.

[0048] In some embodiments, R 1 is selected from

[0049]

[0050]

[0051]

[0052] and their substituents.

[0053] In some embodiments, R 1 is selected from

[0054] and their substituents.

[0055] In some embodiments, R 1 is

[0056] In some embodiments, R 1 is

[0057] In some embodiments, R 1 is

[0058] In some embodiments, R 1 is

[0059] In some embodiments, wherein R 1 is

[0060] In some embodiments, R 1 is

[0061] In some embodiments, R 1 is

[0062] In some embodiments, R 1 is

[0063] In some embodiments, R 1 is

[0064] In some embodiments, R 1 is

[0065] 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 -;

[0066] 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 )2-.

[0067] In some embodiments, Y is -O-, -S-, -NH-, -OCH2-, -SCH2-, -CH2O-, -CH2S-, -CH2-.

[0068] In some embodiments, Y is -O-.

[0069] In some embodiments, Y is -S-.

[0070] In some embodiments, Y is -S(=O)-.

[0071] In some embodiments, Y is -S(=O)2-.

[0072] In some embodiments, Y is -S(=O)C(R 4 )2-.

[0073] In some embodiments, Y is -C(R 4 )2S(=O)-.

[0074] In some embodiments, Y is -S(=O)2C(R 4 )2-.

[0075] In some embodiments, Y is -C(R 4 )2S(=O)2-.

[0076] In some embodiments, Y is -S(=O)CH2-.

[0077] In some embodiments, Y is -CH2S(=O)-.

[0078] In some embodiments, Y is -S(=O)2CH2-.

[0079] In some embodiments, Y is -CH2S(=O)2-.

[0080] In some embodiments, Y is -NR 4 -.

[0081] In some embodiments, Y is -OC(R 4 )2-.

[0082] In some embodiments, Y is -SC(R 4 )2-.

[0083] In some embodiments, Y is -C(R 4 )2O-.

[0084] In some embodiments, Y is -C(R 4 )2S-.

[0085] In some embodiments, Y is -C(R 4 )2NR 4 -.

[0086] In some embodiments, Y is -C(R 4 )2-.

[0087] In some embodiments, Y is -C(R 4 )2-C(R 4 )2-.

[0088] In some embodiments, Y is -CR 4 =CR 4 -;

[0089] 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 4 -. In some embodiments, Y is -CH2-. In some embodiments, Y is -CH2-CH2-. In some embodiments, Y is -CH=CH-.

[0090] In some embodiments, Z is -OR 4 ;-N(R 4 )2;-SR 4; -CF3; -OCF3; -OH; C3-C8 cycloalkyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkenyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkynyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkenyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or heterocycloalkynyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 .

[0091] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4 , -CF3, -OCF3, or selected from

[0092] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4 .

[0093] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4 , and at least one R of Z 4 is selected from

[0094]

[0095] In some embodiments, Z is -OR 4 or -SR 4 , and the R of Z 4 is

[0096]

[0097] In some embodiments, Z is selected from

[0098]

[0099] In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is

[0100] In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is

[0101] In some embodiments, Z is

[0102] In some embodiments, R 1 or R 3 is substituted with a halogen.

[0103] In some embodiments, R 1 or R 3 is substituted with chlorine.

[0104] In some embodiments, R 1 or R 3 is substituted with fluorine.

[0105] In some embodiments, R 1 or R 3 is substituted with C1-C4 heteroalkyl.

[0106] In some embodiments, at least one R within Z 4 is selected from

[0107] In some embodiments, the FSH modulators disclosed herein have a structure selected from the following: 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, and Compound 8-44.

[0108] In some embodiments, the FSH modulators disclosed herein have a structure selected from the following: 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 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,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.

[0109] In another aspect, methods of modulating FSH using the compounds described herein are described. In some embodiments, the compounds described herein selectively modulate FSH and substantially do not modulate TSH. In some embodiments, the method comprises administering to a subject a compound described herein. In some embodiments, the compound described herein is an FSH agonist. In some embodiments, the selectivity of the compound described herein for FSH is at least 3-fold that of TSH (e.g., at least 3, 5, 10, 20, 50, or 100-fold). In some embodiments, the in vitro or in vivo EC of FSH activation 50 is not more than about 100 nM (e.g., not more than 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, or 500 pM).

[0110] In some embodiments, the methods described herein comprise treating a disease or condition, comprising administering to a subject in need thereof a compound described herein. 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, gastric cancer, testicular cancer, or ovarian cancer. In some embodiments, the disease or condition is a cardiovascular condition. In some embodiments, the cardiovascular condition 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 primary ovarian insufficiency (POI).

[0111] In some embodiments, the disease or condition is polycystic ovary syndrome (PCOS).

[0112] In some embodiments, the disease or condition is Turner syndrome.

[0113] In some embodiments, the disease or condition is Klinefelter syndrome.

[0114] In some embodiments, the disease or condition is primary ovarian insufficiency (POI).

[0115] In another aspect, the present disclosure describes a pharmaceutical composition comprising any of the compounds described herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient or carrier.

[0116] In another aspect, the present disclosure describes a pharmaceutically acceptable lipid nanoparticle formulation comprising a compound described herein.

[0117] In some embodiments, the method comprises treating a condition or disease, including administering to a subject in need thereof a compound described herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

[0118] In some embodiments, the method comprises the use of a compound described herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for treating a condition or disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0119] The novel features of the present disclosure are set forth with particularity in the appended claims. The features and advantages of the present disclosure will be better understood from the following detailed description, which illustrates exemplary embodiments that utilize the principles of the present disclosure, and the accompanying drawings, in which:

[0120] Figure 1 The nuclear magnetic resonance of Compound 1-01 is shown.

[0121] Figure 2 The nuclear magnetic resonance of Compound 1-02A is shown.

[0122] Figure 3 The nuclear magnetic resonance of Compound 1-02 is shown.

[0123] Figure 4 The nuclear magnetic resonance of Compound 1-03 is shown.

[0124] Figure 5 The nuclear magnetic resonance of Compound 1-04 is shown.

[0125] Figure 6 The nuclear magnetic resonance of Compound 1-05 is shown.

[0126] Figure 7 The nuclear magnetic resonance of Compound 1-06 is shown.

[0127] Figure 8 The nuclear magnetic resonance of Compound 2-01 is shown.

[0128] Figure 9 The nuclear magnetic resonance of Compound 2-02 is shown.

[0129] Figure 10 The nuclear magnetic resonance of Compound 2-03 is shown.

[0130] Figure 11 Show the nuclear magnetic resonance of compound 2-04.

[0131] Figure 12 Show the nuclear magnetic resonance of compound 2-05.

[0132] Figure 13 Show the nuclear magnetic resonance of compound 2-06.

[0133] Figure 14 Show the nuclear magnetic resonance of compound 2-07.

[0134] Figure 15 Show the nuclear magnetic resonance of compound 2-08.

[0135] Figure 16 Show the nuclear magnetic resonance of compound 3-01.

[0136] Figure 17 Show the nuclear magnetic resonance of compound 3-02.

[0137] Figure 18 Show the nuclear magnetic resonance of compound 3-03.

[0138] Figure 19 Show the nuclear magnetic resonance of compound 3-04.

[0139] Figure 20 Show the nuclear magnetic resonance of compound 3-07.

[0140] Figure 21 Show the nuclear magnetic resonance of compound 3-08.

[0141] Figure 22 Show the nuclear magnetic resonance of compound 3-09.

[0142] Figure 23 Show the nuclear magnetic resonance of compound 3-10A.

[0143] Figure 24 Show the nuclear magnetic resonance of compound 3-10.

[0144] Figure 25 Show the nuclear magnetic resonance of compound 3-11.

[0145] Figure 26 Show the nuclear magnetic resonance of compound 3-12.

[0146] Figure 27 Show the nuclear magnetic resonance of compound 4-01A.

[0147] Figure 28 Show the nuclear magnetic resonance of compound 4-01.

[0148] Figure 29Shows the nuclear magnetic resonance of compound 4-02A.

[0149] Figure 30 Shows the nuclear magnetic resonance of compound 4-02.

[0150] Figure 31 Shows the nuclear magnetic resonance of compound 4-03A.

[0151] Figure 32 Shows the nuclear magnetic resonance of compound 4-03.

[0152] Figure 33 Shows the nuclear magnetic resonance of compound 4-04A.

[0153] Figure 34 Shows the nuclear magnetic resonance of compound 4-04.

[0154] Figure 35 Shows the nuclear magnetic resonance of compound 4-05A.

[0155] Figure 36 Shows the nuclear magnetic resonance of compound 4-05.

[0156] Figure 37 Shows the nuclear magnetic resonance of compound 4-06A.

[0157] Figure 38 Shows the nuclear magnetic resonance of compound 4-06.

[0158] Figure 39 Shows the nuclear magnetic resonance of compound 4-07A.

[0159] Figure 40 Shows the nuclear magnetic resonance of compound 4-07.

[0160] Figure 41 Shows the nuclear magnetic resonance of compound 4-08A.

[0161] Figure 42 Shows the nuclear magnetic resonance of compound 4-08.

[0162] Figure 43 Shows the nuclear magnetic resonance of compound 5-01.

[0163] Figure 44 Shows the nuclear magnetic resonance of compound 5-02.

[0164] Figure 45 Shows the nuclear magnetic resonance of compound 5-03.

[0165] Figure 46 Shows the nuclear magnetic resonance of compound 5-04.

[0166] Figure 47 Shows the nuclear magnetic resonance of compound 5-05.

[0167] Figure 48 Shows the nuclear magnetic resonance of compound 5-06.

[0168] Figure 49 Shows the nuclear magnetic resonance of compound 5-07.

[0169] Figure 50 Shows the nuclear magnetic resonance of compound 5-08.

[0170] Figure 51 Shows the nuclear magnetic resonance of compound 6-01A.

[0171] Figure 52 Shows the nuclear magnetic resonance of compound 6-01B.

[0172] Figure 53 Shows the nuclear magnetic resonance of compound 6-01.

[0173] Figure 54 Shows the nuclear magnetic resonance of compound 6-02A.

[0174] Figure 55 Shows the nuclear magnetic resonance of compound 6-02B.

[0175] Figure 56 Shows the nuclear magnetic resonance of compound 6-02.

[0176] Figure 57 Shows the nuclear magnetic resonance of compound 6-03.

[0177] Figure 58 Shows the nuclear magnetic resonance of compound 6-04.

[0178] Figure 59 Shows the nuclear magnetic resonance of compound 6-05.

[0179] Figure 60 Shows the nuclear magnetic resonance of compound 6-06.

[0180] Figure 61 Shows the nuclear magnetic resonance of compound 6-07.

[0181] Figure 62 Shows the nuclear magnetic resonance of compound 6-08.

[0182] Figure 63 Shows the nuclear magnetic resonance of compound 8-01.

[0183] Figure 64 Shows the nuclear magnetic resonance of compound 8-02.

[0184] Figure 65 Shows the nuclear magnetic resonance of compound 8-03.

[0185] Figure 66 The nuclear magnetic resonance of compound 8-05 is shown.

[0186] Figure 67 The nuclear magnetic resonance of compound 8-06 is shown.

[0187] Figure 68 The nuclear magnetic resonance of compound 8-07A is shown.

[0188] Figure 69 The nuclear magnetic resonance of compound 8-07 is shown.

[0189] Figure 70 The nuclear magnetic resonance of compound 8-09 is shown.

[0190] Figure 71 The nuclear magnetic resonance of compound 8-10 is shown.

[0191] Figure 72 The nuclear magnetic resonance of compound 8-14 is shown.

[0192] Figure 73 The nuclear magnetic resonance of compound 8-15 is shown.

[0193] Figure 74 The nuclear magnetic resonance of compound 8-16B is shown.

[0194] Figure 75 The nuclear magnetic resonance of compound 8-16 is shown.

[0195] Figure 76 The nuclear magnetic resonance of compound 8-17 is shown.

[0196] Figure 77 The nuclear magnetic resonance of compound 8-20 is shown.

[0197] Figure 78 The nuclear magnetic resonance of compound 8-21 is shown.

[0198] Figure 79 The nuclear magnetic resonance of compound 8-22 is shown.

[0199] Figure 80 The nuclear magnetic resonance of compound 8-23 is shown.

[0200] Figure 81 The nuclear magnetic resonance of compound 8-24 is shown.

[0201] Figure 82 The nuclear magnetic resonance of compound 8-25 is shown.

[0202] Figure 83 The nuclear magnetic resonance of compound 8-26A is shown.

[0203] Figure 84 The nuclear magnetic resonance of compound 8-26 is shown.

[0204] Figure 85 Shows the nuclear magnetic resonance of compound 8-27.

[0205] Figure 86 Shows the nuclear magnetic resonance of compound 8-28.

[0206] Figure 87 Shows the nuclear magnetic resonance of compound 8-29.

[0207] Figure 88 Shows the nuclear magnetic resonance of compound 8-30.

[0208] Figure 89 Shows the nuclear magnetic resonance of compound 8-31.

[0209] Figure 90 Shows the nuclear magnetic resonance of compound 8-32.

[0210] Figure 91 Shows the nuclear magnetic resonance of compound 8-33.

[0211] Figure 92 Shows the nuclear magnetic resonance of compound 8-34.

[0212] Figure 93 Shows the nuclear magnetic resonance of compound 8-39.

[0213] Figure 94 Shows the nuclear magnetic resonance of compound 8-44.

[0214] Figure 95 Shows the nuclear magnetic resonance of compound 8-77.

[0215] Figure 96 Shows the nuclear magnetic resonance of compound 8-75.

[0216] Figure 97 Shows the nuclear magnetic resonance of compound 8-76.

[0217] Figure 98 Shows the nuclear magnetic resonance of compound 8-78.

[0218] Figure 99 Shows the nuclear magnetic resonance of compound 8-81.

[0219] Figure 100 Shows the nuclear magnetic resonance of compound 8-61.

[0220] Figure 101 Shows the nuclear magnetic resonance of compound 8-60.

[0221] Figure 102 Shows the nuclear magnetic resonance of compound 8-63.

[0222] Figure 103 The nuclear magnetic resonance of compound 8-58 is shown.

[0223] Figure 104 The nuclear magnetic resonance of compound 8-51 is shown.

[0224] Figure 105 The nuclear magnetic resonance of compound 8-67 is shown.

[0225] Figure 106 The nuclear magnetic resonance of compound 8-74 is shown.

[0226] Figure 107 The nuclear magnetic resonance of compound 8-4 is shown.

[0227] Figure 108 The nuclear magnetic resonance of compound 8-8 is shown.

[0228] Figure 109 The nuclear magnetic resonance of compound 8-4a is shown.

[0229] Figure 110 The nuclear magnetic resonance of compound 8-13 is shown.

[0230] Figure 111 The nuclear magnetic resonance of compound 8-57 is shown.

[0231] Figure 112 The nuclear magnetic resonance of compound 8-18 is shown.

[0232] Figure 113 The nuclear magnetic resonance of compound 8-35 is shown.

[0233] Figure 114 The nuclear magnetic resonance of compound 8-36 is shown.

[0234] Figure 115 The nuclear magnetic resonance of compound 8-37 is shown.

[0235] Figure 116 The nuclear magnetic resonance of compound 8-38 is shown.

[0236] Figure 117 The nuclear magnetic resonance of compound 8-41 is shown.

[0237] Figure 118 The nuclear magnetic resonance of compound 8-42 is shown.

[0238] Figure 119 The nuclear magnetic resonance of compound 8-43 is shown.

[0239] Figure 120 The nuclear magnetic resonance of compound 8-45 is shown.

[0240] Figure 121 The nuclear magnetic resonance of compound 8-46 is shown.

[0241] Figure 122 Shows the nuclear magnetic resonance of compound 8-47.

[0242] Figure 123 Shows the nuclear magnetic resonance of compound 8-49.

[0243] Figure 124 Shows the nuclear magnetic resonance of compound 8-50.

[0244] Figure 125 Shows the nuclear magnetic resonance of compound 8-52A.

[0245] Figure 126 Shows the nuclear magnetic resonance of compound 8-54A.

[0246] Figure 127 Shows the nuclear magnetic resonance of compound 8-55.

[0247] Figure 128 Shows the nuclear magnetic resonance of compound 8-56.

[0248] Figure 129 Shows the nuclear magnetic resonance of compound 8-62.

[0249] Figure 130 Shows the nuclear magnetic resonance of compound 8-64.

[0250] Figure 131 Shows the nuclear magnetic resonance of compound 8-65.

[0251] Figure 132 Shows the nuclear magnetic resonance of compound 8-69.

[0252] Figure 133 Shows the nuclear magnetic resonance of compound 8-70.

[0253] Figure 134 Shows the nuclear magnetic resonance of compound 8-71.

[0254] Figure 135 Shows the nuclear magnetic resonance of compound 8-79.

[0255] Figure 136 Shows the nuclear magnetic resonance of compound 8-82.

[0256] Figure 137 Shows the nuclear magnetic resonance of compound 8-83.

[0257] Figure 138 Shows the nuclear magnetic resonance of compound 8-84.

[0258] Figure 139 Shows the nuclear magnetic resonance of compound 8-86.

[0259] Figure 140 Nuclear magnetic resonance of compound 8-87 is shown.

[0260] Figure 141 Nuclear magnetic resonance of compound 8-89 is shown.

[0261] Figure 142 Nuclear magnetic resonance of compound 9-13 is shown.

[0262] Figure 143 Nuclear magnetic resonance of compound 9-21 is shown.

[0263] Figure 144 Nuclear magnetic resonance of compound 9-4 is shown.

[0264] Figure 145 Nuclear magnetic resonance of compound 9-5 is shown.

[0265] Figure 146 Nuclear magnetic resonance of compound 9-11 is shown.

[0266] Figure 147 Nuclear magnetic resonance of compound 9-14 is shown.

[0267] Figure 148 Nuclear magnetic resonance of compound 9-9 is shown.

[0268] Figure 149 Nuclear magnetic resonance of compound 9-15 is shown.

[0269] Figure 150 Nuclear magnetic resonance of compound 9-2 is shown.

[0270] Figure 151 Nuclear magnetic resonance of compound 9-7 is shown.

[0271] Figure 152 Nuclear magnetic resonance of compound 9-12 is shown.

[0272] Figure 153 Nuclear magnetic resonance of compound 9-16 is shown.

[0273] Figure 154 Nuclear magnetic resonance of compound 9-17 is shown.

[0274] Figure 155 Nuclear magnetic resonance of compound 9-18 is shown.

[0275] Figure 156 Nuclear magnetic resonance of compound 9-19 is shown.

[0276] Figure 157 Nuclear magnetic resonance of compound 9-20 is shown.

[0277] Figure 158 Nuclear magnetic resonance of compound 10-1 is shown.

[0278] Figure 159 Show the nuclear magnetic resonance of Compound 10-2.

[0279] Figure 160 Show the nuclear magnetic resonance of Compound 10-3.

[0280] Figure 161 Show the nuclear magnetic resonance of Compound 10-6.

[0281] Figure 162 Show the nuclear magnetic resonance of Compound 10-7.

[0282] Figure 163 Show the nuclear magnetic resonance of Compound 10-8.

[0283] Figure 164 Show the nuclear magnetic resonance of Compound 10-9.

[0284] Figure 165 Show the nuclear magnetic resonance of Compound 10-10.

[0285] Figure 166 Show the nuclear magnetic resonance of Compound 11-1A.

[0286] Figure 167 Show the nuclear magnetic resonance of Compound 11-2.

[0287] Figure 168 Show the nuclear magnetic resonance of Compound 11-1.

[0288] Figure 169 Show the nuclear magnetic resonance of Compound 11-3.

[0289] Figure 170 Show the nuclear magnetic resonance of Compound 12-2.

[0290] Figure 171 Show the nuclear magnetic resonance of Compound 12-23.

[0291] Figure 172 Show the nuclear magnetic resonance of Compound 12-13.

[0292] Figure 173 Show the nuclear magnetic resonance of Compound 12-15.

[0293] Figure 174 Show the nuclear magnetic resonance of Compound 12-16.

[0294] Figure 175 Show the nuclear magnetic resonance of Compound 12-1.

[0295] Figure 176 Show the nuclear magnetic resonance of Compound 12-4.

[0296] Figure 177 The nuclear magnetic resonance of Compound 12-18 is shown.

[0297] Figure 178 The nuclear magnetic resonance of Compound 12-19 is shown.

[0298] Figure 179 The nuclear magnetic resonance of Compound 13-1 is shown.

[0299] Figure 180 The nuclear magnetic resonance of Compound 13-4 is shown.

[0300] Figure 181 The nuclear magnetic resonance of Compound 13-9 is shown.

[0301] Figure 182 The nuclear magnetic resonance of Compound 13-7 is shown.

[0302] Figure 183 The nuclear magnetic resonance of Compound 13-8 is shown.

[0303] Figure 184 The nuclear magnetic resonance of Compound 13-2 is shown.

[0304] Figure 185 The nuclear magnetic resonance of Compound 13-5 is shown.

[0305] Figure 186 The nuclear magnetic resonance of Compound 15-1 is shown.

[0306] Figure 187 The nuclear magnetic resonance of Compound 15-3 is shown.

[0307] Figure 188 The nuclear magnetic resonance of Compound 15-4 is shown.

[0308] Figure 189 The nuclear magnetic resonance of Compound 15-5 is shown.

[0309] Figure 190 The nuclear magnetic resonance of Compound 15-9 is shown.

[0310] Figure 191 The nuclear magnetic resonance of Compound 15-2 is shown.

[0311] Figure 192 The nuclear magnetic resonance of Compound 15-6 is shown.

[0312] Figure 193 The nuclear magnetic resonance of Compound 15-10 is shown. Detailed Description

[0313] Definitions

[0314] The terms used herein are for the purpose of describing particular circumstances only and are not intended to be limiting. In this application, unless otherwise specifically stated, the use of the singular includes the plural.

[0315] Unless the context clearly dictates otherwise herein, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents. It should also be noted that, unless the context clearly dictates otherwise herein, the term "or" is generally used in its inclusive sense, i.e., "and / or." In addition, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed disclosure.

[0316] Unless otherwise indicated, the abbreviations used herein have their conventional meanings within the chemical and biological arts. The chemical structures and chemical formulas listed herein are constructed according to the standard rules of chemical valence known in the chemical arts.

[0317] The symbol represents the point of attachment of the chemical moiety to the remainder of the molecule or chemical formula.

[0318] As used herein, the term "about" or "approximately" can mean within an acceptable error range of a particular value as determined by one of ordinary skill in the art, which can in part depend on how the value is measured or determined, i.e., the limitations of the measurement system. For example, in accordance with the practice in the art, "about" can mean within one standard deviation or more than one standard deviation. Alternatively, "about" can mean a range up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, especially with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold of a value. Where a particular value is described in this application and the claims, unless otherwise stated, it should be assumed that the term "about" means within an acceptable error range of the particular value.

[0319] As used herein, the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include"), or "containing" (and any form of containing, such as "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 in this specification can be implemented with respect to any method or composition of the present disclosure, and vice versa. In addition, the compositions of the present disclosure can be used to implement the methods of the present disclosure.

[0320] As used herein, the term "derivative" refers to a chemical or biological substance that is structurally related to a second substance and can be derived from the second substance by modification of the second substance. Specifically, if a first compound is a derivative of a second compound and the second compound is associated with chemical and / or biological activity, then 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" can include prodrugs, metabolites, enantiomers, diastereomers, esters (e.g., acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphates, sulfonates, sulfates, and disulfide-containing esters), ethers, amides, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary ammonium derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphates, metal salts, sulfonates, etc. In some cases, derivatives can include minor substitutions (i.e., additional alkyl / alkylene groups) of the parent compound that retain the chemical and / or biological activity of the parent compound.

[0321] As used herein, the term "pharmaceutically acceptable salt" generally refers to acid or base salts that are generally recognized in the art as being suitable for contact with the tissues of humans or animals without undue toxicity, irritation, allergic response, or other problems or complications. Such salts include inorganic and organic acid salts of basic residues (such as amines), and alkali metal 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, p-aminobenzenesulfonic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic 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 (such as acetic acid), HOOC-(CH2)n-COOH (where n is 0-4), and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. One of ordinary skill in the art will recognize from the present disclosure and the knowledge in the art that other pharmaceutically acceptable salts include those listed in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA, page 1418 (1985). Generally, pharmaceutically acceptable acid or base salts can be synthesized from the parent compound containing 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.

[0322] As used herein, the term "pharmaceutically acceptable excipient, carrier, or diluent" refers to an excipient, carrier, or diluent that can be administered with an agent to a subject without destroying its pharmacological activity and is non-toxic when administered in a dose sufficient to deliver a therapeutically effective amount of the agent.

[0323] As used herein, the term "therapeutically effective amount" refers to the amount of an agent (e.g., nucleic acid, drug, payload, composition, therapeutic agent, diagnostic agent, prophylactic agent, etc.) to be delivered that is sufficient to treat, diagnose, or prevent an infection, disease, disorder, and / or condition, improve its symptoms, and / or delay its onset when administered to a subject suffering from or susceptible to the infection, disease, disorder, and / or condition.

[0324] The ranges provided herein are to be understood as shorthand for all values within the range. For example, a range of 1 to 50 should be understood to include any number, combination of numbers, or sub-range within 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 intermediate decimal values between the above integers, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. For sub-ranges, "nested sub-ranges" extending from either endpoint of the range are specifically contemplated. For example, the nested sub-ranges of the exemplary range 1 to 50 may include, in one direction, 1 to 10, 1 to 20, 1 to 30, and 1 to 40, or in the other direction, 50 to 40, 50 to 30, 50 to 20, and 50 to 10.

[0325] As used herein, the term "subject" refers to an animal that is the subject of treatment, observation, or experiment. By way of example only, subjects include, but are not limited to, mammals, including but not limited to humans or non-human mammals, such as non-human primates, cows, horses, canines, sheep, or felines.

[0326] As used herein, the term "aromatic" generally refers to a planar ring having a delocalized π-electron system that contains 4n + 2 π electrons, where n is an integer. Aromatic compounds may be optionally substituted. The term "aromatic" includes aryl (e.g., phenyl, naphthyl) and heteroaryl (e.g., pyridyl, quinolinyl).

[0327] As used herein, the term "halo" or "halogen" generally refers to bromine, chlorine, fluorine, or iodine.

[0328] As used herein, the term "haloalkyl" generally refers to an alkyl group as defined above that is substituted with one or more halo groups 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 otherwise specifically stated in this specification, haloalkyl may be optionally substituted.

[0329] As used herein, the term "haloalkoxy" generally refers to an alkoxy group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, and the like. Unless otherwise specifically stated in this specification, haloalkoxy may be optionally substituted.

[0330] As used herein, the term "fluoroalkyl" generally refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine.

[0331] As used herein, the term "tautomer" generally refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. The compounds given herein may exist in the form of tautomers. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom accompanied by the conversion of a single bond and an adjacent double bond. In the bonding arrangements where tautomerization can occur, there may be a chemical equilibrium of tautomers. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Some examples of the interconversion of tautomers include:

[0332]

[0333] As used herein, the term "effective amount" or "therapeutically effective amount" generally refers to an amount of an agent or compound administered that will, to some extent, alleviate one or more symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein required to provide a clinically significant reduction of the symptoms of a disease. The appropriate "effective" amount in any individual case can be determined using techniques such as dose escalation studies. An "effective amount" is an amount sufficient to enable the compound to achieve a given purpose relative to the situation in which the compound is absent (e.g., achieve the effect of administration, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or alleviate one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or alleviation of one or more symptoms of a disease, and can also be referred to as a "therapeutically effective amount". "Alleviating" one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of a symptom, or eliminating the symptom. A "prophylactically effective amount" of a drug is an amount of the drug that, when administered to a subject, will have the desired prophylactic effect, e.g., prevent or delay the onset (or recurrence) of an injury, disease, pathology, or condition, or reduce the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition or its symptoms. A complete prophylactic effect does not necessarily occur upon administration of a single dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount can be administered in one or more administrations. As used herein, a "reducing amount of activity" refers to the amount of an antagonist required to reduce enzyme activity relative to the situation in which the antagonist is absent. As used herein, a "function-disrupting amount" refers to the amount of an antagonist required to disrupt the function of an enzyme or protein relative to the situation in which the antagonist is absent. The exact amount can depend on the purpose of the treatment and can be determined by those 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 ed., 2003, Gennaro, ed., Lippincott, Williams & Wilkins).

[0334] As used herein, unless otherwise indicated, the term "substituted" means replacement of one or more hydrogen groups in a given structure with a group of a specific substituent, and the specific substituent includes but is not limited to: halogen group, alkyl group, alkenyl group, alkynyl group, aryl group, heterocyclic group, mercapto group, alkylthio group, oxo group, thioxo group, arylthio group, alkylthioalkyl group, arylthioalkyl group, alkylsulfonyl group, alkylsulfonylalkyl group, arylsulfonylalkyl group, alkoxy group, aryloxy group, aralkyloxy group, aminocarbonyl group, alkylaminocarbonyl group, arylaminocarbonyl group, alkoxycarbonyl group, aryloxycarbonyl group, haloalkyl group, amino group, trifluoromethyl group, cyano group, nitro group, alkylamino group, arylamino group, alkylaminoalkyl group, arylaminoalkyl group, aminoalkylamino group, hydroxy group, alkoxyalkyl group, carboxyalkyl group, alkoxycarbonylalkyl group, aminocarbonylalkyl group, acyl group, aralkyloxycarbonyl group, carboxylic acid, sulfonic acid, sulfonyl group, phosphonic acid, aryl group, heteroaryl group, heterocycle and aliphatic group. It should be understood that the substituent may be further substituted. Exemplary substituents include amino group, alkylamino group, etc.

[0335] As used herein, the term "substituent" generally refers to a positional variable on an atom of a core molecule, which is substituted at a specified atomic position to replace one or more hydrogens on the specified atom, provided that the normal valence of the specified atom is not exceeded and the substitution results in a stable compound. Such a combination is permitted only if the combination of substituents and / or variables results in a stable compound. Those of ordinary skill in the art should note that any carbon and heteroatom assumed to have a valence that appears not to be satisfied as described or shown herein have a sufficient number of hydrogen atoms to satisfy the valence as described or shown. In some cases, one or more substituents with a double bond (e.g., "oxo group" or "=O") as a point of attachment may be described, shown, or listed in a substituent group herein, where the structure may show only a single bond as the point of attachment to the core structure of formula (I). Those of ordinary skill in the art should understand that although only a single bond is shown, a double bond is anticipated for those substituents.

[0336] As used herein, the term "alkyl" generally refers to a straight-chain or branched-chain hydrocarbon chain group having from one to twenty carbon atoms and attached to the remainder of the molecule by a single bond. An alkyl containing up to 10 carbon atoms is called a C1-C 10 alkyl. Similarly, for example, an alkyl containing up to 6 carbon atoms is a C1-C6 alkyl. Alkyls containing other numbers of carbon atoms (and other moieties defined herein) are represented in a similar manner. Alkyl includes but is not limited to C1-C 10Alkyl, 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 (isopropyl), n-butyl, isobutyl, sec-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethylpropyl, and the like. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, the alkyl is -CH(CH3)2 or -C(CH3)3. Unless otherwise specifically stated in this specification, the alkyl may be optionally substituted as described below. "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the remainder of the molecule to a group. In some embodiments, the alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, the alkylene is -CH2-. In some embodiments, the alkylene is -CH2CH2-. In some embodiments, the alkylene is -CH2CH2CH2-.

[0337] As used herein, the term "aryl" refers to a group derived from a hydrocarbon ring system containing at least one aromatic ring. In some embodiments, the aryl contains hydrogen and 6 to 30 carbon atoms. The aryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl groups include, but are not limited to, those derived from anthracenylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, Aryl groups of hydrocarbon ring systems of fluoranthene, fluorene, indane, indene, naphthalene, acenaphthylene, phenanthrene, pleiadene, pyrene, and benzophenanthrene. In some embodiments, the aryl is phenyl. Unless otherwise specifically stated in this specification, the aryl may optionally be substituted, for example, by halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)2NH-C1-C6 alkyl, etc. In some embodiments, the aryl is optionally substituted by 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, the aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted by halogen. In some embodiments, the aryl is substituted by alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, where each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl is independently unsubstituted or substituted by halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.

[0338] As used herein, the term "alkenyl" generally refers to a class of alkyl groups in which there is at least one carbon-carbon double bond. In one embodiment, the alkenyl has the formula -C(R a )=CR a 2, where R a refers to the remainder of the alkenyl, which may be the same or different. In some embodiments, R a is H or alkyl. In some embodiments, the alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, etc. Non-limiting examples of alkenyl include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2. "Alkenylene" or "alkenylene chain" refers to an alkylene in which there is at least one carbon-carbon double bond. In some embodiments, the alkenylene is -CH=CH-, -CH2CH2CH=CH-, or -CH=CHCH2CH2-. In some embodiments, the alkenylene is -CH=CH-. In some embodiments, the alkenylene is -CH2CH2CH=CH-. In some embodiments, the alkenylene is -CH=CHCH2CH2-.

[0339] As used herein, the term "alkynyl" generally refers to a class of alkyl groups in which there is at least one carbon-carbon triple bond. In one embodiment, the alkynyl has the formula -C≡CR a , where R a refers to the remainder of the alkynyl group. In some embodiments, R a is H or an alkyl group. In some embodiments, the 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≡CCH3, and -CH2C≡CH. "Alkynylene" or "alkynylene chain" refers to an alkylene group in which there is at least one carbon-carbon triple bond. In some embodiments, the alkynylene is -C≡C-, -CH2CH2C≡C-, or -C≡CCH2CH2-. In some embodiments, the alkynylene is -C≡C-. In some embodiments, the alkynylene is -CH2CH2C≡C-. In some embodiments, the alkynylene is -C≡CCH2CH2-.

[0340] As used herein, the term "cycloalkyl" generally refers to a monocyclic or polycyclic non-aromatic group in which each ring-forming atom (i.e., backbone atom) is a carbon atom. In some embodiments, the cycloalkyl is saturated or partially unsaturated. In some embodiments, the cycloalkyl is a spiro compound or a bridged compound. In some embodiments, the cycloalkyl is fused to an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having three to ten carbon atoms, three to eight carbon atoms, three to six carbon atoms, or three to five carbon atoms. Monocyclic cycloalkyl groups 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 groups include, for example, adamantyl, 1,2-dihydronaphthyl, 1,4-dihydronaphthyl, tetrainyl, decalinyl, 3,4-dihydronaphthalen-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. Unless otherwise specifically stated in this specification, the cycloalkyl may be optionally substituted. Depending on its structure, the cycloalkyl may be monovalent or divalent (i.e., cycloalkylene).

[0341] As used herein, the term "heterocycle" or "heterocyclic" generally refers to a heteroaromatic ring (also referred to as heteroaryl) and a heterocycloalkyl ring (also referred to as a heteroalicyclic group) that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein each heterocyclic group has 3 to 12 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. A "heterocyclic group" 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, spiro, or bridged compound. Non-aromatic heterocyclic groups (also referred to as heterocycloalkyls) include rings having 3 to 12 atoms in their ring systems, and aromatic heterocyclic groups include rings having 5 to 12 atoms in their ring systems. 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 yl yl, thiazepinyl groups such as a radical, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxolanyl, 1,3-dioxolanyl, pyrazolinyl, dithiolanyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-one, isoindolin-1-one, isoindoline-1,3-dione, 3,4-dihydroisoquinolin-1(2H)-one, 3,4-dihydroquinolin-2(1H)-one, isoindoline-1,3-dithione, benz[d]oxazol-2(3H)-one, 1H-benz[d]imidazol-2(3H)-one, benz[d]thiazol-2(3H)-one and quinazolinyl. Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolazinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furanopyridinyl. The above groups are C-attached (or C-linked) or N-linked where possible. For example, groups derived from pyrrole include pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). In addition, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). Heterocyclic groups include benzo-fused ring systems. The non-aromatic heterocycles are optionally substituted by one or two oxo groups (=O), such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both of the two rings of the bicyclic heterocycle are aromatic.

[0342] As used herein, the term "heterocycloalkyl" generally refers to a cycloalkyl group that includes at least one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated in this specification, a heterocycloalkyl group can be a monocyclic or bicyclic ring system, which can include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocyclic group can be optionally oxidized. The nitrogen atom can be optionally quaternized. The heterocycloalkyl group can be partially or fully saturated. Examples of heterocycloalkyl groups include, but are not limited to, dioxolanyl, thieno[1,3]dithiolanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithiolanyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 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, the heterocycloalkyl has 2 to 10 carbons in the ring. In some embodiments, the heterocycloalkyl has 2 to 10 carbons and 1 or 2 N atoms in the ring. In some embodiments, the heterocycloalkyl has 2 to 10 carbons and 3 or 4 N atoms in the ring. In some embodiments, the heterocycloalkyl has 2 to 12 carbons, 0 - 2 N atoms, 0 - 2 O atoms, 0 - 2 P atoms, and 0 - 2 S atoms in the ring. In some embodiments, the heterocycloalkyl has 2 to 12 carbons, 1 - 3 N atoms, 0 - 2 O atoms, and 0 - 2 S atoms in the ring. It should be understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is different from the total number of atoms (i.e., the backbone atoms of the heterocycloalkyl ring) including heteroatoms that make up the heterocycloalkyl. Unless otherwise specifically stated in this specification, the heterocycloalkyl can be optionally substituted. As used herein, the term "heterocycloalkylene" can refer to a divalent heterocycloalkyl.

[0343] As used herein, the term "heteroaryl" generally refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryl is monocyclic or bicyclic. Exemplary examples of monocyclic heteroaryl include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizinyl, indolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl. Exemplary examples of monocyclic heteroaryl include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Exemplary examples of bicyclic heteroaryl include indolizinyl, indolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl. In some embodiments, the heteroaryl is pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furyl. In some embodiments, the heteroaryl ring contains 0-6 N atoms. In some embodiments, the heteroaryl ring contains 1-4 N atoms. In some embodiments, the heteroaryl ring contains 4-6 N atoms. In some embodiments, the heteroaryl ring contains 0-4 N atoms, 0-1 O atom, 0-1 P atom, and 0-1 S atom. In some embodiments, the heteroaryl ring contains 1-4 N atoms, 0-1 O atom, and 0-1 S atom. 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 is partially reduced to form a heterocycloalkyl as defined herein. In some embodiments, the heteroaryl is completely reduced to form a heterocycloalkyl as defined herein.

[0344] As used herein, the term "heteroalkyl" generally refers to an alkyl group in which one or more of the backbone atoms of the alkyl group are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -N(aryl)-), sulfur (e.g., -S-, -S(=O)-, or -S(=O)2-), or combinations thereof. In some embodiments, the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In some embodiments, the heteroalkyl is attached to the remainder of the molecule at a heteroatom of the heteroalkyl. In some embodiments, the heteroalkyl is a C1-C6 heteroalkyl. Representative heteroalkyls include, but are not limited to, -OCH2OMe, -OCH2CH2OH, -OCH2CH2OMe, or -OCH2CH2OCH2CH2NH2. "Heteroalkylene" or "heteroalkylene chain" refers to a straight or branched divalent heteroalkyl chain that attaches the remainder of the molecule to a group. Unless otherwise specifically stated in this specification, the heteroalkyl or heteroalkylene may be optionally substituted. Representative heteroalkylenes include, but are not limited to, -OCH2CH2O-, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-.

[0345] As used herein, the term "heteroalkenyl" refers to an alkenyl group in which one or more of the backbone atoms of the alkenyl group are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -N(aryl)-), sulfur (e.g., -S-, -S(=O)-, or -S(=O)2-), or combinations thereof. In some embodiments, the heteroalkenyl is attached to the remainder of the molecule at a carbon atom of the heteroalkenyl. In some embodiments, the heteroalkenyl is attached to the remainder of the molecule at a heteroatom of the heteroalkenyl. In some embodiments, the heteroalkyl is a C1-C6 heteroalkenyl.

[0346] As used herein, the term "heteroalkynyl" refers to an alkynyl group in which one or more of the backbone atoms of the alkynyl group are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -N(aryl)-), sulfur (e.g., -S-, -S(=O)-, or -S(=O)2-), 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.

[0347] As used herein, the term "heteroatom" or "ring heteroatom" generally refers to an atom including oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si) or any combination thereof.

[0348] As used herein, the term "substituent" refers to a group selected from the following moieties:

[0349] (A) Oxo group, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -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

[0350] (B) Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, which are substituted by at least one substituent selected from the following:

[0351] (i) Oxo group, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -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

[0352] (ii) Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, which are substituted by at least one substituent selected from the following:

[0353] (a) Oxo group, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -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

[0354] (b) An alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, which is substituted with at least one substituent selected from the group consisting of: oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -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, and unsubstituted heteroaryl.

[0355] 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 substituent having a limited size. In other embodiments, at least one or all of these groups are substituted with at least one lower-level substituent.

[0356] FSH regulator

[0357] For ovulation induction, the only approved drug to date is clomiphene citrate, which is a mixture of estrogen agonist and antagonist isomers and is used to increase the release of endogenous FSH and LH. The purpose of prescribing clomiphene is to increase the endogenous plasma FSH level and LH level to a level sufficient to support the development of one or two follicles to the ovulation point. The mechanism of clomiphene or the off-label use of aromatase inhibitors is indirect; it assumes that the response of the hypothalamic-pituitary-ovarian axis is homogeneous among patient subgroups to achieve a comparable responder in patients. The FSH regulators described herein (e.g., orally active FSH receptor agonists) can exhibit improved ovulation induction through low-dose FSH agonists, for example, by acting directly on the ovary and exerting efficacy without hypothalamic-pituitary input. In this regard, compared with what can be achieved by administering clomiphene (approved) or aromatase inhibitors (off-label), the FSH regulators described herein (e.g., oral FSH receptor agonists) can provide improved ovulation induction efficacy and control precision.

[0358] According to one embodiment, the present disclosure relates to a method for allosterically modulating the activity of FSHR in a biological sample, which comprises 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 allosterically modulating the activity of FSHR or its mutant in a biological sample in a positive manner, which comprises contacting the biological sample with a compound of the present disclosure or a composition comprising the compound.

[0359] The compounds of the present disclosure are potent and selective modulators of the FSH receptor. In some cases, their selectivity for the FSH receptor can be 3 to 10 times higher than that for the LH receptor, and even 10 to 100 times higher than that for the TSH receptor. In some embodiments, the EC 50 or IC 50 for unrelated G protein-coupled receptors (GPCRs) or non-GPCR targets reaches greater than 10 μM. In some cases, the selectivity of the FSH modulator for the FSH receptor can be 100 to 200 times higher than that for the LH receptor. The present disclosure includes the use of the compounds of the present disclosure in regulating and / or modulating the FSHR signaling cascade, which can be advantageously applied as a research tool for diagnosing and / or treating any disease caused by FSHR signaling.

[0360] For example, the compounds of the present disclosure can be used in vitro as a unique tool for understanding the biological effects of FSH, including evaluating factors that are considered to affect the production of FSH and the interaction between FSH and FSHR (e.g., the mechanism of FSH signal transduction / receptor activation) and many factors affected by it. The compounds of the present invention can also be used to develop other compounds that interact with FSHR, because the compounds of the present invention provide important structure-activity relationship (SAR) information, which is beneficial to the development. The compounds of the present disclosure that bind to FSHR can be used as reagents for detecting FSHR in living cells, fixed cells, biological fluids, tissue homogenates, purified natural biological materials, etc. For example, by labeling such compounds, cells with 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 for in situ staining, FACS (fluorescence-activated cell sorting), Western blotting, ELISA (enzyme-linked immunosorbent assay), etc., receptor purification, or purification of cells expressing FSHR on the cell surface or inside permeabilized cells. The compounds of the present disclosure that bind to FSHR can also be used to distinguish the effects of FSH that do not depend on the carbohydrate moiety of the glycoprotein containing FSH, and to identify the essential and alternative cellular responses of small molecule FSHR agonists relative to glycoprotein FSH.

[0361] The compounds of the present disclosure can also be used as commercial research reagents for various medical research and diagnostic applications. Such applications may include, but are not limited to: serving as calibration standards for quantifying the activity of candidate FSH agonists in various functional assays; serving as blocking reagents in random compound screening, i.e., when searching for new FSH receptor ligand families, the compound can be used to block the recovery of the claimed FSH compounds of the present invention; for co-crystallization with the FSHR receptor, i.e., the compounds of the present disclosure will allow the formation of crystals of compounds that bind to FSHR, enabling the determination of the receptor / compound structure by X-ray crystallography or cryo-electron microscopy; other research and diagnostic applications where the FSHR is preferably activated or such activation is conveniently calibrated for a known amount of FSH agonist, etc.; serving as a probe in an assay for determining the expression of FSHR on the cell surface; and developing assays for detecting compounds that bind to the same site as the FSHR-binding ligand.

[0362] The compounds of the present disclosure can be applied by themselves and / or in combination with physical measurements for the diagnosis of therapeutic effectiveness. Pharmaceutical compositions containing such compounds and the use of such compounds for treating FSHR-mediated diseases are novel methods with broad prospects for broad-spectrum treatment, leading to a direct and immediate improvement in the health status of humans or animals. Their impact has particular benefits for effectively combating infertility, either alone or in combination with other fertility-promoting treatments.

[0363] Specifically, the compounds of the present disclosure enhance the natural role of FSH in ovulation induction and assisted reproductive technologies. The orally bioavailable and active new chemical entities of the present disclosure improve patient convenience and physician compliance.

[0364] The compounds of the present disclosure are active in primary screening (CHO with or without FSH), selective in secondary screening (inactive or weakly active against TSHR and LHR), and potent in granulosa cell estradiol assays. No hERG or any toxic effects were observed in vitro.

[0365] In certain embodiments, the present disclosure provides a method for in vitro fertilization, which includes:

[0366] (a) treating a mammal according to the method described above,

[0367] (b) collecting eggs from the mammal;

[0368] (c) fertilizing the eggs; and

[0369] (d) implanting the fertilized eggs into a host mammal.

[0370] This disclosure describes FSH modulator compounds, pharmaceutically acceptable salts or solvates thereof, pharmaceutical compositions comprising an FSH modulator compound (or a pharmaceutically acceptable salt or solvate thereof), lipid nanoparticle compositions comprising an FSH modulator, and methods of treating a disease, the method comprising administering to a subject in need thereof an FSH modulator compound, a pharmaceutically acceptable salt or solvate thereof, a pharmaceutical composition comprising an 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) as described herein.

[0371] In some embodiments, the compounds of the present disclosure may exhibit low or no activity as agonists against the FSHR. Such low-activity agonists may have structural features similar to those of a potent FSHR agonist, which is an antagonist of the glycoprotein hormone FSH. In some embodiments, an inactive (e.g., low-activity) FSHR compound may replace a potent FSHR agonist having similar structural features and inhibit its activity. Such compounds may also be used as diagnostic agents by replacing the agonist, without having agonist activity themselves.

[0372] In some cases, the inactive compounds of the present disclosure may attenuate the activity of a more active compound by replacing the agonist activity of the more active compound. In some embodiments, the inactive compounds may be used, for example, to prevent overstimulation of agonist responses in females and / or to avoid or alleviate ovarian hyperstimulation syndrome.

[0373] In some cases, the FSH modulator or composition described herein is a compound of formula (I):

[0374]

[0375] or a pharmaceutically acceptable salt thereof.

[0376] In some embodiments, R 1 is C1-C 5 alkyl that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; C1-C 5 alkenyl that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; C3-C 5 heteroaryl that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; C6 aryl that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; or unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5C3-C8 cycloalkyl substituted with a group; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 C3-C8 cycloalkenyl substituted with a group; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 C3-C8 cycloalkynyl substituted with a group; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 heterocycloalkyl substituted with a group; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 heterocycloalkenyl substituted with a group; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 heterocycloalkynyl substituted with a group; or unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 C1-C 16 alkynyl.

[0377] In some embodiments, Y is -OC(R 4 )2-.

[0378] In some embodiments, Z is -OR 4 ; -N(R 4 )2; -SR 4 ; -CF3; -OCF3; -OH; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 C1-C 16 heteroalkyl; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 C1-C 16 alkyl; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 C1-C 16 alkenyl; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 C3-C8 cycloalkyl; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 C3-C8 cycloalkenyl; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 C3-C8 cycloalkynyl; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 heterocycloalkyl; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 heterocycloalkenyl; unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 heterocycloalkynyl; or unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 C3-C 16 alkynyl.

[0379] In some embodiments, R 2is -CF3, -OCF3 or -OCH2CH3.

[0380] In some embodiments, R 3 is hydrogen; halogen; -CF3; -OCF3; -OH; C1-C 5 unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 heteroalkyl; C1-C 5 unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 alkyl; C1-C 5 unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 alkenyl; C3-C 5 unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 heteroaryl; C6 aryl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkenyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkynyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkenyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkynyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or C1-C 5 alkynyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 .

[0381] In some embodiments, each R 4 is independently hydrogen; halogen; -CF3; -OCF3; -OH; C1-C 5 unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 heteroalkyl; C1-C 5 unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 alkyl; C1-C 5 unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 alkenyl; C3-C 5 unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16Heteroaryl; C6 aryl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkenyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkynyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; Heterocycloalkyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; Heterocycloalkenyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; Heterocycloalkynyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; or C1-C 5 alkynyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 16 .

[0382] In some embodiments, each R 5 is 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)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.

[0383] In some embodiments, each R 6 is 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.

[0384] 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 -.

[0385] In some embodiments, Z is -OR 4 ; -N(R 4 )2; -SR 4 ; -CF3; -OCF3; -OH; C1-C 5 unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 heteroalkyl; C1-C 5 unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 alkyl; C1-C 5 unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 alkenyl; C3-C8 cycloalkyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkenyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkynyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heteroalkyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heteroalkenyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heteroalkynyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or C3-C 5 alkynyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 .

[0386] In some embodiments, R 2 is -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -CF3, -OCF 3、 -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R or -N(R)2;

[0387] 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 -.

[0388] In some embodiments, R is hydrogen; halogen; -CF3; -OCF3; -OH; C1-C 5 unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 heteroalkyl; C1-C 5 unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 alkyl; C1-C 5 unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 alkenyl; C3-C 5 unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 heteroaryl; C6 aryl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkenyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkynyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkenyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkynyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or C1-C 5 alkynyl unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 .

[0389] In some embodiments, Z is -O-tert-butyl.

[0390] In some embodiments, R 3 is a C3-C 5 heteroaryl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; a C6 aryl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; a C3-C8 cycloalkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; a C3-C8 cycloalkenyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; a C3-C8 cycloalkynyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; a heterocycloalkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; a heterocycloalkenyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; or a heterocycloalkynyl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 .

[0391] In some embodiments, R 3 is a C3-C 5 heteroaryl unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 16 .

[0392] In some embodiments, R 3 is selected from

[0393]

[0394]

[0395] and their substituents.

[0396] In some embodiments, R 3 is selected from

[0397]

[0398] and their substituents.

[0399] In some embodiments, R 3 is selected from

[0400] In some embodiments, R 3 is

[0401] In some embodiments, R 3 is

[0402] In some embodiments, R 3 is

[0403] In some embodiments, R 3 is

[0404] In some embodiments, R 3 is

[0405] In some embodiments, R 3 is

[0406] In some embodiments, R 3 is

[0407] In some embodiments, R 3 is

[0408] In some embodiments, R 3 is

[0409] In some embodiments, R 3 is

[0410] In some embodiments, R 2 is - halogen, - OR, - SR, - CN, - NO2, - CF3, - OCF3 or - C(=O)CH3.

[0411] In some embodiments, R 2 is - OCH3, - SCH3, - CN, - NO2, - CF3 or - OCF3.

[0412] In some embodiments, R 2 is - OCH3, - SCH3 or - OCF3.

[0413] In some embodiments, R 2 is - SCH3.

[0414] In some embodiments, R 2 is - OCF3.

[0415] In some embodiments, R 2 is -CF3.

[0416] In some embodiments, R 2 is -OCH2CH3.

[0417] In some embodiments, R 2 is -OCH3.

[0418] In some embodiments, R 1 is an unsubstituted or C3-C 5 heteroaryl substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; an unsubstituted or C6 aryl substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; an unsubstituted or C3-C8 cycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; an unsubstituted or C3-C8 cycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; an unsubstituted or C3-C8 cycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; an unsubstituted or heterocycloalkyl substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; an unsubstituted or heterocycloalkenyl substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; or an unsubstituted or heterocycloalkynyl substituted with 1, 2, 3, 4, or 5 groups selected from R 5 .

[0419] In some embodiments, R 1 is an unsubstituted or C6 aryl substituted with 1, 2, 3, 4, or 5 groups selected from R 5 .

[0420] In some embodiments, R 1 is an unsubstituted or C3-C 5 heteroaryl substituted with 1, 2, 3, 4, or 5 groups selected from R 16 .

[0421] In some embodiments, R 1 is selected from

[0422]

[0423]

[0424] and their substituents.

[0425] In some embodiments, R 1 is selected from

[0426] and their substituents.

[0427] In some embodiments, R 1 is

[0428] In some embodiments, R 1 is

[0429] In some embodiments, R 1 is

[0430] In some embodiments, R 1 is

[0431] In some embodiments, wherein R 1 is

[0432] In some embodiments, R 1 is

[0433] In some embodiments, R 1 is

[0434] In some embodiments, R 1 is

[0435] In some embodiments, R 1 is

[0436] In some embodiments, R 1 is

[0437] 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 -;

[0438] 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 )2-.

[0439] In some embodiments, Y is -O-, -S-, -NH-, -OCH2-, -SCH2-, -CH2O-, -CH2S-, -CH2-.

[0440] In some embodiments, Y is -O-.

[0441] In some embodiments, Y is -S-.

[0442] In some embodiments, Y is -S(=O)-.

[0443] In some embodiments, Y is -S(=O)2-.

[0444] In some embodiments, Y is -S(=O)C(R 4 )2-.

[0445] In some embodiments, Y is -C(R 4 )2S(=O)-.

[0446] In some embodiments, Y is -S(=O)2C(R 4 )2-.

[0447] In some embodiments, Y is -C(R 4 )2S(=O)2-.

[0448] In some embodiments, Y is -S(=O)CH2-.

[0449] In some embodiments, Y is -CH2S(=O)-.

[0450] In some embodiments, Y is -S(=O)2CH2-.

[0451] In some embodiments, Y is -CH2S(=O)2-.

[0452] In some embodiments, Y is -NR 4 -.

[0453] In some embodiments, Y is -OC(R 4 )2-.

[0454] In some embodiments, Y is -SC(R 4 )2-.

[0455] In some embodiments, Y is -C(R 4 )2O-.

[0456] In some embodiments, Y is -C(R 4 )2S-.

[0457] In some embodiments, Y is -C(R 4 )2NR 4 -.

[0458] In some embodiments, Y is -C(R 4 )2-.

[0459] In some embodiments, Y is -C(R 4 )2-C(R 4 )2-.

[0460] In some embodiments, Y is -CR 4 =CR 4 -;

[0461] In some embodiments, Y is -NH-. In some embodiments, Y is -OCH2-.

[0462] In some embodiments, Y is -SCH2-.

[0463] In some embodiments, Y is -CH2O-.

[0464] In some embodiments, Y is -CH2S-.

[0465] In some embodiments, Y is -CH2NR 4 -.

[0466] In some embodiments, Y is -CH2-.

[0467] In some embodiments, Y is -CH2-CH2-.

[0468] In some embodiments, Y is -CH=CH-.

[0469] In some embodiments, Z is -OR 4 ; -N(R 4 )2; -SR 4 ; -CF3; -OCF3; -OH; unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5C3-C8 cycloalkenyl substituted by a group; unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 C3-C8 cycloalkynyl substituted by a group; unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 heterocycloalkyl substituted by a group; unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 heterocycloalkenyl substituted by a group; or unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 heterocycloalkynyl substituted by a group.

[0470] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4 , -CF3, -OCF3, or selected from

[0471] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4 .

[0472] In some embodiments, Z is -OR 4 , -N(R 4 )2, -SR 4 , and at least one R of Z 4 is selected from

[0473] In some embodiments, Z is -OR 4 or -SR 4 , and the R of Z 4 is

[0474]

[0475] In some embodiments, Z is selected from

[0476] In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is

[0477] In some embodiments, Z is

[0478] In some embodiments, Z is

[0479] In some embodiments, Z is

[0480] In some embodiments, Z is

[0481] In some embodiments, Z is

[0482] In some embodiments, Z is

[0483] In some embodiments, Z is

[0484] In some embodiments, Z is

[0485] In some embodiments, R 1 or R 3 is substituted with a halogen.

[0486] In some embodiments, R 1 or R 3 is substituted with chlorine.

[0487] In some embodiments, R 1 or R 3 is substituted with fluorine.

[0488] In some embodiments, R 1 or R 3 is substituted with C1-C4 heteroalkyl.

[0489] In some embodiments, at least one R within Z 4 is selected from

[0490] In some embodiments, the FSH modulators disclosed herein have a structure selected from the following: 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, and Compound 8-44.

[0491] In some embodiments, the FSH modulators disclosed herein have structures selected from the following: 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 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,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.

[0492] In some cases, the FSH modulators described herein may have the structure of any of the compounds in Table 1.

[0493] Table 1. Structures of additional exemplary FSH modulators.

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500] In some cases, the FSH modulators described herein may have any of the structures described herein, including but not limited to those described throughout the present application Figure 1-193 , in the Examples and / or synthetic schemes, and their pharmaceutically acceptable salts, solvates, or formulations.

[0501] In another aspect, methods of modulating FSH using the compounds described herein are described. In some embodiments, the compounds described herein selectively modulate FSH and substantially do not modulate TSH. In some embodiments, the method comprises administering to a subject a compound described herein. In some embodiments, the compound described herein is an FSH agonist. In some embodiments, the selectivity of the compound described herein for FSH is at least 3-fold that of TSH (e.g., at least 3, 5, 10, 20, 50, or 100-fold). In some embodiments, the in vitro or in vivo EC 50 of FSH activation does not exceed about 100 nM (e.g., does not exceed 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, or 500 pM).

[0502] Any method described herein may include treating a disease or condition, including administering to a subject in need thereof any compound (or a pharmaceutically acceptable salt or solvate thereof) described herein. 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, gastric cancer, testicular cancer, or ovarian cancer. In some embodiments, the disease or condition is a cardiovascular condition. In some embodiments, the cardiovascular condition is atherosclerosis. In some embodiments, the disease or condition is a body composition disorder (such as 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 (such as osteoporosis). In some embodiments, the disease or condition is Turner syndrome, Klinefelter syndrome, polycystic ovary syndrome (PCOS), and / or primary ovarian insufficiency (POI).

[0503] In some embodiments, the disease or condition is polycystic ovary syndrome (PCOS).

[0504] In some embodiments, the disease or condition is Turner syndrome.

[0505] In some embodiments, the disease or condition is Klinefelter syndrome.

[0506] In some embodiments, the disease or condition is primary ovarian insufficiency (POI).

[0507] The present disclosure further describes a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof according to any one of the claims, and a pharmaceutically acceptable excipient or carrier.

[0508] A pharmaceutically acceptable lipid nanoparticle formulation may comprise any compound described herein.

[0509] Any method described herein may include treating a condition or disease by administering to a subject in need thereof any compound, pharmaceutically acceptable salt, and / or pharmaceutically acceptable solvate described herein.

[0510] Any method described herein may include the use of any compound, pharmaceutically acceptable salt, and / or pharmaceutically acceptable solvate described herein in the manufacture of a medicament for treating a condition or disease.

[0511] 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 manufacturing costs and ease of handling. These characteristics form the basis for reproducible effects, including the lack of cross-reactivity, and reliable and safe interactions with the target structure.

[0512] The modulation of the activity of FSHR or its mutants in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological sample storage and bioassays.

[0513] Other forms of the compound

[0514] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted in vivo to the parent drug. Prodrugs are often useful because in some cases they may be more readily administered than the parent drug. They may be, for example, bioavailable by oral administration, while the parent is not. Prodrugs may also have improved solubility in a pharmaceutical composition compared to the parent drug. In some embodiments, the prodrug is designed to increase effective water solubility. Non-limiting examples of prodrugs are the compounds described herein that are administered in the form of an ester ("prodrug") to facilitate transport across cell membranes (where water solubility is disadvantageous for migration), but which are then metabolically hydrolyzed to the carboxylic acid (the active entity) once inside the cell (where water solubility is beneficial). Another example of a prodrug can be a short peptide (polyamino acid) conjugated to an acidic group, where the peptide is metabolized to expose the active moiety. In certain embodiments, the prodrug is chemically converted to the biological, pharmaceutical or therapeutic active form of the compound upon in vivo administration. In certain embodiments, the prodrug is enzymatically metabolized to the biological, pharmaceutical or therapeutic active form of the compound in one or more steps or processes.

[0515] In one aspect, prodrugs are designed to alter the metabolic stability or transport characteristics 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 an understanding of pharmacokinetic, pharmacodynamic processes and in vivo drug metabolism, once a drug active compound is known, a prodrug of that compound can be designed. (See, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pp. 388 - 392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pp. 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, Pro - drugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium Series).

[0516] In some embodiments, some of the compounds described herein can be prodrugs of another derivative or active compound.

[0517] In some embodiments, the sites on the aromatic ring moiety of the compounds described herein are sensitive to various metabolic reactions. Thus, incorporation of suitable substituents on the aromatic ring structure can reduce, minimize or eliminate such metabolic pathways. In a specific embodiment, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are halogen or alkyl (by way of example only).

[0518] In another embodiment, the compounds described herein are isotopically labeled (e.g., with a radioactive isotope) or labeled by other additional methods, including but not limited to using a chromophore or a fluorescent moiety, a bioluminescent label or a chemiluminescent label.

[0519] The compounds described herein include isotopically labeled compounds identical to those described in the various formulas and structures given herein, except that in fact one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, such as 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 aspect, the isotopically labeled compounds described herein, such as those incorporating radioactive isotopes such as 3 H and 14 C, can be used for drug and / or substrate tissue distribution assays. In one aspect, substitution with an isotope such as deuterium provides certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0520] In additional or further embodiments, the compounds described herein are metabolized when administered to an organism in need thereof, producing metabolites that are then used to produce the desired effect, including the desired therapeutic effect.

[0521] 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) acid addition salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, etc.; or an organic acid 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]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy-naphthoic acid, salicylic acid, stearic acid, mucic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, etc.; (2) salts formed when the acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth metal ion (e.g., magnesium or calcium), or an aluminum ion. In some cases, the compounds described herein can coordinate with an organic base such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris-(hydroxymethyl)methylamine. In other cases, the compounds described herein can form salts with amino acids such as, but not limited to, arginine, lysine, etc. Acceptable inorganic bases for forming salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

[0522] It should be understood that the reference to pharmaceutically acceptable salts includes solvate addition forms, particularly solvates. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and can be formed during the crystallization of the compound with a pharmaceutically acceptable solvent such as water, ethanol, etc. When the solvent is water, a hydrate is formed; or when the solvent is an alcohol, an alcoholate is formed. 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 non-solvated form as well as solvated form. Generally, for the compounds and methods provided herein, the solvated form is considered equivalent to the non-solvated form.

[0523] Synthetic methods

[0524] In some embodiments, the synthesis of the compounds described herein is achieved using means described in the chemical literature, using the methods described herein, or by a combination thereof. Additionally, the solvents, temperatures, and other reaction conditions given herein can vary.

[0525] In other embodiments, the starting materials and reagents used to synthesize the compounds described herein are synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fisher Scientific (Fisher Chemicals), and Acros Organics.

[0526] In further embodiments, the compounds described herein and other related compounds with different substituents are synthesized using the techniques and materials described herein and those recognized in the art (such as those described in, 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 Supplements (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 Edition, (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Edition, Volumes A and B (Plenum 2000, 2001), and Greene and Wuts, Protective Groups in Organic Synthesis 3rd Edition, (Wiley 1999) (the disclosures of all of these documents are incorporated herein by reference)). The general methods for preparing the compounds disclosed herein can be derived from reactions, and these reactions can be modified by using appropriate reagents and conditions to introduce the various moieties present in the formulas provided herein. As a guide, the following synthetic methods can be utilized.

[0527] In the described reactions, it may be necessary to protect reactive functional groups, such as hydroxyl, amino, imino, sulfhydryl or carboxyl groups (if these groups are desired in the final product), to avoid their undesired participation in the reaction. Details of techniques applicable to the generation and removal of protecting groups are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York, NY, 1999 and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994 (such disclosures of these references are incorporated herein by reference).

[0528] It is understood that other similar procedures and reagents may be used and these schemes are only intended as non-limiting examples.

[0529] Pharmaceutical composition

[0530] In one aspect, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of the active compound into a pharmaceutically acceptable formulation. The correct formulation depends on the chosen route of administration. Summaries of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999), such disclosures of these references are incorporated herein by reference.

[0531] As used herein, a pharmaceutical composition refers to a mixture of a compound disclosed herein with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such other chemical components as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersants, surfactants, lubricants, coloring agents, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoaming agents, antioxidants, preservatives, or one or more combinations thereof. The pharmaceutical composition facilitates the administration of the compound to an organism.

[0532] The pharmaceutical formulations described herein can be administered to a subject in a variety of ways via a variety of administration routes, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, buccal, topical or transdermal administration routes. The pharmaceutical formulations 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 melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[0533] In some embodiments, the compounds disclosed herein are administered orally.

[0534] In some embodiments, the compounds disclosed herein are administered topically. In such embodiments, the compounds disclosed herein are formulated into a variety of 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 topically administered to the skin. In another aspect, the compounds disclosed herein are directly administered to the female genital tract (vaginal gels, vaginal rings, intrauterine delivery) using non-degradable or degradable delivery systems. In another aspect, the compounds disclosed herein are directly administered to the male genital tract using non-degradable or degradable delivery systems.

[0535] In another aspect, the compounds disclosed herein are administered by inhalation.

[0536] In another aspect, the compounds disclosed herein are formulated for intranasal administration. Such formulations include nasal sprays, nasal mists, etc.

[0537] In another aspect, the compounds disclosed herein are formulated as eye drops.

[0538] In any of the above aspects, further embodiments are included, wherein an effective amount of the compounds 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 to a mammal by inhalation; and / or (e) administered to a mammal by nasal administration; and / or (f) administered to a mammal by injection; and / or (g) administered topically to a mammal; and / or (h) administered by ocular administration; and / or (i) administered rectally to a mammal; and / or (j) administered non-systemically or topically to a mammal.

[0539] In any of the above aspects, further embodiments are included, which include a single administration of an effective amount of the compounds disclosed herein, including the following further embodiments, wherein: (i) the compound is administered once; (ii) the compound is administered to a mammal multiple times within the span of a day; (iii) the compound is administered continuously; or (iv) the compound is administered sequentially.

[0540] In any of the above aspects, further embodiments are included, which include multiple administrations of an effective amount of the compounds disclosed herein, including the following further embodiments, wherein: (i) the compound is administered continuously or intermittently: such as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to a mammal every 8 hours; (iv) the compound is administered to a mammal every 12 hours; (v) the compound is administered to a mammal every 24 hours. In a further or alternative embodiment, the method includes a drug holiday, wherein the administration of the compounds disclosed herein is temporarily discontinued or the dose of the administered compound is temporarily reduced; at the end of the drug holiday, the administration of the compound is resumed. In one embodiment, the length of the drug holiday ranges from 2 days to 1 year.

[0541] In certain embodiments, the compounds disclosed herein are administered topically rather than systemically.

[0542] In some embodiments, the compounds disclosed herein are administered topically. In some embodiments, the compounds disclosed herein are administered systemically.

[0543] 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.

[0544] In one aspect, the liquid dosage form for oral administration is in the form of an aqueous suspension or solution, selected from the group consisting of, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.

[0545] For administration by inhalation, the compounds disclosed herein are formulated as an aerosol, spray, or powder.

[0546] For buccal or sublingual administration, the compositions can be in the form of tablets, lozenges or gels formulated in a conventional manner.

[0547] In some embodiments, the compounds disclosed herein are prepared as transdermal dosage forms.

[0548] In one aspect, the compounds disclosed herein are formulated into pharmaceutical compositions suitable for intramuscular, subcutaneous or intravenous injection.

[0549] 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, sticks, balms, creams or ointments.

[0550] In some embodiments, the compounds disclosed herein are formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories or retention enemas.

[0551] Methods of administration and treatment regimens

[0552] In one aspect, the compounds disclosed herein are used to prepare a medicament for treating the diseases or conditions described herein. Further, a method for treating any disease or condition described herein in a subject in need of such treatment comprises administering to the subject 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.

[0553] In certain embodiments, the compositions containing the compounds disclosed herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient having the disease or condition in an amount sufficient to cure or at least partially arrest at least one symptom of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous therapy, the health status, weight and response of the patient to the drug, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including but not limited to dose escalation clinical trials.

[0554] In prophylactic applications, the compositions containing the compounds disclosed herein are administered to patients susceptible or otherwise at risk of a particular disease, disorder or condition.

[0555] In certain embodiments, the dose of the administered drug can be temporarily reduced or temporarily discontinued for a specific length of time (i.e., a "drug holiday").

[0556] Dosages for adult treatment are typically in the range of 0.01 mg - 5000 mg per day or from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is conveniently provided in a single dose or divided doses.

[0557] In some embodiments, the dose is from about 0.1 mg per day to about 5,000 mg per day. In some embodiments, the dose is 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, from about 0.1 mg per day to about 1,000 mg per day, from about 0.1 mg per day to about 5,000 mg per day, 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 300 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, from about 1 mg per day to about 900 mg per day, from about 1 mg per day to about 1,000 mg per day, from about 1 mg per day to about 5,000 mg per day, from about 50 mg per day to about 100 mg per day, from about 50 mg per day to about 300 mg per day, from about 50 mg per day to about 500 mg per day, from about 50 mg per day to about 600 mg per day, from about 50 mg per day to about 700 mg per day, from about 50 mg per day to about 800 mg per day, from about 50 mg per day to about 900 mg per day, from about 50 mg per day to about 1,000 mg per day, from about 50 mg per day to about 5,000 mg per day, from about 100 mg per day to about 300 mg per day, from about 100 mg per day to about 500 mg per day, from about 100 mg per day to about 600 mg per day, from about 100 mg per day to about 700 mg per day, from about 100 mg per day to about 800 mg per day, from about 100 mg per day to about 900 mg per day, from about 100 mg per day to about 1,000 mg per day, from about 100 mg per day to about 5,000 mg per day, from about 300 mg per day to about 500 mg per day, from about 300 mg per day to about 600 mg per day, from about 300 mg per day to about 700 mg per day, from about 300 mg per day to about 800 mg per day, from about 300 mg per day to about 900 mg per day, from about 300 mg per day to about 1,000 mg per day, from about 300 mg per day to about 5,000 mg per day, from about 500 mg per day to about 600 mg per day, from about 500 mg per day to about 700 mg per day, from about 500 mg per day to about 800 mg per day, from about 500 mg per day to about 900 mg per day, from about 500 mg per day to about 1,000 mg per day, from about 500 mg per day to about 5,000 mg, from about 600 mg per day to about 700 mg per day, from about 600 mg per day to about 800 mg per day, from about 600 mg per day to about 900 mg per day, from about 600 mg per day to about 1,000 mg per day, from about 600 mg per day to about 5,000 mg per day, from about 700 mg per day to about 800 mg per day, from about 700 mg per day to about 900 mg per day, from about 700 mg per day to about 1,000 mg per day, from about 700 mg per day to about 5,000 mg per day, from about 800 mg per day to about 900 mg per day, from about 800 mg per day to about 1,000 mg per day, from about 800 mg per day to about 5,000 mg per day, from about 900 mg per day to about 1,000 mg per day, from about 900 mg per day to about 5,000 mg per day, or from 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 at most 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.,

[0558] 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, from about 1 mg per day to about 900 mg per day, from about 1 mg per day to about 1,000 mg per day, from about 50 mg per day to about 100 mg per day, from about 50 mg per day to about 200 mg per day, from about 50 mg per day to about 300 mg per day, from about 50 mg per day to about 400 mg per day, from about 50 mg per day to about 500 mg per day, from about 50 mg per day to about 600 mg per day, from about 50 mg per day to about 700 mg per day, from about 50 mg per day to about 800 mg per day, from about 50 mg per day to about 900 mg per day, from about 50 mg per day to about 1,000 mg per day, from about 100 mg per day to about 200 mg per day, from about 100 mg per day to about 300 mg per day, from about 100 mg per day to about 400 mg per day, from about 100 mg per day to about 500 mg per day, from about 100 mg per day to about 600 mg per day, from about 100 mg per day to about 700 mg per day, from about 100 mg per day to about 800 mg per day, from about 100 mg per day to about 900 mg per day, from about 100 mg per day to about 1,000 mg per day, from about 200 mg per day to about 300 mg per day, from about 200 mg per day to about 400 mg per day, from about 200 mg per day to about 500 mg per day, from about 200 mg per day to about 600 mg per day, from about 200 mg per day to about 700 mg per day, from about 200 mg per day to about 800 mg per day, from about 200 mg per day to about 900 mg per day, from about 200 mg per day to about 1,000 mg per day, from about 300 mg per day to about 400 mg per day, from about 300 mg per day to about 500 mg per day, from about 300 mg per day to about 600 mg per day, from about 300 mg per day to about 700 mg per day, from about 300 mg per day to about 800 mg per day, from about 300 mg per day to about 900 mg per day, from about 300 mg per day to about 1,000 mg per day, from about 400 mg per day to about 500 mg per day, from about 400 mg per day to about 600 mg per day, from about 400 mg per day to about 700 mg per day, from about 400 mg per day to about 800 mg per day, from about 400 mg per day to about 900 mg per day, from about 400 mg per day to about 1,000 mg, from about 500 mg to about 600 mg per day, from about 500 mg to about 700 mg per day, from about 500 mg to about 800 mg per day, from about 500 mg to about 900 mg per day, from about 500 mg to about 1,000 mg per day, from about 600 mg to about 700 mg per day, from about 600 mg to about 800 mg per day, from about 600 mg to about 900 mg per day, from about 600 mg to about 1,000 mg per day, from about 700 mg to about 800 mg per day, from about 700 mg to about 900 mg per day, from about 700 mg to about 1,000 mg per day, from about 800 mg to about 900 mg per day, from about 800 mg to about 1,000 mg per day, or from about 900 mg to about 1,000 mg per day. In some embodiments, the dose is about 1 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg per day. In some embodiments, the dose is at least about 1 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg per day. In some embodiments, the dose is at most about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg per day.,

[0559] In some embodiments, the dose is from about 0.1 mg / kg to about 200 mg / kg. In some embodiments, the dose is from about 0.1 mg / kg to about 1 mg / kg, from about 0.1 mg / kg to about 3 mg / kg, from about 0.1 mg / kg to about 5 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 50 mg / kg, from about 0.1 mg / kg to about 70 mg / kg, from about 0.1 mg / kg to about 90 mg / kg, from about 0.1 mg / kg to about 120 mg / kg, from about 0.1 mg / kg to about 150 mg / kg, from about 0.from about 1 mg / kg to about 200 mg / kg, from about 1 mg / kg to about 3 mg / kg, from about 1 mg / kg to about 5 mg / kg, from about 1 mg / kg to about 10 mg / kg, from about 1 mg / kg to about 50 mg / kg, from about 1 mg / kg to about 70 mg / kg, from about 1 mg / kg to about 90 mg / kg, from about 1 mg / kg to about 120 mg / kg, from about 1 mg / kg to about 150 mg / kg, from about 1 mg / kg to about 200 mg / kg, from about 3 mg / kg to about 5 mg / kg, from about 3 mg / kg to about 10 mg / kg, from about 3 mg / kg to about 50 mg / kg, from about 3 mg / kg to about 70 mg / kg, from about 3 mg / kg to about 90 mg / kg, from about 3 mg / kg to about 120 mg / kg, from about 3 mg / kg to about 150 mg / kg, from about 3 mg / kg to about 200 mg / kg, from about 5 mg / kg to about 10 mg / kg, from about 5 mg / kg to about 50 mg / kg, from about 5 mg / kg to about 70 mg / kg, from about 5 mg / kg to about 90 mg / kg, from about 5 mg / kg to about 120 mg / kg, from about 5 mg / kg to about 150 mg / kg, from about 5 mg / kg to about 200 mg / kg, from about 10 mg / kg to about 50 mg / kg, from about 10 mg / kg to about 70 mg / kg, from about 10 mg / kg to about 90 mg / kg, from about 10 mg / kg to about 120 mg / kg, from about 10 mg / kg to about 150 mg / kg, from about 10 mg / kg to about 200 mg / kg, from about 50 mg / kg to about 70 mg / kg, from about 50 mg / kg to about 90 mg / kg, from about 50 mg / kg to about 120 mg / kg, from about 50 mg / kg to about 150 mg / kg, from about 50 mg / kg to about 200 mg / kg, from about 70 mg / kg to about 90 mg / kg, from about 70 mg / kg to about 120 mg / kg, from about 70 mg / kg to about 150 mg / kg, from about 70 mg / kg to about 200 mg / kg, from about 90 mg / kg to about 120 mg / kg, from about 90 mg / kg to about 150 mg / kg, from about 90 mg / kg to about 200 mg / kg, from about 120 mg / kg to about 150 mg / kg, from about 120 mg / kg to about 200 mg / kg, or from 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 0.1 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, or about 150 mg / kg. In some embodiments, the dose is at most 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.

[0560] Example

[0561] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0562] Chemical synthesis

[0563] All reactions were carried out in dried glassware. NMR was performed on a 400 MHz Bruker.

[0564] Example 1

[0565] Reaction Scheme 1

[0566]

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

[0568]

[0569] To a mixture of 1-bromo-2-methoxy-4-methyl-benzene (10 g, 49.74 mmol, 1 equiv) in CCl4 (100 mL) was added AIBN (816.71 mg, 4.97 mmol, 0.1 equiv) and NBS (9.29 g, 52.22 mmol, 1.05 equiv), 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 chromatography ( 80 g flash silica column, eluent 0 - 10% ethyl acetate / petroleum ether gradient, 60 mL / min). The compound 1-bromo-4-(bromomethyl)-2-methoxy-benzene was obtained as a yellow oil (13.9 g, 49.65 mmol, 99% yield). 1H NMR (400 MHz, chloroform-d) δ = 7.50 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 6.88 (br d, J = 8.0 Hz, 1H), 4.46 (s, 2H), 3.92 (s, 3H).

[0570] Synthesis of Methyl 2-[(4-Bromo-3-methoxyphenyl)methoxy]acetate

[0571]

[0572] To a mixture of methyl 2-hydroxyacetate (4.50 g, 50.01 mmol, 3.86 mL, 2 equiv) in THF (50 mL) was added NaH (2.10 g, 52.51 mmol, 60% purity, 2.1 equiv). 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. The mixture was stirred at 20 - 40 °C for 34 h. The reaction mixture was quenched with saturated NH4Cl (100 mL) and extracted with EtOAc (100 mL * 3). The combined organic phases were washed with brine (100 mL * 1), 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 ( 80 g Flash silica gel column, eluent was 0 - 11% ethyl acetate / petroleum ether gradient, 60 mL / min). The compound methyl 2-[(4-bromo-3-methoxyphenyl)methoxy]acetate was obtained as a yellow oil (3.88 g, 13.42 mmol, 54% yield). 1H 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).

[0573] Synthesis of 2-[(4-Bromo-3-methoxyphenyl)methoxy]acetic Acid

[0574]

[0575] To a solution of methyl 2-[(4-bromo-3-methoxyphenyl)methoxy]acetate (3.68 g, 12.73 mmol, 1 equiv) in THF (20 mL) was added a solution of LiOH·H₂O (2.14 g, 50.91 mmol, 4 equiv) in H₂O (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, the cake was collected and dried in vacuo. Compound 2-[(4-bromo-3-methoxyphenyl)methoxy]acetic acid was obtained as a yellow solid (2.9 g, 10.54 mmol, 83% yield). ¹H NMR (400 MHz, DMSO-d₆) δ = 12.70 (br s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 1.2 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 4.52 (s, 2H), 4.08 (s, 2H), 3.84 (s, 3H).

[0576] Synthesis of 6-bromo-7-methoxy-isochroman-4-one

[0577]

[0578] At 0 °C, (COCl)₂ (1.79 g, 14.09 mmol, 1.23 mL, 1.55 equiv) and DMF (0.1 mL) were added to a solution of 2-[(4-bromo-3-methoxyphenyl)methoxy]acetic acid (2.5 g, 9.09 mmol, 1 equiv) in DCM (25 mL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 2-[(4-bromo-3-methoxyphenyl)methoxy]acetyl chloride was obtained as a yellow oil (2.67 g, crude).

[0579] At 0 °C under N₂ atmosphere, stannic tetrachloride (1 M, 18.65 mL, 2.05 equiv) was added to a solution of 2-[(4-bromo-3-methoxyphenyl)methoxy]acetyl chloride (2.67 g, 9.10 mmol, 1 equiv) in chlorobenzene (25 mL). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with saturated NaHCO₃ (100 mL) and H₂O (100 mL), and extracted with EtOAc (200 mL × 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na₂SO₄. 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 ( 40 g Silica gel quick column, eluent: 0 - 20% ethyl acetate / petroleum ether gradient, 50 mL / min). The compound 6-bromo-7-methoxy-isochroman-4-one (1.08 g, 4.20 mmol, 46% yield) was obtained as a yellow solid. 1 1H NMR (400 MHz, chloroform-d) δ = 8.25 (s, 1H), 6.67 (s, 1H), 4.85 (s, 2H), 4.33 (s, 2H), 3.98 (s, 3H). Synthesis of ethyl 2-(6-bromo-7-methoxy-4-oxo-isochroman-3-yl)-2-oxo-acetate

[0580]

[0581] Under -78 °C and N2 atmosphere, n-BuLi (2.5 M, 1.01 mL, 1.3 equivalents) was added dropwise to a solution of N-isopropylpropan-2-amine (393.61 mg, 3.89 mmol, 549.74 μL, 2 equivalents) in THF (10 mL). The mixture was stirred at -78 °C for 15 min, then slowly warmed to -10 °C and stirred for 30 min under N2 atmosphere. Under -78 °C and N2 atmosphere, 6-bromo-7-methoxy-isochroman-4-one (500 mg, 1.94 mmol, 1 equivalent) in THF (5 mL) was added dropwise to the reaction mixture. The mixture was stirred at -78 °C for 1 h under N2 atmosphere. After 1 h, diethyl oxalate was added dropwise to the mixture of (454.77 mg, 3.11 mmol, 425.02 μL, 1.6 equivalents) in THF (2 mL) at -78 °C. The reaction mixture was slowly warmed to 0 °C and stirred for 1 h under N2. The reaction mixture was cooled to -5 °C, then acidified to pH = 6 with 1 M aqueous HCl. A precipitate formed in the reaction mixture. The mixture was filtered, the filter cake was collected and dried in vacuo to obtain ethyl 2-(6-bromo-7-methoxy-4-oxo-isochroman-3-yl)-2-oxo-acetate (410 mg, crude product) as a yellow solid. 1 1H NMR (400 MHz, 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 = 7.2 Hz, 3H).

[0582] Synthesis of ethyl 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazole-3-carboxylate

[0583]

[0584] Under N2 atmosphere, AcOH (344.68 mg, 5.74 mmol, 328.58 μL, 5 eq) and (3,5-dichlorophenyl)hydrazine hydrochloride (245.08 mg, 1.15 mmol, 1 eq) were added to a solution of ethyl 2-(6-bromo-7-methoxy-4-oxoisochroman-3-yl)-2-oxoacetate (410 mg, 1.15 mmol, 1 eq) in t-BuOH (5 mL). The mixture was stirred at 110 °C for 16 h. 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 min. It was filtered, and the filter cake was collected and dried in vacuo. 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 (400 MHz, DMSO-d6) δ = 7.90 (t, J = 2.0 Hz, 1H), 7.80 (d, J = 2.0 Hz, 2H), 7.29 (s, 1H), 6.94 (s, 1H), 5.30 (s, 2H), 4.32 (q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H).

[0585] Synthesis of 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazole-3-carboxylic acid

[0586]

[0587] 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 eq) in THF (5 mL) and EtOH (2 mL) was added a solution of LiOH·H2O (70.76 mg, 1.69 mmol, 2 eq) in H2O (5 mL). The mixture was stirred at 40 °C for 16 h. 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. A precipitate formed in the reaction mixture. The mixture was filtered, and the filter cake was collected and dried in vacuo. 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. 11H NMR (400 MHz, DMSO-d6) δ = 7.88 (t, J = 2.0 Hz, 1H), 7.79 (d, J = 2.0 Hz, 2H), 7.30 (s, 1H), 6.96 (s, 1H), 5.27 (s, 2H), 3.89 (s, 3H).

[0588] Synthesis of [8-Bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone

[0589]

[0590] 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 to the mixture. The mixture was stirred at 25 - 40 °C for 18 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL * 3). The combined organic phases were washed with brine (20 mL) and 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 ( 4 g Silica gel flash column, eluent was 0 - 40% ethyl acetate / petroleum ether gradient, 40 mL / min). The compound [8-Bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isochromeno[4,3-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone was obtained as a yellow solid (180 mg, 317.32 μmol, 60% yield). 1 1H NMR (400 MHz, chloroform-d) δ = 7.52 (d, J = 1.6 Hz, 2H), 7.46 (t, J = 1.6 Hz, 1H), 7.17 (s, 1H), 6.82 (s, 1H), 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).

[0591] 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

[0592]

[0593] 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 H2O (1.5 mL) was added K2CO3 (52.63 mg, 380.78 μmol, 2 equiv), Pd(dppf)Cl2 (13.93 mg, 19.04 μmol, 0.1 equiv), and the mixture was stirred at 60 °C under N2 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 chromatography ( 4 g silica flash column, eluent 0 - 42% ethyl acetate / petroleum ether gradient, 40 mL / min). 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 was obtained as a yellow solid (75 mg, 127.02 μmol, 67% yield).

[0594] 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

[0595]

[0596] 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 K2CO3 (3 M, 84.68 μL, 2 equiv) and H2O2 (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 Na2SO3 (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. 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 um; mobile phase: [water (TFA)-ACN]; gradient: 38%-68% B, over min), then lyophilized. 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 was obtained as a yellow solid (22.74 mg, 31.47 μmol, 25% yield, 100% purity, TFA). LCMS (ESI): C 30 H 28 C l2 Calculated m / z [M + H] for C 1 H NMR (400 MHz, 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 = 7.2 Hz, 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.

[0597] 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

[0598]

[0599] 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 H2O (1 mL) was added K2CO3 (35.08 mg, 253.85 μmol, 2 equiv), Pd(dppf)Cl2 (9.29 mg, 12.69 μmol, 0.1 equiv), and the mixture was stirred at 80 °C under N2 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*10um; mobile phase: [water (TFA)-ACN]; gradient: 55%-85% B, over min), and then lyophilized. 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 was obtained as a gray solid (25.06 mg, 36.72 μmol, 29% yield, 100% purity, TFA). LCMS (ESI): C 28 H 28 C l2 Calculated m / z [M+H] for C 1 H NMR (400 MHz, chloroform-d) δ = 7.59 (s, 2H), 7.46 (br d, J = 13.2 Hz, 2H), 7.41 - 7.36 (m, 1H), 6.91 - 6.82 (m, 1H), 6.54 (s, 1H), 5.28 (br s, 2H), 3.94 (brd, J = 14.8 Hz, 6H), 3.88 - 3.83 (m, 2H), 3.73 (br t, J = 4.8 Hz, 2H), 3.51 (s, 2H), 1.57 (s, 6H). Figure 12 Shows the nuclear magnetic resonance of compound 2-05.

[0600] Synthesis of compound 2-02

[0601]

[0602] Compound 2-02 was synthesized by a procedure similar to that of Example 1. LCMS (ESI): C 29 H 28Calculated m / z [M+H] for 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 The nuclear magnetic resonance of compound 2-02 is shown.

[0603] Synthesis of compound 2-03

[0604]

[0605] Compound 2-03 was synthesized by a procedure similar to that of Example 1. LCMS (ESI): C 28 H 28 Calculated m / z [M+H] for H N5O5S: 546.17; Found: 546.3. 1 H NMR (400 MHz, 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 = 12.0 Hz, 2H), 6.33 - 6.22 (m, 1H), 5.31 (s, 2H), 3.90 (s, 3H), 3.84 (br d, J = 4.8 Hz, 2H), 3.78 (br d, J = 4.8 Hz, 2H), 3.49 (s, 2H), 1.55 (s, 6H). Figure 10 The nuclear magnetic resonance of compound 2-03 is shown.

[0606] Synthesis of compound 2-04

[0607]

[0608] Compound 2-04 was synthesized by a procedure similar to that of Example 1. LCMS (ESI): C 27 H 28 Calculated m / z [M+H] for H N5O4S: 518.18; Found: 518.3. 11H 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.

[0609] Synthesis of compound 2-06

[0610]

[0611] Compound 2-06 was synthesized by a procedure similar to that of Example 1. LCMS (ESI): C 27 H 28 Calculated m / z [M+H] for C12H15Cl2N5O3: 540.15; Found: 540.3. 1 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.

[0612] Synthesis of compound 2-07

[0613]

[0614] Compound 2-07 was synthesized by a procedure similar to that of Example 1. LCMS (ESI): C 26 H 28 Calculated m / z [M+H] for C12H15N5O4S: 506.18; Found: 506.4. 1 1H 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.

[0615] Synthesis of Compound 2-08

[0616]

[0617] Compound 2-08 was synthesized by a procedure similar to that of Example 1. LCMS (ESI): C 25 H 28 Calculated m / z [M+H] for C 1 H Figure 15 N5O3S: 578.18; Found: 578.3.

[0618] Example 2

[0619] Reaction Scheme 2

[0620]

[0621] Synthesis of 1-bromo-4-(bromomethyl)-2-methoxy-benzene

[0622]

[0623] 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 for 16 h under a N2 atmosphere. The mixture was concentrated to give a residue. The residue was purified by flash silica chromatography ( 220 g flash silica column, eluent 0 - 7% ethyl acetate / petroleum ether gradient, 80 mL / min). Compound 1-bromo-4-(bromomethyl)-2-methoxy-benzene was obtained as a colorless oil (34 g, 121.45 mmol, 98% yield). 11H NMR (400 MHz, chloroform-d) δ = 7.50 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 1.9 Hz, 1H), 6.87 (dd, J = 1.8, 8.1 Hz, 1H), 4.45 (s, 2H), 3.94 - 3.90 (m, 3H).

[0624] Synthesis of Ethyl 2-[(4-Bromo-3-methoxyphenyl)methylthio]acetate

[0625] At 0 °C, NaH (1.50 g, 37.51 mmol, 60% purity, 1.5 eq) was added dropwise to a solution of ethyl 2-thioacetate (3.85 g, 32.04 mmol, 3.51 mL, 1.28 eq) in THF (70 mL). After 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 eq) 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 phases were 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 ( 80 g Flash silica gel column, eluent 0 - 25% ethyl acetate / petroleum ether gradient, 60 mL / min). Ethyl 2-[(4-Bromo-3-methoxyphenyl)methylthio]acetate was obtained as a colorless oil (5.9 g, 18.48 mmol, 74% yield) 1 1H NMR (400 MHz, chloroform-d) δ = 7.46 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 1.4 Hz, 1H), 6.81 (dd, J = 1.5, 8.0 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 3.79 (s, 2H), 3.06 (s, 2H), 1.29 (t, J = 7.1 Hz, 3H).

[0626] Synthesis of 2-[(4-Bromo-3-methoxyphenyl)methylthio]acetic Acid

[0627]

[0628] A mixture of ethyl 2-[(4-bromo-3-methoxyphenyl)methylthio]acetate (14.5 g, 45.42 mmol, 1 equiv) and LiOH·H₂O (7.62 g, 181.70 mmol, 30 mL, 4 equiv) in EtOH (150 mL) was stirred at 25 °C for 2 h under a N₂ atmosphere. 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 (150 mL × 3). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated to give the product. The crude product, 2-[(4-bromo-3-methoxyphenyl)methylthio]acetic acid (12 g, crude), obtained as a colorless oil, was used directly without further purification. 1 ¹H NMR (400 MHz, methanol-d₄) δ = 7.44 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 6.83 (br d, J = 7.8 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 2H), 3.12 (s, 2H).

[0629] Synthesis of 6-bromo-7-methoxy-isothiochroman-4-one

[0630]

[0631] To a solution of 2-[(4-bromo-3-methoxyphenyl)methylthio]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-methoxyphenyl)methylthio]acetyl chloride (13 g, crude), obtained as a yellow oil, was used directly without further purification.

[0632] At 0 °C, SnCl₄ (1 M, 83.98 mL, 2 equiv) was added to a solution of 2-[(4-bromo-3-methoxyphenyl)methylthio]acetyl chloride (13 g, 41.99 mmol, 1 equiv) in chlorobenzene (100 mL). The mixture was stirred at 0 °C for 1 h. The reaction was quenched with saturated NaHCO₃ (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 phases were washed with brine (500 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography ( 220 g Silica gel quick column, eluent: 0 - 30% ethyl acetate / petroleum ether gradient, 80 mL / min). 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 (400 MHz, chloroform-d) δ = 8.28 (s, 1H), 6.66 (s, 1H), 3.96 (s, 3H), 3.86 (s, 2H), 3.51 (s, 2H).

[0633] Synthesis of ethyl 2-(6-bromo-7-methoxy-4-oxo-isothiochroman-3-yl)-2-oxo-acetate

[0634]

[0635] To a solution of 6-bromo-7-methoxy-isothiochroman-4-one (1.1 g, 4.03 mmol, 1 equiv) in THF (15 mL) at -70 °C was added dropwise LiHMDS (1 M, 5.24 mL, 1.3 equiv) over 10 min. After addition, the mixture was stirred at -70 °C for 0.5 h, 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 h. The mixture was poured into ice water (20 mL), and the reaction mixture was acidified to pH = 6 with 1 M aqueous HCl. A precipitate formed in the reaction mixture. The mixture was filtered, and the filter cake was collected and dried in vacuo. The compound ethyl 2-(6-bromo-7-methoxy-4-oxo-isothiochroman-3-yl)-2-oxo-acetate (1.2 g, 3.22 mmol, 80% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 7.93 (s, 1H), 7.15 (s, 1H), 4.24 (q, J = 7.0 Hz, 2H), 3.94 (s, 3H), 3.90 (s, 2H), 1.28 (t, J = 7.1 Hz, 3H).

[0636] Synthesis of 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isothiochromeno[4,3-c]pyrazole-3-carboxylate

[0637]

[0638] 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 EtOH (2 mL) was stirred at 80 °C for 5 h under a N2 atmosphere. The mixture was filtered, the cake was collected and dried in vacuo 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): C 20 H 16 Calculated m / z [M+H] for C15H10BrCl2N2O3S: 512.94; Found: 512.8. 1 1H NMR (400 MHz, DMSO-d6) δ = 7.91 - 7.87 (m, 1H), 7.77 (d, J = 1.6 Hz, 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).

[0639] Synthesis of 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-5H-isothiochromeno[4,3-c]pyrazole-3-carboxylic acid

[0640]

[0641] 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.H2O (571.25 mg, 13.61 mmol, 6 mL, 5 equiv) in THF (10 mL), EtOH (10 mL) and H2O (2 mL) was stirred at 25 °C for 16 h under a N2 atmosphere. 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 phases were washed with brine (50 mL), dried over anhydrous Na2SO4. 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): C18 H 12 Calculated m / z [M+H] for BrCl₂N₂O₃S: 484.91; Found: 484.7. 1 ¹H NMR (400 MHz, 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).

[0642] Synthesis of (8-Bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,5-dihydroisothiochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone

[0643]

[0644] At 25 °C, HATU (703.89 mg, 1.85 mmol, 1.5 eq) and DIEA (478.51 mg, 3.70 mmol, 644.90 μL, 3 eq) were added 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 eq) in THF (10 mL). After addition, the mixture was stirred at this temperature for 0.5 h, then 3,3-dimethylmorpholine (156.35 mg, 1.36 mmol, 1.1 eq) 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 phases were washed with brine (50 mL) and 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 ( 10 g Flash silica gel column, eluent with 0 - 20% ethyl acetate / petroleum ether gradient, 40 mL / min). The compound (8-Bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,5-dihydroisothiochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone was obtained as a yellow oil (0.6 g, 1.03 mmol, 83% yield). LCMS (ESI): C 24 H 23 Calculated m / z [M+H] for BrCl₂N₃O₃S: 581.99; Found: 582.0.

[0645] 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

[0646]

[0647] 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), K2CO3 (165.85 mg, 1.20 mmol, 2 equiv) and Pd(dppf)Cl2 (43.90 mg, 60.00 μmol, 0.1 equiv) in dioxane (5 mL) and H2O (0.5 mL) was degassed and purged with N2 twice, then heated to 60 °C under N2 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 chromatography ( 10 g Flash silica column, eluent 0 - 40% ethyl acetate / petroleum ether gradient, 40 mL / min). 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 was obtained as a yellow solid (0.2 g, 329.75 μmol, 55% yield). LCMS (ESI): C 30 H 26 Calculated m / z [M + H] for C22H20Cl2N5O3S: 606.11; found: 606.2.

[0648] 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

[0649]

[0650] At 0 °C, K2CO3 (136.72 mg, 989.25 μmol, 3 eq) and H2O2 (0.420 g, 3.70 mmol, 355.93 μL, 30% purity, 11.23 eq) were added 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 eq) in DMSO (3 mL). The mixture was stirred at 0 - 25 °C for 2 h. The reaction was quenched with saturated Na2SO3 (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with brine (50 mL) and dried over anhydrous Na2SO4. 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 um; mobile phase: [water (TFA)-ACN]; gradient: 42% - 72% B, over 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 was obtained as a white solid (160 mg, 216.64 μmol, 66% yield, TFA). LCMS (ESI): C 30 H 28 Calculated m / z [M+H] for C25H24Cl2N5O4S: 624.12; found: 624.2. 1 H NMR (400 MHz, methanol-d4) 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 Nuclear magnetic resonance of compound 3-01 is shown. 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

[0651]

[0652] 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), K2CO3 (118.46 mg, 857.16 μmol, 2 equiv) and Pd(dppf)Cl2 (31.36 mg, 42.86 μmol, 0.1 equiv) in a mixture of dioxane (5 mL) and H2O (0.5 mL) was degassed and purged with N2 three times, then heated to 60 °C under N2 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 ( 10 g Flash silica gel column, eluent was 0 - 40% ethyl acetate / petroleum ether gradient, 40 mL / min). 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 was obtained as a white solid (220 mg, 376.38 μmol, 88% yield). LCMS (ESI): C 28 H 28 Calculated m / z [M+H] for C22H25Cl2N5O3S: 584.1211; found: 584.2. 1 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 The nuclear magnetic resonance of compound 3-03 is shown.

[0653] Reaction Scheme 3

[0654]

[0655] Synthesis of 8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide

[0656]

[0657] At 25 °C, HATU (702.17 mg, 1.85 mmol, 1.5 equiv) and DIEA (477.34 mg, 3.69 mmol, 643.32 μL, 3 equiv) were added 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). 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 phases were 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 ( 10 g flash silica gel column, eluent 0 - 20% ethyl acetate / petroleum ether gradient, 40 mL / min). The compound 8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide was obtained as a yellow oil (0.65 g, 1.17 mmol, 95% yield). LCMS (ESI): C 23 H 22 Calculated m / z [M + H] for CBrCl2N3O2S: 554.00; Found: 554.1. 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

[0658]

[0659] 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)nicotinonitrile (165.72 mg, 720.31 μmol, 1 equiv), K2CO3 (199.10 mg, 1.44 mmol, 2 equiv) and Pd(dppf)Cl2 (52.71 mg, 72.03 μmol, 0.1 equiv) in a mixture of dioxane (5 mL) and H2O (0.5 mL) were degassed and purged with N2 three times, then heated to 60 °C under N2 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 chromatography ( 10 g Flash silica column, eluent 0 - 40% ethyl acetate / petroleum ether gradient, 40 mL / min). The compound N-tert-butyl-8-(5-cyano-3-pyridinyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide was obtained as a yellow solid (0.4 g, 691.43 μmol, 96% yield). LCMS (ESI): C 29 H 25 alculated m / z [M + H] for C25H22Cl2N5O2S: 578.10; found: 578.1.

[0660] Synthesis of N-tert-butyl-8-(5-carbamoyl-3-pyridinyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-5H-isothiochromeno[4,3-c]pyrazole-3-carboxamide

[0661]

[0662] At 0 °C, K2CO3 (286.68 mg, 2.07 mmol, 3 eq) and H2O2 (0.790 g, 6.97 mmol, 669.49 μL, 30% purity, 10.08 eq) were added 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 eq) in DMSO (5 mL). The mixture was stirred at 0 - 25 °C for 2 h. The reaction was quenched with saturated Na2SO3 (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with brine (50 mL) and dried over anhydrous Na2SO4. 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 um; mobile phase: [water (TFA)-ACN]; gradient: 50% - 80% B, over min). 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 was obtained as a white solid (160 mg, 225.18 μmol, 33% yield, TFA). LCMS (ESI): C 29 H 27 Calculated m / z [M+H] for C22H22Cl2N5O3S: 596.12; found: 596.2. 1 H NMR (400 MHz, methanol-d4) 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 1H NMR spectrum of compound 3-02 is shown.

[0663] 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

[0664]

[0665] 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 Na2SO3 (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL * 2). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. 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 * 10um; mobile phase: [water (TFA)-ACN]; gradient: 38%-68% B, over 9 min). Obtained as a white solid was 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). LCMS (ESI): C 29 H 27 Calculated m / z [M+H] for Cl2N5O4S: 612.12; found: 612.2. 1 H NMR (400 MHz, chloroform-d) δ = 8.92 (s, 1H), 8.57 (s, 1H), 8.02 - 7.97 (m, 1H), 7.56 (t, J = 1.8 Hz, 1H), 7.49 (d, J = 1.7 Hz, 2H), 7.18 (s, 1H), 7.02 (s, 1H), 4.58 (d, J = 15.4 Hz, 1H), 4.03 (d, J = 15.3 Hz, 1H), 3.89 (s, 3H), 3.21 (s, 3H), 1.57 (s, 9H). Figure 20 Nuclear magnetic resonance of compound 3-07 is shown.

[0666] 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

[0667]

[0668] 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) in dioxane (5 mL) and H2O (0.5 mL), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (93.67 mg, 450.20 μmol, 1 equiv), K2CO3 (124.44 mg, 900.39 μmol, 2 equiv) and Pd(dppf)Cl2 (32.94 mg, 45.02 μmol, 0.1 equiv) were degassed and purged with N2 three times, then heated to 60 °C under N2 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 chromatography ( 10 g Flash silica column, eluent 0 - 40% ethyl acetate / petroleum ether gradient, 40 mL / min). 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 was obtained as a white solid (0.2 g, 359.39 μmol, 80% yield). LCMS (ESI): C 27 H 27 Calculated m / z [M+H] for C22H22Cl2N5O2S: 556.13; found: 556.3. 1 H NMR (400 MHz, chloroform-d) δ = 7.52 (d, J = 1.7 Hz, 2H), 7.45 (s, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 6.93 (s, 1H), 6.50 (d, J = 2.1 Hz, 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 The nuclear magnetic resonance of compound 3-04 is shown.

[0669] Example 3

[0670] Reaction Scheme 4

[0671]

[0672] Synthesis of 5-bromo-6-methoxy-benzofuran-3-one

[0673]

[0674] At 0 °C, NBS (15.87 g, 89.18 mmol, 1.2 eq) was added to a mixture of 6-methoxybenzofuran-3(2H)-one (12.2 g, 74.32 mmol, 1 eq) in DMF (60 mL). The mixture was stirred at 15 °C for 20 h. The mixture was poured into H2O (600 mL). A precipitate formed in the reaction mixture. The resulting mixture was filtered, and the filter cake was dried in vacuo to give 5-bromo-6-methoxybenzofuran-3(2H)-one as a brown solid (16.5 g, 61.78 mmol, 83% yield, 91% purity). 1 1H NMR (400 MHz, DMSO-d6) δ = 7.81 (s, 1H), 7.08 - 6.97 (m, 1H), 4.83 (s, 2H), 3.96 (s, 3H).

[0675] Synthesis of 4: Ethyl 2-(5-bromo-6-methoxy-3-oxo-2,3-dihydrobenzofuran-2-yl)-2-oxoacetate

[0676]

[0677] At -78 °C under a N2 atmosphere, LDA (2 M, 47.15 mL, 1.2 eq) was added to a mixture of 5-bromo-6-methoxybenzofuran-3(2H)-one (19.1 g, 78.58 mmol, 1 eq) in THF (150 mL). 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 eq) 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 phases were washed with brine (200 mL) and dried over Na2SO4. 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 as a brown solid (35 g, crude). 1 1H NMR (400 MHz, DMSO-d6) δ = 8.26 (s, 1H), 7.38 (s, 1H), 4.34 (q, J = 7.09 Hz, 2H), 3.94 (s, 3H), 1.30 (t, J = 7.09 Hz, 3H).

[0678] Synthesis of Ethyl 7-bromo-6-methoxy-1-(4-methoxybenzyl)-1H-benzofuro[3,2-c]pyrazole-3-carboxylate

[0679]

[0680] 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 AcOH (2 mL) was added (4-methoxyphenyl)methylhydrazine hydrochloride (164.94 mg, 874.31 μmol, 1 equiv), and the mixture was stirred at 110 °C for 1 h. The pH of the reaction mixture was adjusted to 7 with saturated NaHCO3, and the resulting mixture was extracted with ethyl acetate (50 mL * 3). The combined organic phases were concentrated in vacuo to give a residue. The residue was purified by flash silica gel column 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. Synthesis of ethyl 6-methoxy-7-(1-methylpyrazol-3-yl)-1H-benzofuro[3,2-c]pyrazole-3-carboxylate

[0681]

[0682] 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) was added TFA (160.95 mg, 1.41 mmol, 104.85 μL, 1 equiv), 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 column chromatography (petroleum ether:ethyl acetate = 5:1 - 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.

[0683] 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

[0684]

[0685] To a mixture of ethyl 6-methoxy-7-(1-methylpyrazol-3-yl)-1H-benzo[f]chromene-3-carboxylate (320 mg, 940.26 μmol, 1 equiv) and 3-thiopheneboronic acid (180.47 mg, 1.41 mmol, 1.5 equiv) in DCM (10 mL) was added Cu(OAc)2 (170.78 mg, 940.26 μmol, 1 equiv), Py (148.75 mg, 1.88 mmol, 151.78 μL, 2 equiv), 4A MS (50 mg), and the mixture was stirred at 25 °C for 16 h under an O2 (15 psi) atmosphere. H2O (20 mL) and NH3·H2O (1 mL) were added, and the resulting mixture was extracted with ethyl acetate (20 mL * 3). The combined organic phases were concentrated in vacuo to give a residue. The residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) and by preparative TLC (petroleum ether:ethyl acetate = 2:1) (3rd purification) to give ethyl 6-methoxy-7-(1-methylpyrazol-3-yl)-1-(3-thienyl)benzo[f]chromene-3-carboxylate as a brown solid (23 mg, 54.44 μmol, 6% yield). 1H NMR (400 MHz, DMSO-d6) δ = 8.18 (s, 1H), 7.63 (dd, J = 1.3, 3.2 Hz, 1H), 7.58 (dd, J = 3.2, 5.1 Hz, 1H), 7.49 - 7.41 (m, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.21 (s, 1H), 6.74 (d, J = 2.0 Hz, 1H), 4.47 (q, J = 7.2, 2H), 3.91 (s, 6H), 1.42 (t, J = 7.2, 3H).

[0686] Ethyl 6-methoxy-7-(1-methylpyrazol-3-yl)-2-(3-thienyl)benzo[f]chromene-3-carboxylate was obtained as a brown solid (180 mg, 426.08 μmol, 45% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 8.43 (s, 1H), 7.56 (dd, J = 1.3, 3.2 Hz, 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 = 2.2 Hz, 1H), 4.43 (q, J = 7.2, 2H), 3.98 (s, 6H), 1.41 (t, J = 7.2, 3H).

[0687] Synthesis of 6-Methoxy-7-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)benzo[f]chromeno[3,2-c]pyrazole-3-carboxylic acid

[0688]

[0689] To a mixture of ethyl 6-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)benzo[f]chromeno[3,2-c]pyrazole-3-carboxylate (23 mg, 54.44 μmol, 1 equiv) in H2O (1 mL) and THF (2 mL) was added LiOH·H2O (6.85 mg, 163.33 μmol, 3 equiv), and the mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo to remove THF. The pH of the reaction mixture was adjusted to 6 with 1 M aqueous HCl. A precipitate formed in the reaction mixture, and the resulting mixture was filtered and the cake was dried in vacuo to give 6-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)benzo[f]chromeno[3,2-c]pyrazole-3-carboxylic acid as a pale green solid (20 mg, 50.71 μmol, 93% yield).

[0690] (3,3-Dimethylmorpholin-4-yl)[6-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)benzo[f]chromeno[3,2-c]pyrazol-3-yl]methanone synthesis

[0691]

[0692] To a mixture of 6-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)benzo[f]chromeno[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 h. The mixture was filtered. The filtrate was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 52%-82% B over 9 min), then lyophilized to give (3,3-dimethylmorpholin-4-yl)[6-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)benzo[f]chromeno[3,2-c]pyrazol-3-yl]methanone as a yellow solid (5.69 mg, 9.40 μmol, 19% yield, TFA). LCMS (ESI): C 25H 26 Calculated m / z [M+H] for N5O4S: 492.16; Found: 492.1. 1H NMR (400 MHz, DMSO-d6) δ = 7.81 (s, 1H), 7.54 (dd, J = 1.3, 3.2 Hz, 1H), 7.48 (dd, J = 3.2, 5.1 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.19 (dd, J = 1.4, 5.2 Hz, 1H), 7.17 (s, 1H), 6.30 (d, J = 2.2 Hz, 1H), 3.56 (s, 3H), 3.50 (s, 3H), 3.47 (br d, J = 5.3 Hz, 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.

[0693] (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 synthesis

[0694]

[0695] 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): C 25 H 26 Calculated m / z [M+H] for N5O4S: 492.16; Found: 492.1. 1H NMR (400 MHz, DMSO-d6) δ = 8.36 - 8.28 (m, 1H), 7.75 - 7.71 (m, 2H), 7.64 (dd, J = 1.4, 3.2 Hz, 1H), 7.53 (s, 1H), 7.33 (dd, J = 1.4, 5.1 Hz, 1H), 6.73 (d, J = 2.3 Hz, 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.

[0696] Example 4

[0697] Reaction Scheme 5

[0698]

[0699] Synthesis of ethyl 7-bromo-6-methoxy-1H-benzo[f]chromeno[3,2-c]pyrazole-3-carboxylate

[0700]

[0701] A mixture of ethyl 7-bromo-6-methoxy-1-(4-methoxybenzyl)-1H-benzo[f]chromeno[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 column chromatography (petroleum ether:ethyl acetate = 5:1 - 2:1) to afford ethyl 7-bromo-6-methoxy-1H-benzo[f]chromeno[3,2-c]pyrazole-3-carboxylate as a white solid (145 mg, 427.55 μmol, 98% yield).

[0702] Synthesis of ethyl 7-bromo-6-methoxy-1-(thiophen-3-yl)benzo[f]chromeno[3,2-c]pyrazole-3-carboxylate and ethyl 7-bromo-6-methoxy-2-(thiophen-3-yl)benzo[f]chromeno[3,2-c]pyrazole-3-carboxylate

[0703]

[0704] To a mixture of ethyl 7-bromo-6-methoxy-1H-benzo[f]chromene-3-carboxylate (145 mg, 427.55 μmol, 1 equiv) and 3-thiopheneboronic acid (82.06 mg, 641.33 μmol, 1.5 equiv) in DCM (10 mL) was added Cu(OAc)2 (77.66 mg, 427.55 μmol, 1 equiv), Py (67.64 mg, 855.10 μmol, 69.02 μL, 2 equiv), 4A MS (50 mg, 1.00 equiv), and the mixture was stirred at 25 °C for 16 h under an O2 atmosphere (15 psi). H2O (10 mL) and 25% NH3·H2O (0.5 mL) were added to the mixture, and the resulting mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phases were concentrated in vacuo to give a residue. The residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to give ethyl 7-bromo-6-methoxy-2-(3-thienyl)benzo[f]chromene-3-carboxylate (68 mg, 161.42 μmol, 38% yield) as a white solid and ethyl 7-bromo-6-methoxy-1-(3-thienyl)benzo[f]chromene-3-carboxylate (40 mg, 94.95 μmol, 22% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ = 8.10 (s, 1H), 7.56 (dd, J = 1.3, 3.1 Hz, 1H), 7.39 (dd, J = 3.3, 5.1 Hz, 1H), 7.32 (dd, J = 1.2, 5.2 Hz, 1H), 7.19 (s, 1H), 4.42 (q, J = 7.2 Hz, 2H), 4.00 (s, 3H), 1.45 - 1.41 (m, 3H).

[0705] Ethyl 7-bromo-6-methoxy-2-(3-thienyl)benzo[f]chromene-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).

[0706] Synthesis of ethyl 7-bromo-6-methoxy-1-(3-thienyl)benzo[f]chromene-3-carboxylate

[0707]

[0708] Ethyl 7-bromo-6-methoxy-1-(3-thienyl)benzo[furan[3,2-c]pyrazole-3-carboxylate (200 mg, 474.76 μmol, 1 equiv) was added to a mixture of THF (2 mL) and H2O (1 mL), and LiOH·H2O (59.76 mg, 1.42 mmol, 3 equiv) was added. 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, and the resulting mixture was filtered and the filter cake was dried in vacuo to give 7-bromo-6-methoxy-1-(3-thienyl)benzo[furan[3,2-c]pyrazole-3-carboxylic acid as a brown solid (160 mg, 406.91 μmol, 86% yield).

[0709] Synthesis of [7-bromo-6-methoxy-1-(3-thienyl)benzo[furan[3,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone

[0710]

[0711] HATU (72.52 mg, 190.74 μmol, 1.5 equiv), DIEA (32.87 mg, 254.32 μmol, 44.30 μL, 2 equiv) were added to a mixture of 7-bromo-6-methoxy-1-(3-thienyl)benzo[furan[3,2-c]pyrazole-3-carboxylic acid (50 mg, 127.16 μmol, 1 equiv) in DMF (1 mL), and then 3,3-dimethylmorpholine (21.97 mg, 190.74 μmol, 1.5 equiv) was added. The mixture was stirred at 25 °C for 16 h. H2O (5 mL) was added to the mixture, and then the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phases were concentrated in vacuo to give a residue. The residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 0 - 30%) to give [7-bromo-6-methoxy-1-(3-thienyl)benzo[furan[3,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone as a yellow solid (40 mg, 81.57 μmol, 64% yield).

[0712] Synthesis of 5-[3-(3,3-dimethylmorpholine-4-carbonyl)-6-methoxy-1-(3-thienyl)benzo[furan[3,2-c]pyrazol-7-yl]pyridine-3-carbonitrile

[0713]

[0714] 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 H2O (0.5 mL) and dioxane (1 mL) was added Pd(dppf)Cl2 (5.97 mg, 8.16 μmol, 0.1 equiv), K2CO3 (33.82 mg, 244.71 μmol, 3 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (22.52 mg, 97.89 μmol, 1.2 equiv), and the mixture was stirred at 80 °C under N2 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-dimethylmorpholin-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.

[0715] Synthesis of 5-[3-(3,3-dimethylmorpholin-4-carbonyl)-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazol-7-yl]pyridine-3-carbonitrile and 5-[3-(3,3-dimethylmorpholin-4-carbonyl)-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazol-7-yl]pyridine-3-carbonitrile

[0716]

[0717] 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) was added H2O2 (66.22 mg, 584.15 μmol, 56.12 μL, 30% purity, 10 equiv), K2CO3 (16.15 mg, 116.83 μmol, 2 equiv), and the mixture was stirred at 60 °C for 1 h. Saturated aqueous Na2SO3 (20 mL) was added to the mixture. The mixture was adjusted to pH = 7 with 1 N HCl, the resulting mixture was tested with KI paper (no blue color), and the resulting mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phases were concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 um; mobile phase: [water (TFA)-ACN]; gradient: 33%-63% B over 9 min), then lyophilized to give 5-[3-(3,3-dimethylmorpholine-4-carbonyl)-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazol-7-yl]pyridine-3-carboxamide as an off-white solid (8.55 mg, 13.11 μmol, 22% yield, 99% purity, TFA). LCMS (ESI): calculated m / z [M+H] for C25H25N5O4S: 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.

[0718] Obtained 5-[3-(3,3-dimethylmorpholine-4-carbonyl)-6-methoxy-1-(3-thienyl)benzofuro[3,2-c]pyrazol-7-yl]pyridine-3-carbonitrile as a brown solid (9.42 mg, 14.86 μmol, 25% yield, 99% purity, TFA). LCMS (ESI): Calculated m / z [M+H] for CHNOS: 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.

[0719] Synthesis of compound 4-04

[0720]

[0721] Compound 4-04 was synthesized by a procedure similar to that of Example 4. LCMS (ESI): Calculated m / z [M+H] for CHNOS: 504.16; Found: 504.1. 1H NMR (400 MHz, DMSO-d6) 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.

[0722] Synthesis of compound 4-03A

[0723]

[0724] Compound 4-03A was synthesized by a procedure similar to that of Example 4. LCMS (ESI): calculated m / z [M+H] for C25H25N3O4S is 532.16; found: 532.1. 1H NMR (400 MHz, DMSO-d6) δ = 9.02 (d, J = 1.8 Hz, 1H), 8.93 (d, J = 1.8 Hz, 1H), 8.44 (br s, 1H), 8.25 (br s, 1H), 8.07 (s, 1H), 7.74 (dd, J = 3.2, 5.0 Hz, 1H), 7.70 - 7.64 (m, 3H), 7.34 (d, J = 5.0 Hz, 1H), 3.94 (s, 3H), 3.53 (br d, J = 4.4 Hz, 2H), 3.48 (br d, J = 4.4 Hz, 2H), 3.39 (s, 2H), 1.45 (s, 6H). Figure 31 Nuclear magnetic resonance of compound 4-03A is shown.

[0725] Synthesis of compound 4-04A

[0726]

[0727] Compound 4-04A was synthesized by a procedure similar to that of Example 4. LCMS (ESI): C 26 H 26 Calculated m / z [M+H] for C22H24N4O4S is 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 Nuclear magnetic resonance of compound 4-04A is shown.

[0728] Example 5

[0729] Reaction Scheme 6

[0730]

[0731] Synthesis of 6-bromo-5-methoxy-indan-1-one

[0732]

[0733] At 0 °C, AlCl3 (1.57 g, 11.76 mmol, 642.80 μL, 1.1 eq) was added to a solution of 1-bromo-2-methoxy-benzene (2 g, 10.69 mmol, 1.33 mL, 1 eq) and 3-chloropropanoyl chloride (1.49 g, 11.76 mmol, 1.13 mL, 1.1 eq) in DCM (10 mL). The mixture was stirred at 0 °C for 0.5 h, then H2SO4 (10 mL) was added. The mixture was then concentrated in vacuo to remove DCM. The resulting mixture was stirred at 100 °C for 2 h. The mixture was slowly poured into water and left to stand overnight. A precipitate formed in the reaction mixture, which was filtered and the filter cake was dried in vacuo to give the crude product. The crude product was purified by flash silica chromatography ( 40 g Flash silica column, eluent 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 1H NMR (400 MHz, 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).

[0734] Synthesis of ethyl 2-(6-bromo-5-methoxy-1-oxo-indan-2-yl)-2-oxo-acetate

[0735]

[0736] At -78 °C under a N2 atmosphere, LDA (2 M, 1.24 mL, 1.5 eq) was added to a mixture of 6-bromo-5-methoxy-indan-1-one (400 mg, 1.66 mmol, 1 eq) in THF (6 mL). The mixture was stirred at -78 °C for 15 min, then diethyl oxalate (387.96 mg, 2.65 mmol, 362.58 μL, 1.6 eq) was added. The mixture was stirred at 0 °C for 1 h. The reaction mixture was acidified to pH = 6 with 1 M aqueous HCl, at which point a precipitate formed in the reaction mixture. The precipitate was filtered and the filter cake was dried in vacuo to give ethyl 2-(6-bromo-5-methoxy-1-oxo-indan-2-yl)-2-oxo-acetate (470 mg, 1.38 mmol, 83% yield) as a white solid. 11H NMR (400 MHz, 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 = 7.07 Hz, 3H).

[0737] Synthesis of Ethyl 7-bromo-1-(3,5-dichlorophenyl)-6-methoxy-4H-indeno[1,2-c]pyrazole-3-carboxylate

[0738]

[0739] To a mixture of ethyl 2-(6-bromo-5-methoxy-1-oxo-indan-2-yl)-2-oxo-acetate (300 mg, 879.37 μmol, 1 equiv) in t-BuOH (4 mL) was added 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). 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 grey solid. Synthesis of 7-bromo-1-(3,5-dichlorophenyl)-6-methoxy-4H-indeno[1,2-c]pyrazole-3-carboxylic acid

[0740]

[0741] 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 H2O (3 mL) was added LiOH·H2O (88.77 mg, 2.12 mmol, 3 equiv). The mixture was stirred at 15 °C for 16 h. The reaction mixture was acidified to pH = 3 with 1 M aqueous HCl, and a precipitate formed in the reaction mixture. The precipitate was filtered and dried in vacuo 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. 11H NMR (400 MHz, DMSO-d6) δ = 7.88 (d, J = 1.63 Hz, 2H), 7.84 (d, J = 1.75 Hz, 1H), 7.50 (d, J = 6.38 Hz, 2H), 3.92 (s, 3H), 3.77 (s, 2H). Synthesis of [7-bromo-1-(3,5-dichlorophenyl)-6-methoxy-4H-indeno[1,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone

[0742]

[0743] 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 min, then 3,3-dimethylmorpholine (82.18 mg, 713.50 μmol, 1.2 equiv) was added. The mixture was stirred at 25 °C for 16 h. The mixture was poured into H2O (20 mL), whereby a precipitate formed in the reaction mixture. The precipitate was filtered off and dried in vacuo 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 as a yellow solid (150 mg, 272.10 μmol, 46% yield).

[0744] 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

[0745]

[0746] 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 H2O (0.4 mL) was added Pd(dppf)Cl2 (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 K2CO3 (112.82 mg, 816.31 μmol, 3 equiv). The mixture was stirred at 80 °C under N2 atmosphere for 16 h. The mixture was 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 um; mobile phase: [water (TFA)-ACN]; gradient: 65%-95% B, over 9 min), then lyophilized 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 as a yellow solid (42.8 mg, 72.05 μmol, 26% yield, 93% purity). LCMS (ESI): C 28 H 28 Calculated m / z [M+H] for C 1 H NMR (400 MHz, DMSO-d6) δ = 8.16 (s, 1H), 7.89 (d, J = 1.75 Hz, 2H), 7.82 (t, J = 1.81 Hz, 1H), 7.70 (d, J = 2.13 Hz, 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 1H NMR spectrum of compound 5-05 is shown.

[0747] Synthesis of N-tert-butyl-7-(5-cyano-3-pyridinyl)-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide

[0748]

[0749] To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (179.90 mg, 781.95 μmol, 1.2 equiv) in dioxane (2.5 mL) and H2O (0.5 mL) was added K2CO3 (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)Cl2 (95.36 mg, 130.33 μmol, 0.2 equiv). The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. The reaction mixture was poured into H2O (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 Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography ( 4 g flash silica gel column, eluent 0 - 70% petroleum ether gradient / ethyl acetate, 30 mL / min), to afford N-tert-butyl-7-(5-cyano-3-pyridyl)-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide as a brown solid (200 mg, 413.58 μmol, 63% yield).

[0750] Synthesis of 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-6-methoxy-4H-indeno[1,2-c]pyrazol-7-yl]nicotinamide

[0751]

[0752] 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 H2O2 (290 mg, 2.56 mmol, 245.76 μL, 30% purity, 20.99 equiv) and K2CO3 (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 Na2S2O3 (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 phases were concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 * 25 mm * 5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 40%-70% B, over 9 min), then lyophilized to give 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholin-4-carbonyl)-6-methoxy-4H-indeno[1,2-c]pyrazol-7-yl]pyridine-3-carboxamide as an off-white solid (5.33 mg, 8.82 μmol, 7% yield, 98% purity). LCMS (ESI): C 30 H 28 Calculated m / z [M+H] for C27H24N5O4Cl2: 592.14; found: 592.2. 1 1H NMR (400 MHz, DMSO-d6) δ = 8.97 (d, J = 1.96 Hz, 1H), 8.82 (d, J = 2.08 Hz, 1H), 8.37 - 8.32 (m, 1H), 8.18 - 8.12 (m, 1H), 7.90 (d, J = 1.71 Hz, 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.

[0753] Reaction Scheme 7

[0754]

[0755] Synthesis of 7-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-6-methoxy-N-methyl-4H-indeno[1,2-c]pyrazole-3-carboxamide

[0756]

[0757] 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 min, 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 h, then poured into H2O (20 mL), and a precipitate was observed. The precipitate was collected by filtration and the filter cake was dried in vacuo to give 7-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-6-methoxy-N-methyl-4H-indeno[1,2-c]pyrazole-3-carboxamide as an off-white solid (520 mg, 993.79 μmol, 90% yield).

[0758] 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

[0759]

[0760] To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (158.29 mg, 688.01 μmol, 1.2 equiv) in dioxane (2.5 mL) and H2O (0.5 mL) was added K2CO3 (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)Cl2 (83.90 mg, 114.67 μmol, 0.2 equiv). The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. The reaction mixture was poured into H2O (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 layers were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica chromatography ( 4 g flash silica 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 as a brown solid (140 mg, 256.20 μmol, 45% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 9.00 (dd, J = 12.16, 1.90 Hz, 2H), 8.45 (t, J = 2.02 Hz, 1H), 7.89 (d, J = 1.71 Hz, 2H), 7.74 (t, J = 1.71 Hz, 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).

[0761] 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

[0762]

[0763] 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 H2O2 (290 mg, 2.56 mmol, 245.76 μL, 30% purity, 15.53 equiv) and K2CO3 (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 Na2S2O3 (10 mL), and the mixture was stirred at 15 °C for an additional 1 h, then extracted with ethyl acetate (10 mL * 3). The combined organic phases were concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 um; mobile phase: [water (TFA)-ACN]; gradient: 42%-72% B), then lyophilized 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): C 31 H 28 Calculated m / z [M+H] for C28H25Cl2N5O5F3: 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 Nuclear magnetic resonance of compound 5-02 is shown.

[0764] 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

[0765]

[0766] 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 eq) in dioxane (2.5 mL) and H2O (0.5 mL) was added K2CO3 (174.33 mg, 1.26 mmol, 3 eq), 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 eq), and Pd(dppf)Cl2 (61.53 mg, 84.09 μmol, 0.2 eq). The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*5 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 70%-100% B, over 9 min), then lyophilized 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 as an orange solid (13.19 mg, 24.14 μmol, 5% yield, 96% purity). LCMS (ESI): C 27 H 28 Calculated m / z [M+H] for C25H25Cl2N5O2: 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 Nuclear magnetic resonance of compound 5-06 is shown.

[0767] Example 6

[0768] Reaction 7

[0769]

[0770] Synthesis of tert-butyl N-amino-N-(3-thienyl)carbamate (2)

[0771]

[0772] 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), Cs2CO3 (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 N2 three times, then heated at 80 °C for 16 h under N2. 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 phases were washed with brine (200 mL * 3), dried over anhydrous Na2SO4. Filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography ( 330 g Flash silica column, eluent 0 - 20% ethyl acetate / petroleum ether gradient, 80 mL / min). The compound tert-butyl N-amino-N-(3-thienyl)carbamate was obtained as a brown oil (7 g, 32.67 mmol, 27% yield). 1H NMR (400 MHz, chloroform-d) δ = 7.36 (br d, J = 4.3 Hz, 1H), 7.18 (dd, J = 3.4, 5.3 Hz, 1H), 7.14 (br s, 1H), 4.58 - 4.17 (m, 2H), 1.56 (s, 9H).

[0773] Synthesis of 3-thienylhydrazine

[0774]

[0775] 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 at 15 °C for 1 h. The mixture was concentrated in vacuo to give 3-thienylhydrazine (600 mg, crude, HCl) as a grey solid, which was used in the next step without further purification.

[0776] To a mixture of 3-thienylhydrazine (600 mg, 3.98 mmol, 6.79e-1 eq., HCl) in t-BuOH (20 mL) was added AcOH (1.76 g, 29.31 mmol, 1.68 mL, 5 eq.) and ethyl 2-(6-bromo-5-methoxy-1-oxo-indan-2-yl)-2-oxo-acetate (2 g, 5.86 mmol, 1 eq.). The mixture was stirred at 90 °C for 16 h and then concentrated in vacuo to give the crude product. The crude product was triturated first with EtOH (4 mL) at 15 °C for 20 min and then second 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 (400 MHz, DMSO-d6) δ = 8.04 (dd, J = 3.12, 1.41 Hz, 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 = 7.15 Hz, 3H).

[0777] Synthesis of 7-bromo-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxylic acid

[0778]

[0779] 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 eq.) in H2O (8 mL) and THF (8 mL) was added LiOH.H2O (510.42 mg, 12.16 mmol, 3 eq.). The mixture was stirred at 15 °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. These precipitates were collected by filtration and the filter cake was dried in vacuo 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.

[0780] Synthesis of [7-bromo-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone

[0781]

[0782] 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, 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 h, then poured into H2O (20 mL), and a precipitate formed in the reaction mixture. The mixture was filtered, the filter cake was collected and dried in vacuo to give [7-bromo-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone as a black solid (520 mg, 1.06 mmol, 83% yield).

[0783] 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

[0784]

[0785] 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 H2O (0.5 mL) was added K2CO3 (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)Cl2 (65.92 mg, 90.09 μmol, 0.2 equiv). The mixture was stirred at 80 °C under N2 for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 45%-75% B), and then lyophilized 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 as an orange solid (26.4 mg, 39.36 μmol, 9% yield, 90% purity, TFA). LCMS (ESI): C 28 H 28 Calculated m / z [M+H] for C28H30N5O5SF3: 490.18; found: 490.2. 1 H NMR (400 MHz, DMSO-d6) δ = 7.99 (s, 1H), 7.69 (d, J = 2.08 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.91 (dd, J = 3.06, 1.10 Hz, 1H), 7.87 - 7.82 (m, 1H), 7.40 (s, 1H), 6.69 (d, J = 2.08 Hz, 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 Nuclear magnetic resonance of compound 5-07 is shown.

[0786] (3,3-Dimethylmorpholin-4-yl)-[7-(5-cyano-3-pyridinyl)-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazol-3-yl]methanone synthesis

[0787]

[0788] To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (169.59 mg, 737.11 μmol, 1.2 equiv) in dioxane (2.5 mL) and H2O (0.5 mL) was added K2CO3 (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)Cl2 (89.89 mg, 122.85 μmol, 0.2 equiv). The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (5 mL * 3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography ( 4 g flash silica gel column, eluent 0 - 70% petroleum ether gradient / ethyl acetate, 30 mL / min), to afford (3,3-dimethylmorpholin-4-yl)-[7-(5-cyano-3-pyridyl)-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazol-3-yl]methanone as a brown solid (150 mg, 293.20 μmol, 48% yield). Synthesis of 5-[3-(3,3-dimethylmorpholin-4-carbonyl)-6-methoxy-1-(3-thienyl)-4H-indeno[1,2-c]pyrazol-7-yl]nicotinamide

[0789]

[0790] 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 K2CO3 (54.03 mg, 390.94 μmol, 2 equiv) and H2O2 (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 Na2S2O3 (10 mL), then stirred at 15 °C for an additional 1 h, and then extracted with ethyl acetate (10 mL * 3). The combined organic phases were dried over anhydrous Na2SO4. Filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 um; mobile phase: [water (TFA)-ACN]; gradient: 28% - 58% B over 9 min), and then lyophilized 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 as a yellow solid (99.06 mg, 153.91 μmol, 79% yield, 100% purity, TFA). LCMS (ESI): C 30 H 28 Calculated m / z [M + H] for C25H25N5O6SF3: 530.18; found: 530.2. 1 1H NMR (400 MHz, DMSO-d6) δ = 9.00 (d, J = 1.96 Hz, 1H), 8.84 (d, J = 2.08 Hz, 1H), 8.37 - 8.32 (m, 1H), 8.21 (s, 1H), 7.98 (dd, J = 3.00, 1.28 Hz, 1H), 7.77 (dd, J = 5.01, 3.18 Hz, 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 1H NMR spectrum of compound 5-03 is shown.

[0791] Synthesis of 7-bromo-N-tert-butyl-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide

[0792]

[0793] 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, 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 H2O (20 mL), a precipitate formed in the reaction mixture, the mixture was filtered, the filter cake was collected and dried in vacuo to afford 7-bromo-N-tert-butyl-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide as a black solid (500 mg, 1.09 mmol, 84.98% yield).

[0794] 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

[0795]

[0796] 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 H2O (0.5 mL) was added K2CO3 (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)Cl2 (63.57 mg, 86.88 μmol, 0.2 equiv). The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 um; mobile phase: [water (TFA)-ACN]; gradient: 52%-82% B), and then lyophilized 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 as an off-white solid (56.24 mg, 93.80 μmol, 22% yield, 96% purity, TFA). LCMS (ESI): C 27 H 28 Calculated m / z [M+H] for C26H28N5O4SF3: 462.19; found: 462.2. 1 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 50 The nuclear magnetic resonance of compound 5-08 is shown.

[0797] 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

[0798]

[0799] To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (179.90 mg, 781.95 μmol, 1.2 equiv) in dioxane (2.5 mL) and H2O (0.5 mL) was added K2CO3 (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)Cl2 (95.36 mg, 130.33 μmol, 0.2 equiv). The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. The reaction mixture was poured into H2O (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 Na2SO4. Filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography ( 4 g flash silica gel column, eluent 0 - 70% petroleum ether gradient / ethyl acetate, 30 mL / min), to afford N-tert-butyl-7-(5-cyano-3-pyridyl)-6-methoxy-N-methyl-1-(3-thienyl)-4H-indeno[1,2-c]pyrazole-3-carboxamide as a brown solid (200 mg, 413.58 μmol, 63% yield).

[0800] 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

[0801]

[0802] 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 H2O2 (140 mg, 1.23 mmol, 118.64 μL, 30% purity, 3.98 equiv) and K2CO3 (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 Na2S2O3 (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 phases were concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 um; mobile phase: [water (TFA)-ACN]; gradient: 35%-65% B over 9 min), then lyophilized 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 as a yellow solid (94.35 mg, 147.13 μmol, 47% yield, 96% purity, TFA). LCMS (ESI): C 29 H 28 Calculated m / z (M + H) for C25H24N5O5SF3: 502.18; found: 502.2. 1 1H NMR (400 MHz, DMSO-d6) δ = 9.01 (d, J = 2.00 Hz, 1H), 8.86 (d, J = 2.00 Hz, 1H), 8.38 (t, J = 2.06 Hz, 1H), 8.22 (s, 1H), 7.97 (dd, J = 3.19, 1.44 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.69 (s, 1H), 7.52 (dt, J = 3.38, 1.56 Hz, 2H), 7.45 (s, 1H), 3.86 (s, 3H), 3.78 (s, 2H) 3.18 (s, 3H), 1.47 (s, 9H). Figure 46 Nuclear magnetic resonance of compound 5-04 is shown.

[0803] Example 7

[0804] Reaction Scheme 8

[0805]

[0806] Synthesis of 7-bromo-6-methoxy-tetrahydronaphthalen-1-one

[0807]

[0808] At 0 °C, H2SO4 (55.66 g, 227.00 mmol, 30.25 mL, 40% purity, 2 eq) was added to a mixture of 6-methoxytetralin-1-one (20 g, 113.50 mmol, 1 eq) and NBS (20.20 g, 113.50 mmol, 1 eq) in H2O (200 mL). The mixture was then stirred at 60 °C for 5 h. The mixture was cooled to room temperature, filtered, and the cake was collected to obtain the crude product. The crude product was purified by flash silica gel chromatography ( 220 g Flash silica gel column, eluent: 0 - 18% ethyl acetate / petroleum ether gradient, 60 mL / min). The compound 7-bromo-6-methoxy-tetralin-1-one, obtained as a white solid (4.2 g, 16.46 mmol, 15% yield). 1 1H NMR (400 MHz, 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).

[0809] Synthesis of ethyl 2-(7-bromo-6-methoxy-1-oxo-tetrahydro-naphthalen-2-yl)-2-oxo-acetate

[0810]

[0811] At -70 °C, LDA (2 M, 10.19 mL, 1.3 equiv) was added dropwise over 10 min to a solution of 7-bromo-6-methoxytetralin-1-one (4 g, 15.68 mmol, 1 equiv) in THF (60 mL). After addition, the mixture was stirred at -70 °C for 0.5 h, 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 phases were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 (250 * 70 mm, 10 um); mobile phase: [water (FA)-ACN]; gradient: 55%-85% B over 20 min). Ethyl 2-(7-bromo-6-methoxy-1-oxotetralin-2-yl)-2-oxoacetate (3.6 g, 10.14 mmol, 65% yield) was obtained as a yellow solid. 1 1H NMR (400 MHz, chloroform-d) δ = 8.19 (s, 1H), 6.72 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 3.00 - 2.93 (m, 2H), 2.89 - 2.82 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H).

[0812] Synthesis of Ethyl 8-Bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylate

[0813]

[0814] A mixture of ethyl 2-(7-bromo-6-methoxy-1-oxotetralin-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 EtOH (40 mL) and AcOH (5.92 g, 98.54 mmol, 5.64 mL, 10 equiv) was stirred at 80 °C for 5 h under a N2 atmosphere. The mixture was cooled to room temperature and filtered, and the filter cake was collected and dried in vacuo 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. 11H NMR (400 MHz, DMSO-d6) δ = 7.94 - 7.88 (m, 1H), 7.74 (d, J = 1.8 Hz, 2H), 7.23 (s, 1H), 6.84 (s, 1H), 4.32 (q, J = 7.0 Hz, 2H), 3.88 (s, 3H), 2.96 (br s, 4H), 1.32 (t, J = 7.1 Hz, 3H).

[0815] Synthesis of 8-Bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylic acid

[0816]

[0817] 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·H2O (1.52 g, 36.28 mmol, 10 mL, 4 equiv) in EtOH (40 mL) was stirred at 25 °C for 16 h under a N2 atmosphere. The reaction mixture was acidified to pH = 6 with 1 M aqueous HCl. A precipitate formed in the reaction mixture. The mixture was filtered, and the filter cake was collected and dried in vacuo 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): C 19 H 14 Calculated m / z [M+H] for BrCl2N2O3: 466.95; Found: 467.0, 468.9.

[0818] Synthesis of [8-Bromo-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone

[0819]

[0820] At 25 °C, HATU (1.22 g, 3.20 mmol, 1.5 eq) and DIEA (828.25 mg, 6.41 mmol, 1.12 mL, 3 eq) were added 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 eq) in DMF (10 mL). After the addition, the mixture was stirred at this temperature for 0.5 h, then 3,3-dimethylmorpholine (246.03 mg, 2.14 mmol, 1 eq) was added and the resulting mixture was stirred at 25 °C for 2 h. Then the mixture was 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 phases were washed with brine (50 mL) and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography ( 20 g Flash silica gel column, eluent 0 - 30% ethyl acetate / petroleum ether gradient, 45 mL / min), to give the crude product. The crude product was further purified by preparative HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 um; mobile phase: [water (TFA) - ACN]; gradient: 70% - 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 was obtained as a white solid (1.05 g, 1.55 mmol, 72% yield, TFA salt). LCMS (ESI): C 25 H 25 Calculated m / z [M + H] for CBrCl2N3O3: 564.04; found: 564.2. 1 1H 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 The nuclear magnetic resonance of compound 6-01A is shown.

[0821] 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

[0822]

[0823] 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), K2CO3 (48.90 mg, 353.80 μmol, 2 equiv) and Pd(dppf)Cl2 (12.94 mg, 17.69 μmol, 0.1 equiv) in a mixture of dioxane (2 mL) and H2O (0.2 mL) were degassed and purged with N2 three times, then heated at 80 °C for 16 h under N2. The residue was diluted with EtOAc (10 mL) and filtered through a pad of Celite. The filtrate was concentrated to give a residue, which was purified by flash silica chromatography ( 10 g Flash silica column, eluent 0 - 35% ethyl acetate / petroleum ether gradient, 45 mL / min), to give the crude product. The crude product was further purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 62% - 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 was obtained as a white solid (30 mg, 44.09 μmol, 25% yield, TFA). LCMS (ESI): C 29 H 30 Calculated m / z [M+H] for C25H28Cl2N5O3: 566.16; found: 566.3. 1 1H NMR (400 MHz, chloroform-d) δ = 7.50 (d, J = 1.4 Hz, 3H), 7.47 - 7.43 (m, 1H), 7.32 (d, J = 1.9 Hz, 1H), 6.92 (s, 1H), 6.53 (d, J = 2.1 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.84 (br d, J = 3.6 Hz, 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 The nuclear magnetic resonance of compound 6-03 is shown.

[0824] Synthesis of [1-(3,5-dichlorophenyl)-7-methoxy-8-(1-methylpyrazol-3-yl)benzo[g]indazol-3-yl]-(3,3-dimethylmorpholin-4-yl)methanone

[0825]

[0826] 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 for 16 h under a N2 atmosphere. The reaction mixture was poured into ice water (20 mL) and quenched with saturated aqueous Na2SO3 solution (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated in vacuo 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: 66%-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 was obtained as a white solid (50 mg, 73.69 μmol, 46% yield, TFA). LCMS (ESI): C 29 H 28 Calculated m / z [M+H] for C22H24Cl2N5O3: 564.15; found: 564.1. 1 1H NMR (400 MHz, chloroform-d) δ = 8.32 (s, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 1.8 Hz, 2H), 7.53 - 7.49 (m, 2H), 7.30 (s, 2H), 6.64 (d, J = 2.1 Hz, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.80 (s, 4H), 3.47 (s, 2H), 1.55 (s, 6H). Figure 57 1H NMR spectrum of compound 6-07 is shown.

[0827] Reaction Scheme 9

[0828]

[0829] 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

[0830]

[0831] [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) in dioxane (5 mL) and H2O (0.5 mL), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (223.85 mg, 972.96 μmol, 1.1 equiv), K2CO3 (244.49 mg, 1.77 mmol, 2 equiv) and Pd(dppf)Cl2 (129.44 mg, 176.90 μmol, 0.2 equiv) were degassed and purged with N2 three times, then heated at 80 °C for 16 h under N2. 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 chromatography ( 12 g Flash silica column, eluent: 0 - 40% ethyl acetate / petroleum ether gradient, 40 mL / min), to give the crude product. The crude product was further purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 65% - 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 was obtained as a white solid (340 mg, 483.98 μmol, 55% yield, TFA). LCMS (ESI): calculated m / z [M+H] for C31H28Cl2N5O3: 588.15; found: 588.2. 1 1H NMR (400 MHz, chloroform-d) δ = 8.78 (d, J = 1.9 Hz, 1H), 8.72 (d, J = 2.1 Hz, 1H), 7.97 (t, J = 2.0 Hz, 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 The nuclear magnetic resonance of compound 6-01B is shown.

[0832] 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

[0833]

[0834] 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 K2CO3 (3 M, 339.86 μL, 2 equiv) and H2O2 (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), and the mixture was extracted with EtOAc (10 mL * 3). The combined organic phases were 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% - 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 was obtained as a white solid (120 mg, 166.55 μmol, 33% yield, TFA). LCMS (ESI): calculated m / z [M + H] for C31H30Cl2N5O4: 606.16; found: 606.2. 1 1H 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 Nuclear magnetic resonance of compound 6-01 is shown.

[0835] Synthesis of 5-[1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-benzo[g]indazol-8-yl]pyridine-3-carboxamide

[0836]

[0837] 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 N2 three times, and then the mixture was stirred at 80 °C for 16 h under a N2 atmosphere. The product was poured into ice water (20 mL) and quenched with saturated Na2SO3 (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL * 3), and the combined organic phases were washed with brine (50 mL) and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 um; mobile phase: [water (TFA)-ACN]; gradient: 42%-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 was obtained as a white solid (15 mg, 20.88 μmol, 38% yield, TFA). LCMS (ESI): calculated m / z [M + H] for C31H28Cl2N5O4: 604.14; found: 604.1. 1H NMR (400 MHz, methanol-d4) δ = 8.87 (br s, 1H), 8.62 (br s, 1H), 8.29 (s, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 1.8 Hz, 2H), 7.69 - 7.60 (m, 3H), 7.53 (s, 1H), 3.91 (s, 3H), 3.74 (s, 4H), 3.47 (s, 2H), 1.51 (s, 6H). Figure 59 Nuclear magnetic resonance of compound 6-05 is shown.

[0838] Reaction Scheme 10

[0839]

[0840] Synthesis of 8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-4,5-dihydrobenzo[g]indazole-3-carboxamide

[0841]

[0842] At 25 °C, 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 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). After addition, the mixture was stirred at 25 °C for 0.5 h, then N-2-dimethylprop-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 phases were 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 ( 20 g Silica gel flash column, eluent: 0 - 30% ethyl acetate / petroleum ether gradient, 60 mL / min), to give the crude product. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 um; mobile phase: [water (TFA)-ACN]; gradient: 75% - 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 was obtained as a white solid (1.1 g, 1.69 mmol, 79% yield, TFA). LCMS (ESI): C 24 H 25 Calculated m / z [M + H] for CBrCl2N3O2: 536.04; found: 535.9. 1 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 The nuclear magnetic resonance of compound 6-02A is shown.

[0843] 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

[0844]

[0845] 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), K2CO3 (77.17 mg, 558.37 μmol, 2 equiv) and Pd(dppf)Cl2 (20.43 mg, 27.92 μmol, 0.1 equiv) in a mixture of dioxane (3 mL) and H2O (0.3 mL) were degassed and purged with N2 three times, then heated to 80 °C under N2 for 16 h. The mixture was cooled and diluted with EtOAc (20 mL), then filtered through a pad of Celite. The filtrate was concentrated to give a residue, which was purified by flash silica chromatography ( 10 g Flash silica column, eluent 0 - 30% ethyl acetate / petroleum ether gradient, 40 mL / min). 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 was obtained as a colorless oil (0.1 g, 185.71 μmol, 67% yield). LCMS (ESI): C 28 H 30 alculated m / z [M+H] for C22H23Cl2N5O2: 538.17; found: 538.3. Figure 58 The NMR of compound 6-04 is shown.

[0846] Synthesis of N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(1-methylpyrazol-3-yl)benzo[g]indazole-3-carboxamide

[0847]

[0848] 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 N2 three times, and then the mixture was stirred at 80 °C for 16 h under a N2 atmosphere. The reaction was quenched with saturated Na2SO3 (5 mL) and the mixture was extracted with EtOAc (10 mL * 2). The combined organic phases were washed with brine (10 ml) and dried over 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 * 25 mm * 10 um; mobile phase: [water (TFA)-ACN]; gradient: 68%-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 was obtained as a white solid (25 mg, 38.43 μmol, 21% yield, TFA). LCMS (ESI): C 28 H 28 Calculated m / z [M + H] for C24H23Cl2N5O2: 536.15; Found: 536.3. 1 1H NMR (400 MHz, chloroform-d) δ = 8.45 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 1.9 Hz, 2H), 7.60 - 7.55 (m, 2H), 7.39 - 7.37 (m, 2H), 6.73 (d, J = 2.1 Hz, 1H), 4.04 (s, 3H), 3.96 (s, 3H), 3.20 (s, 3H), 1.61 (s, 9H). Figure 62 1H NMR spectrum of Compound 6-08 is shown.

[0849] Reaction Scheme 11

[0850]

[0851] 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

[0852]

[0853] 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)nicotinonitrile (235.52 mg, 1.02 mmol, 1.1 equiv), K2CO3 (257.24 mg, 1.86 mmol, 2 equiv) and Pd(dppf)Cl2 (136.19 mg, 186.12 μmol, 0.2 equiv) in a mixture of dioxane (5 mL) and H2O (0.5 mL) were degassed and purged with N2 three times, then heated at 80 °C under N2 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 chromatography ( 12 g Flash silica column, eluent 0 - 40% ethyl acetate / petroleum ether gradient, 40 mL / min), to give the crude product. The crude product was further purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 um; mobile phase: [water (TFA)-ACN]; gradient: 70% - 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 was obtained as a white solid (390 mg, 578.21 μmol, 62% yield, TFA). LCMS (ESI): calculated m / z [M+H] for C30H28Cl2N5O2: 560.15; found: 560.2. 1 1H NMR (400 MHz, chloroform-d) δ = 8.78 (d, J = 1.8 Hz, 1H), 8.72 (d, J = 2.0 Hz, 1H), 7.98 (t, J = 2.0 Hz, 1H), 7.53 (d, J = 1.8 Hz, 2H), 7.48 (d, J = 1.8 Hz, 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.

[0854] 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

[0855]

[0856] 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 K2CO3 (3 M, 356.84 μL, 2 equiv) and H2O2 (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 Na2SO3 (5 mL). The aqueous phase was extracted with ethyl acetate (10 mL * 3). The combined organic phases were 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 um; mobile phase: [water (TFA)-ACN]; gradient: 45%-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 was obtained as a white solid (150 mg, 216.60 μmol, 40% yield, TFA). LCMS (ESI): calculated m / z [M + H] for C30H30Cl2N5O3: 578.16; found: 578.2. 1 1H 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 The nuclear magnetic resonance of compound 6-02 is shown.

[0857] Synthesis of N-tert-butyl-8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-benzo[g]indazole-3-carboxamide

[0858]

[0859] 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 for 5 h under a N2 atmosphere. The residue was then poured into ice water (20 mL) and quenched with saturated Na2SO3 (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 um; mobile phase: [water (TFA)-ACN]; gradient: 50%-80% B, over min). The compound N-tert-butyl-8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-benzo[g]indazole-3-carboxamide was obtained as a white solid (10 mg, 14.48 μmol, 8% yield, TFA). LCMS (ESI): calculated m / z [M + H] for C30H28Cl2N5O3: 576.15; found: 576.2. 1 1H 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 Nuclear magnetic resonance of compound 6-06 is shown.

[0860] Example 8

[0861] Reaction Scheme 12

[0862]

[0863] Synthesis of 8-(5-cyanopyridin-3-yl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid

[0864]

[0865] 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 H2O (4 mL) was added K2CO3 (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)Cl2 (775.27 mg, 1.06 mmol, 0.2 equiv). The mixture was stirred at 60 °C for 16 h under a N2 atmosphere. The reaction mixture was poured into H2O (100 mL) and ethyl acetate (100 mL) and extracted with ethyl acetate (100 mL * 3). The combined organic phases were dried over anhydrous Na2SO4 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 min 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 (400 MHz, 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).

[0866] Synthesis of 8-(5-carbamoyl-3-pyridinyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylic acid

[0867]

[0868] 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 K2CO3 (112.52 mg, 814.13 μmol, 2 equiv) and H2O2 (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 Na2S2O3 solution (10 mL) was added, and the mixture was stirred at 15 °C for 1 h. The pH of the reaction mixture was adjusted to 7 with 1 M aqueous HCl. The mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phases were dried over anhydrous Na2SO4 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 um; mobile phase: [water (TFA)-ACN]; gradient: 30%-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 was obtained as an off-white solid (30 mg, 58.90 μmol, 14% yield).

[0869] Synthesis of tert-butyl 4-[8-(5-carbamoyl-3-pyridinyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carbonyl]-1,4-diazepane-1-carboxylate

[0870]

[0871] 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 H2O (2 mL). A precipitate formed in the reaction mixture. The mixture was filtered, and the filter cake was collected and dried 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]-1,4-diazepane-1-carboxylate (30 mg, crude) was obtained as a black solid.

[0872] 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

[0873]

[0874] 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 4N HCl / EtOAc (1 mL) was stirred at 15 °C for 1 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 18%-48% B over 9 min), and then lyophilized 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): C 32 H 29Calculated m / z [M+H] for N6O5Cl2F3: 591.16; found: 591.2. 1H NMR (400 MHz, DMSO-d6) δ = 8.91 (d, J = 1.9 Hz, 1H), 8.81 - 8.66 (m, 2H), 8.48 (d, J = 2.0 Hz, 1H), 8.12 (t, J = 1.9 Hz, 2H), 7.82 - 7.73 (m, 3H), 7.62 (s, 1H), 7.30 (s, 1H), 6.82 (d, J = 3.6 Hz, 1H), 4.03 (br d, J = 4.5 Hz, 1H), 3.94 (br t, J = 6.0 Hz, 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.

[0875] Reaction Scheme 13

[0876]

[0877] Synthesis of tert-butyl 4-[8-(5-cyano-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carbonyl]-3-methylpiperazine-1-carboxylate

[0878]

[0879] 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 min. 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 h. The reaction mixture was diluted with water (10 mL) and filtered to give a filter cake. The filter cake was collected and dried in vacuo. 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-carboxylate (200 mg, crude) was obtained as a brown solid.1 1H NMR (400 MHz, 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 = 8.0 Hz, 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 = 4.4 Hz, 3H).

[0880] 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-carboxylate

[0881]

[0882] 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-methylpiperazine-1-carboxylate (180 mg, 267.23 μmol, 1 equiv) in DMSO (2 mL) was added K2CO3 (3 M, 178.15 μL, 2 equiv) and H2O2 (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 Na2SO3 (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4, 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-methylpiperazine-1-carboxylate was obtained as a yellow oil (184 mg, 266.05 μmol, 99% yield).

[0883] Synthesis of 5-[1-(3,5-dichlorophenyl)-7-methoxy-3-(2-methylpiperazine-1-carbonyl)-4,5-dihydrobenzo[g]indazol-8-yl]pyridine-3-carboxamide

[0884]

[0885] 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-methylpiperazine-1-carboxylate (130 mg, 187.97 μmol, 1 equiv) in 4N HCl / EtOAc (2 mL) was stirred at 15 °C for 1 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 20%-50% B, over min), then lyophilized to give 5-[1-(3,5-dichlorophenyl)-7-methoxy-3-(2-methylpiperazine-1-carbonyl)-4,5-dihydrobenzo[g]indazole-8-yl]pyridine-3-carboxamide (50 mg, 70.87 μmol, 38% yield, 100% purity, TFA) as an off-white solid. LCMS (ESI): C 32 H 29 Calculated m / z [M+H] for C₂₉H₂₉Cl₂N₆O₅F₃: 591.16; Found: 591.21 H NMR (400 MHz, DMSO-d6) δ = 9.19 - 9.05 (m, 1H), 8.92 (d, J = 2.0 Hz, 1H), 8.78 - 8.61 (m, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.17 - 8.08 (m, 2H), 7.82 - 7.79 (m, 1H), 7.77 (d, J = 1.9 Hz, 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 Nuclear magnetic resonance of compound 8-01. Synthesis of 5-[1-(3,5-dichlorophenyl)-3-(2,4-dimethylpiperazine-1-carbonyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-8-yl]pyridine-3-carboxamide

[0886]

[0887] 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, 7.74e-1 μL, 0.2 equiv) and HCHO (6.59 mg, 81.15 μmol, 6.04 μL, 1.2 equiv, 37%, in H2O). The mixture was stirred at 15 °C for 1 h, then NaBH(OAc)3 (43.00 mg, 202.88 μmol, 3 equiv) was added. The mixture was stirred at 15 °C for 16 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 18%-48% B, over 9 min), then lyophilized 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 as an off-white solid (22.94 mg, 31.88 μmol, 47% yield, 100% purity, TFA). LCMS (ESI): C 33 H 31 Calculated m / z [M+H] for C26H27Cl2N6O5F3: 605.18; found: 605.2. 1 1H NMR (400 MHz, 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 s, 3H), 3.25 - 3.15 (m, 1H), 3.14 - 3.06 (m, 2H), 3.03 - 2.87 (m, 5H), 1.56 - 1.41 (m, 3H). Figure 66 Nuclear magnetic resonance of compound 8-05 is shown.

[0888] Synthesis of 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

[0889]

[0890] At 0 °C, 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) were added 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). 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*25mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 32%-62% B, over 10 min), then lyophilized. 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 was obtained as an off-white solid (10.78 mg, 16.79 μmol, 11% yield, 96% purity). LCMS (ESI): C 31 H 28 Calculated m / z [M+H] for Cl2N7O3: 616.16; found: 616.3. 1 H NMR (400 MHz, methanol-d4) δ = 8.88 (d, J = 2.0 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.22 (t, J = 2.0 Hz, 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 = 6.8 Hz, 3H). Figure 70 The nuclear magnetic resonance of compound 8-09 is shown.

[0891] Reaction Scheme 14

[0892]

[0893] 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

[0894]

[0895] 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 min, 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 h. The mixture was poured into H2O (10 mL). A precipitate formed in the reaction mixture, the mixture was filtered, the filter cake was collected and dried in vacuo to give a residue. The residue was purified by flash silica gel chromatography ( 4 g silica gel flash column, eluent 0 - 10% ethyl acetate:methanol, 18 mL / min), to give 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 as a yellow solid (90 mg, 153.19 μmol, 50.18% yield). LCMS (ESI): C 33 H 29 Calculated m / z [M + H] for C29H28N6O4Cl2F3: 587.17; found: 587.2. 1 1H NMR (400 MHz, methanol-d4) δ = 8.80 (d, J = 1.8 Hz, 1H), 8.68 (s, 1H), 8.08 (br s, 1H), 7.75 - 7.61 (m, 3H), 7.24 (s, 1H), 6.86 (d, J = 13.9 Hz, 1H), 4.33 - 3.96 (m, 2H), 3.92 (s, 3H), 3.87 - 3.72 (m, 2H), 3.71 - 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 The nuclear magnetic resonance of compound 8 - 07A is shown.

[0896] 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

[0897]

[0898] 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 H2O (1 mL) was added LiOH·H2O (6.43 mg, 153.19 μmol, 1 equiv). The mixture was stirred at 60 °C for 16 h. The pH of the reaction mixture was adjusted to 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 Na2SO4 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 um; mobile phase: [water (TFA)-ACN]; gradient: 18%-48% B over 9 min), then lyophilized 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 as a white solid (24.6 mg, 34.19 μmol, 22% yield, 100% purity, TFA). LCMS (ESI): C 33 H 31 Calculated m / z [M+H] for C27H27N6O5Cl2F3: 605.18; found: 605.2. 1 1H NMR (400 MHz, methanol-d4) δ = 8.91 (d, J = 1.5 Hz, 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 = 13.8 Hz, 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 1H NMR of compound 8-07 is shown.

[0899] Synthesis of compound 8-02

[0900]

[0901] Compound 8-02 was synthesized by a procedure similar to that of Example 8. LCMS (ESI): C 31 H 31 Calculated m / z [M+H] for C 31 H 31 Cl2N6O3: 605.18; found: 605.3. 1 H NMR (400 MHz, methanol-d4) δ = 8.93 (d, J = 1.6 Hz, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.31 (s, 1H), 7.69 - 7.60 (m, 3H), 7.24 (s, 1H), 6.87 (s, 1H), 4.07 (br t, J = 5.4 Hz, 2H), 3.91 (s, 3H), 3.43 (br t, J = 5.4 Hz, 2H), 3.30 (br s, 2H), 3.14 - 3.07 (m, 2H), 2.93 - 2.87 (m, 2H), 1.71 (s, 6H). Figure 64 Nuclear magnetic resonance of Compound 8-02 is shown.

[0902] Synthesis of Compound 8-06

[0903]

[0904] Compound 8-06 was synthesized by a procedure similar to that of Example 8. LCMS (ESI): C 32 H 33 Calculated m / z [M+H] for C 32 H 33 Cl2N6O3 is 619.19; 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 Nuclear magnetic resonance of Compound 8-06 is shown.

[0905] Synthesis of Compound 8-10

[0906]

[0907] Compound 8-10 was synthesized by a procedure similar to that of Example 8. LCMS (ESI): C 30 H 30Calculated m / z [M+H] for Cl2N5O4: 594.16; found: 594.2. 1H NMR (400 MHz, methanol-d4) 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 The nuclear magnetic resonance of compounds 8 - 10 is shown.

[0908] Synthesis of compound 8 - 14

[0909]

[0910] Compound 8 - 14 was synthesized by a procedure similar to that of Example 8. LCMS (ESI): C 33 H 30 Calculated m / z [M+H] for C12H11N5O5Cl2F3: 590.16; found: 590.2. 1 1H NMR (400 MHz, 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 The nuclear magnetic resonance of compound 8 - 14 is shown.

[0911] Synthesis of compound 8 - 15

[0912]

[0913] Compound 8 - 15 was synthesized by a procedure similar to that of Example 8. LCMS (ESI): C 32 H 31Calculated m / z [M+H] for Cl2N6O3: 617.18; Found: 617.3. 1H NMR (400 MHz, methanol-d4) δ = 8.93 - 8.86 (m, 1H), 8.56 (brd, J = 9.3 Hz, 1H), 8.26 (dd, J = 1.9, 4.8 Hz, 1H), 7.70 - 7.68 (m, 1H), 7.67 (d, J = 1.6 Hz, 2H), 7.24 (s, 1H), 6.84 (d, J = 1.5 Hz, 1H), 5.60 (br d, J = 5.4 Hz, 1H), 5.05 (br d, J = 4.1 Hz, 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 compound 8-15.

[0914] Synthesis of compound 8-17

[0915]

[0916] Compound 8-17 was synthesized by a procedure similar to that of Example 8. LCMS (ESI): C 32 H 31 Calculated m / z [M+H] for Cl2N6O3: 617.18; Found: 617.2. 1 1H NMR (400 MHz, methanol-d4) δ = 8.91 - 8.83 (m, 1H), 8.57 - 8.50 (m, 1H), 8.23 (q, J = 2.2 Hz, 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, 13.2 Hz, 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.

[0917] Synthesis of compound 8-20

[0918]

[0919] Compound 8-20 was synthesized by a procedure similar to that of Example 8. LCMS (ESI): calculated m / z [M+H] for C31H29Cl2N6O3: 603.16; found: 603.1. 1H NMR (400 MHz, 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 compound 8-20.

[0920] Synthesis of compound 8-21

[0921]

[0922] Compound 8-21 was synthesized by a procedure similar to that of Example 8. LCMS (ESI): C 33 H 31 N6O5Cl2F3 calculated m / z [M+H]: 605.18; found: 605.2. 1 1H NMR (400 MHz, DMSO-d6) δ = 9.42 (br dd, J = 1.6, 7.4 Hz, 1H), 8.93 (d, J = 2.0 Hz, 2H), 8.50 (d, J = 2.1 Hz, 1H), 8.16 - 8.10 (m, 2H), 7.84 - 7.79 (m, 1H), 7.77 (d, J = 1.8 Hz, 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.

[0923] Synthesis of compound 8-22

[0924]

[0925] Compound 8-22 was synthesized by a procedure similar to that of Example 8. LCMS (ESI): calculated m / z [M+H] for C31H31Cl2N6O3: 605.18; found: 605.2. 1H NMR (400 MHz, methanol-d4) δ = 8.92 (d, J = 2.0 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.30 (t, J = 2.0 Hz, 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, 13.6 Hz, 2H), 3.38 (dd, J = 3.2, 13.6 Hz, 2H), 3.15 - 3.06 (m, 2H), 3.01 - 2.89 (m, 2H), 1.52 (d, J = 6.9 Hz, 6H). Figure 79 Nuclear magnetic resonance of Compound 8-22 is shown.

[0926] Synthesis of Compound 8-24

[0927]

[0928] Compound 8-24 was synthesized by a procedure similar to that of Example 8. LCMS (ESI): C 31 H 29 calculated m / z [M+H] for Cl2N6O3: 603.16; found: 603.3. 1 H NMR (400 MHz, methanol-d4) δ = 8.92 (s, 1H), 8.59 (d, J = 1.9 Hz, 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 (brs, 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 Nuclear magnetic resonance of Compound 8-24 is shown.

[0929] Synthesis of Compound 8-26A

[0930]

[0931] Compound 8-26A was synthesized by a procedure similar to that of Example 8. LCMS (ESI): calculated m / z [M+H] 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 nuclear magnetic resonance of compound 8-26A.

[0932] Synthesis of compound 8-26

[0933]

[0934] Compound 8-26 was synthesized by a procedure similar to that of Example 8. LCMS (ESI): calculated m / z [M+H] 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 nuclear magnetic resonance of compound 8-26.

[0935] Synthesis of compound 8-28

[0936]

[0937] Compound 8-28 was synthesized by a procedure similar to that of Example 8. LCMS (ESI): C 31 H 30 N6O3Cl2 calculated m / z [M+H]: 605.18; found: 605.2. 11H NMR (400 MHz, methanol-d4) δ = 8.88 (d, J = 2.0 Hz, 1H), 8.54 (d, J = 2.1 Hz, 1H), 8.23 (t, J = 2.1 Hz, 1H), 7.64 (s, 3H), 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 = 9.0 Hz, 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.

[0938] Synthesis of compound 8-29

[0939]

[0940] Compound 8-29 was synthesized by a procedure similar to that of Example 8. LCMS (ESI): C 32 H 26 Calculated m / z [M+H] for C15H14N5O6Cl2F3: 590.13; Found: 590.2. 1H NMR (400 MHz, methanol-d4) δ = 8.94 (d, J = 1.9 Hz, 1H), 8.63 (s, 1H), 8.35 (q, J = 2.0 Hz, 1H), 7.73 - 7.61 (m, 3H), 7.25 (s, 1H), 6.89 (d, J = 4.6 Hz, 1H), 5.60 (s, 0.5H), 5.06 (s, 0.5H), 4.70 (br d, J = 12.0 Hz, 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.

[0941] Synthesis of compound 8-30

[0942]

[0943] Compound 8-30 was synthesized by a procedure similar to that of Example 8. LCMS (ESI): C 32 H 31Calculated m / z [M+H] for Cl2N6O3: 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.

[0944] Synthesis of compound 8 - 32

[0945]

[0946] Compound 8 - 32 was synthesized by a procedure similar to that of Example 8. LCMS (ESI): C 30 H 28 Calculated m / z [M+H] for Cl2N5O4: 592.14; Found: 592.3. 1 1H NMR (400 MHz, 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 = 7.2 Hz, 2H), 1.60 (s, 6H). Figure 90 Shows the nuclear magnetic resonance of compound 8 - 32.

[0947] Reaction Scheme 15

[0948]

[0949] Synthesis of 5-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)nicotinamide

[0950]

[0951] To a mixture of 5-bromonicotinamide (2 g, 9.95 mmol, 1 equiv) in dioxane (20 mL) was added Pd(dppf)Cl2 (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). The mixture was stirred at 100 °C for 3 h under N2 atmosphere. The dioxane solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (1.65 g, crude), which was a brown liquid, was directly used for the next step.

[0952] Synthesis of Ethyl 8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylate

[0953]

[0954] To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (1.34 g, 5.4 mmol, 1.35 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 H2O (4 mL) were added K2CO3 (1.11 g, 8.06 mmol, 2 equiv) and Pd(dppf)Cl2 (589.87 mg, 806.16 μmol, 0.2 equiv). The mixture was stirred at 60 °C for 16 h under N2 atmosphere. The reaction mixture was poured into H2O (20 mL) and ethyl acetate (20 mL), and then the mixture was separated. The aqueous phase was extracted with ethyl acetate (10 mL * 3). The combined organic phases were 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 ( 40 g flash silica gel column, eluent: 0 - 80% petroleum ether gradient / ethyl acetate, 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 grey solid.

[0955] Synthesis of 8-(5-carbamoyl-3-pyridyl)-1-(3,5-dichlorophenyl)-7-methoxy-4,5-dihydrobenzo[g]indazole-3-carboxylic acid

[0956]

[0957] 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 H2O (10 mL) was added LiOH·H2O (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 then the resulting mixture was 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 as a gray solid (1 g, 1.96 mmol, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ = 8.90 (d, J = 2.1 Hz, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.14 - 8.02 (m, 2H), 7.79 (d, J = 1.8 Hz, 1H), 7.73 (d, J = 1.8 Hz, 2H), 7.60 (br s, 1H), 7.28 (s, 1H), 6.78 (s, 1H), 3.84 (s, 3H), 3.04 - 2.92 (m, 4H).

[0958] 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-carboxylate

[0959]

[0960] 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 min, then 1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (35.55 mg, 157.07 μmol, 1 equiv) was added. The mixture was stirred at 15 °C for 16 h. 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*10um; mobile phase: [water (TFA)-ACN]; gradient: 52%-82% B, over 9 min), then lyophilized 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-carboxylate (20 mg, 23.33 μmol, 15% yield, 97% purity, TFA). 1H NMR (400 MHz, methanol-d4) δ = 8.97 (d, J = 1.6 Hz, 1H), 8.68 (s, 1H), 8.42 (s, 1H), 7.63 (d, J = 5.8 Hz, 3H), 7.25 (s, 1H), 6.92 (d, J = 6.9 Hz, 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), 2.28 - 2.14 (m, 1H), 2.04 - 1.90 (m, 2H), 1.69 - 1.47 (m, 2H), 1.46 (d, J = 1.6 Hz, 9H). LCMS (ESI): C 39 H 39 Calculated m / z [M+H] for C29H32N6O7Cl2F3: 717.23; found: 717.2.

[0961] 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

[0962]

[0963] 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 4N HCl / dioxane (2 mL) was stirred at 15 °C for 1 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (TFA conditions; or neutral conditions; or basic conditions), and then lyophilized 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 as a white solid (11.9 mg, 16.27 μmol, 58% yield, 100% purity, TFA). 1H NMR (400 MHz, methanol-d4) δ = 8.91 (d, J = 1.8 Hz, 1H), 8.58 (s, 1H), 8.28 (d, J = 1.8 Hz, 1H), 7.70 - 7.60 (m, 3H), 7.23 (s, 1H), 6.87 (d, J = 5.3 Hz, 1H), 5.00 - 4.87 (m, 1H), 4.51 - 4.17 (m, 1H), 4.09 - 3.92 (m, 1H), 3.91 (s, 3H), 3.82 - 3.72 (m, 1H), 3.33 (br s, 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): C 34 H 31 Calculated m / z [M+H] for C₂₉H₃₀N₆O₅Cl₂F₃: 617.18; found: 617.2. Figure 80 Nuclear magnetic resonance of compound 8-23 is shown.

[0964] Reaction Scheme 16

[0965]

[0966] Synthesis of Compound 8-16A

[0967]

[0968] Compound 8-16A was synthesized by a method similar to that of Example 8. LCMS (ESI): C 35 H 34 Calculated m / z [M+H] for Cl2N6O5: 689.20; Found: 689.2. 1H NMR (400 MHz, methanol-d4) δ = 8.96 - 8.79 (m, 1H), 8.62 - 8.44 (m, 1H), 8.22 (br s, 1H), 7.67 - 7.60 (m, 3H), 7.21 (br s, 1H), 6.82 (br d, J = 9.4 Hz, 1H), 5.12 (br d, J = 15.8 Hz, 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 (br d, J = 5.0 Hz, 4H), 2.85 - 2.77 (m, 1H), 1.65 (dd, J = 5.9, 8.8 Hz, 1H), 1.46 (d, J = 13.2 Hz, 9H).

[0969] Synthesis of Compound 8-16B

[0970]

[0971] Compound 8-16B was synthesized by a method similar to that of Example 8. LCMS (ESI): C 30 H 27 Calculated m / z [M+H] for Cl2N6O3: 589.14; Found: 589.1. 1H NMR (400 MHz, methanol-d4) δ = 9.05 - 8.80 (m, 1H), 8.78 - 8.44 (m, 1H), 8.27 (s, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.64 (d, J = 1.6 Hz, 2H), 7.24 (s, 1H), 6.83 (s, 1H), 5.22 (br d, J = 1.5 Hz, 1H), 4.69 (br d, J = 3.1 Hz, 1H), 3.95 (br d, J = 12.8 Hz, 1H), 3.91 (s, 3H), 3.86 (br d, 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 1H NMR showing Compound 8-16B

[0972] Synthesis of Compound 8-16

[0973]

[0974] Compound 8-16 was synthesized by a method similar to that of Example 8. LCMS (ESI): C 31 H 29 Calculated m / z [M+H] for Cl2N6O3: 603.16; Found: 603.1. 1H NMR (400 MHz, methanol-d4) δ = 8.93 (d, J = 1.0 Hz, 1H), 8.58 (s, 1H), 8.31 (t, J = 2.0 Hz, 1H), 7.68 - 7.66 (m, 1H), 7.64 (d, J = 1.8 Hz, 2H), 7.23 (s, 1H), 6.83 (s, 1H), 5.25 (br s, 1H), 4.70 (br s, 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 1H NMR showing Compound 8-16

[0975] Synthesis of Compound 8-25A

[0976]

[0977] Compound 8-25A was synthesized by a method similar to that of Example 8. LCMS (ESI): C 39 H 41 Calculated m / z [M+H] for N6O7Cl2F3: 719.24; Found: 719.4. 1 1H NMR (400 MHz, methanol-d4) δ = 9.61 (d, J = 1.7 Hz, 1H), 9.30 (br s, 1H), 9.03 (br s, 1H), 8.31 (br s, 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 (br d, J = 5.7 Hz, 2H), 1.70 - 1.59 (m, 3H), 1.54 (br d, J = 6.8 Hz, 1H).

[0978] Synthesis of Compound 8-25

[0979]

[0980] Compound 8-25 was synthesized by a method similar to that of Example 8. LCMS (ESI): C 34 H 33 Calculated m / z [M+H] for C 34 H 33 N6O5Cl2F3: 619.19; Found: 619.2. 1 1H NMR (400 MHz, methanol-d4) δ = 8.91 (s, 1H), 8.58 (br s, 1H), 8.28 (t, J = 1.9 Hz, 1H), 7.70 - 7.56 (m, 3H), 7.24 (s, 1H), 6.87 (br s, 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 (br s, 2H), 2.51 - 2.18 (m, 1H), 1.26 - 0.76 (m, 6H). Figure 82 The nuclear magnetic resonance of compound 8-25 is shown.

[0981] Synthesis of compound 8-27

[0982]

[0983] Compound 8-27 was synthesized by a method similar to that of Example 8. LCMS (ESI): C 33 H 28 Calculated m / z [M+H] for C 33 H 28 N5O6Cl2F3: 604.1; Found: 604.2. 1 1H NMR (400 MHz, 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 = 5.4 Hz, 2H), 4.49 (d, J = 5.5 Hz, 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 (br t, J = 6.4 Hz, 2H). Figure 85 The nuclear magnetic resonance of compound 8-27 is shown.

[0984] Synthesis of compound 8-31A

[0985]

[0986] Compound 8-31A was synthesized by a method similar to that of Example 8. LCMS (ESI): C 38 H 37Calculated m / z [M+H] for N6O7Cl2F3: 703.21; Found: 703.2. 1 H NMR (400 MHz, methanol-d4) δ = 8.95 (d, J = 1.7 Hz, 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 (br d, J = 5.9 Hz, 0.25H), 4.83 - 4.72 (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 (br s, 9H).

[0987] Synthesis of Compound 8-31

[0988]

[0989] Compound 8-31 was synthesized by a method similar to that of Example 8. LCMS (ESI): C 34 H 31 Calculated m / z [M+H] for N6O5Cl2F3: 617.18; Found: 617.2. 1 H NMR (400 MHz, 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 = 1.8 Hz, 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 1H NMR showing Compound 8-31.

[0990] Synthesis of Compound 8-33A

[0991]

[0992] Compound 8-33A was synthesized by a method similar to that of Example 8. LCMS (ESI): C 37 H 35Calculated m / z [M+H] for N6O7Cl2F3: 689.2; Found: 689.2. 1 H NMR (400 MHz, methanol-d4) δ = 8.95 (s, 1H), 8.65 (s, 1H), 8.39 (br s, 1H), 7.70 - 7.60 (m, 3H), 7.25 (d, J = 2.3 Hz, 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 (br d, J = 10.5 Hz, 2H), 1.48 (br d, J = 17.1 Hz, 9H).

[0993] Synthesis of Compound 8-33

[0994]

[0995] Compound 8-33 was synthesized by a method similar to that of Example 8. LCMS (ESI): C 32 H 27 Calculated m / z [M+H] for N6O5Cl2F3: 589.14; Found: 589.2. 1 H NMR (400 MHz, methanol-d4) δ = 8.93 (s, 1H), 8.59 (br s, 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 (br d, J = 11.4 Hz, 1H). Figure 91 1H NMR showing Compound 8-33.

[0996] Synthesis of Compound 8-34

[0997]

[0998] Compound 8-34 was synthesized by a method similar to that of Example 8. LCMS (ESI): C 28 H 26Calculated m / z [M+H] for Cl2N5O3: 550.13; Found: 550.2. 1H NMR (400 MHz, methanol-d4) δ = 9.27 (s, 1H), 9.08 (s, 1H), 8.89 (br s, 1H), 7.82 (br d, J = 2.6 Hz, 3H), 7.50 (s, 1H), 7.22 (d, J = 7.0 Hz, 1H), 4.15 (s, 3H), 3.95 - 3.86 (m, 1H), 3.81 (q, J = 7.1 Hz, 1H), 3.51 (s, 3H), 3.48 (s, 1H), 3.35 - 3.32 (m, 1H), 3.07 (br s, 2H), 1.46 (q, J = 6.5 Hz, 3H). Figure 92 Shows the nuclear magnetic resonance of Compound 8-34.

[0999] Synthesis of Compound 8-39

[1000]

[1001] Compound 8-39 was synthesized by a method similar to that of Example 8. LCMS (ESI): C 29 H 26 Calculated m / z [M+H] for Cl2N5O3: 562.13; Found: 562.2. 1H NMR (400 MHz, methanol-d4) δ = 9.02 (s, 1H), 8.78 (br s, 1H), 8.56 (br s, 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 (br s, 2H), 0.82 - 0.51 (m, 4H). Figure 93 Shows the nuclear magnetic resonance of Compound 8-39.

[1002] Synthesis of Compound 8-44

[1003]

[1004] Compound 8-44 was synthesized by a method similar to that of Example 8. LCMS (ESI): C 31 H 29Calculated m / z [M+H] for Cl2N5O4: 606.16; found: 606.2. 1H NMR (400 MHz, methanol-d4) δ = 8.90 (d, J = 2.0 Hz, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.22 (t, J = 2.1 Hz, 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 Nuclear magnetic resonance of compound 8-44 is shown.

[1005] Reaction Scheme 17

[1006]

[1007] Synthesis of Ethyl 8-bromo-1-(pyridin-2-yl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate

[1008]

[1009] 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 N2 three times, then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. 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 Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 25 g Silica gel flash column, eluent: 60 - 40% petroleum ether / ethyl acetate gradient, 60 mL / min). 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) was obtained as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.57 (d, J = 4.0 Hz, 1H), 8.19 (dt, J = 1.6, 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.66 (m, J = 5.1, 1H), 7.45 - 7.38 (m, 1H), 7.37 - 7.31 (m, 1H), 6.79 (d, J = 1.6 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 3.03 - 2.88 (m, 4H), 1.33 (t, J = 7.2 Hz, 3H).

[1010] Synthesis of Ethyl 8-Bromo-1-(2-pyridinyl)-4,5-dihydrobenzo[g]indazole-3-carboxylate

[1011]

[1012] A mixture of ethyl 8-bromo-1-(2-pyridinyl)-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)Cl2 (165.36 mg, 225.99 μmol, 0.1 equiv), and K2CO3 (936.98 mg, 6.78 mmol, 3 equiv) in dioxane (10 mL) and H2O (1 mL) was degassed and purged with N2 three times, then the mixture was stirred at 60 °C for 16 h under a N2 atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 25 g Silica gel flash column, eluent: 100 - 95% petroleum ether / ethyl acetate gradient, 60 mL / min). The compound ethyl 8-bromo-1-(2-pyridinyl)-4,5-dihydrobenzo[g]indazole-3-carboxylate (530 mg, 1.33 mmol, 58.89% yield) was obtained as a gray solid. LCMS (ESI): Calculated m / z [M + H] for C19H16N3O2Br: 398.25; Found: 397.1.

[1013] Synthesis of 1-(Pyridin-2-yl)-8-(pyridin-3-yl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic Acid

[1014]

[1015] To a solution of ethyl 1-(2-pyridinyl)-8-(3-pyridinyl)-4,5-dihydrobenzo[g]indazole-3-carboxylate (360 mg, 908.08 μmol, 1 equiv) in THF (2 mL) and H2O (2 mL) was added LiOH·H2O (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 Na2SO4, filtered and concentrated under reduced pressure to give a residue. 1-(2-Pyridinyl)-8-(3-pyridinyl)-4,5-dihydrobenzo[g]indazole-3-carboxylic acid was obtained as a gray solid (240 mg, 651.49 μmol, 71.74% yield).

[1016] Synthesis of Compound 8-77

[1017]

[1018] To a solution of 1-(2-pyridinyl)-8-(3-pyridinyl)-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 h. 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 h. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 18%-48% B over 15 min). 1-[1-(2-Pyridinyl)-8-(3-pyridinyl)-4,5-dihydrobenzo[g]indazole-3-carbonyl]piperidin-3-one was obtained as a brown oil (38.29 mg, 84.33 μmol, 77.67% yield, 99% purity). LCMS (ESI): calculated m / z [M+H] for C27H24O2N5: 450.19; found: 450.3. 11H NMR (400 MHz, DMSO-d6) δ = 8.63 - 8.57 (m, 1H), 8.56 - 8.48 (m, 2H), 8.19 - 8.11 (m, 1H), 7.85 - 7.79 (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.

[1019] Synthesis of compound 8 - 75

[1020]

[1021] Compound 8 - 75 was synthesized by a method similar to that of Example 8. LCMS (ESI): C 31 H 29 Calculated m / z [M + H] for C 1 H7N5O5F3: 522.22; Found: 522.2. Figure 96 Shows the nuclear magnetic resonance of compound 8 - 75.

[1022] Synthesis of compound 8 - 76

[1023]

[1024] Compound 8 - 76 was synthesized by a method similar to that of Example 8. LCMS (ESI): C 28 H 24Calculated m / z [M+H] for N6O4F3: 451.18; Found: 451.1. 1 H NMR (400 MHz, DMSO-d6) δ = 8.67 (d, J = 1.3 Hz, 1H), 8.63 (br d, J = 4.8 Hz, 1H), 8.59 (br d, J = 3.4 Hz, 1H), 8.22 - 8.12 (m, 2H), 8.02 (br d, J = 7.4 Hz, 1H), 7.92 - 7.85 (m, 1H), 7.68 - 7.60 (m, 3H), 7.55 (d, J = 8.0 Hz, 1H), 7.14 (br d, J = 3.1 Hz, 1H), 4.52 (s, 1H), 4.17 (s, 1H), 4.11 (br t, J = 4.7 Hz, 1H), 3.84 (br d, J = 5.5 Hz, 1H), 3.30 (br s, 2H), 3.06 - 2.98 (m, 2H), 2.90 (br d, J = 4.9 Hz, 2H). Figure 97 Nuclear magnetic resonance of compound 8 - 76 is shown.

[1025] Synthesis of compound 8 - 78

[1026]

[1027] Compound 8 - 78 was synthesized by a method similar to that of Example 8. LCMS (ESI): C 28 H 26 Calculated m / z [M+H] for N6O2: 479.21; Found: 479.3. 1 H NMR (400 MHz, methanol-d4) δ = 8.59 (d, J = 4.4 Hz, 1H), 8.45 (d, J = 4.4 Hz, 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 = 7.2 Hz, 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 Nuclear magnetic resonance of compound 8 - 78 is shown.

[1028] Synthesis of compound 8 - 81

[1029]

[1030] Compound 8-81 was synthesized by a method similar to that of Example 8. LCMS (ESI): calculated m / z [M+H] for C28H24N6O2: 477.2; found: 477.2. 1 1H NMR (400 MHz, methanol-d4) δ = 8.61 - 8.53 (m, 1H), 8.50 - 8.41 (m, 2H), 8.13 (dt, J = 1.6, 8.0 Hz, 1H), 7.88 - 7.78 (m, 2H), 7.61 (dd, J = 4.8, 7.6 Hz, 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 The nuclear magnetic resonance of compound 8-81 is shown.

[1031] Reaction Scheme 18

[1032]

[1033] 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

[1034]

[1035] 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) was added DIEA (380.62 mg, 2.94 mmol, 512.96 μL, 3 equiv) and HATU (559.89 mg, 1.47 mmol, 1.5 equiv) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 h, 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 h. 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 chromatography ( 25 g flash silica column, eluent 85% ethyl acetate / petroleum ether gradient, 30 mL / min). 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 was obtained as a yellow oil (160 mg, 226.75 μmol, 23.10% yield). LCMS (ESI): calculated m / z [M+H] for C36H39N6O5Cl2: 705.23; found: 705.4. Synthesis of 5-(1-(3,5-dichlorophenyl)-3-(2,2-dimethylpiperazine-1-carbonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indazole-8-yl)nicotinamide

[1036]

[1037] 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 h. 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]indazole-8-yl)nicotinamide (145 mg, 225.87 μmol, 99.61% yield, HCl) was obtained as a yellow solid. LCMS (ESI): C 31 H 32 Calculated m / z [M+H] for C 1 H

[1038] Synthesis of Compound 8-61

[1039]

[1040] At 25 °C, AcOH (37.42 mg, 623.08 μmol, 35.67 μL, 10 eq) and 2,2-dimethoxypropane (7.79 mg, 74.77 μmol, 9.16 μL, 1.2 eq) were added dropwise 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 (40 mg, 62.31 μmol, 1 eq, HCl) in DCM (3 mL). After the addition, the mixture was stirred at this temperature for 30 min, and then NaBH(OAc)3 (26.41 mg, 124.62 μmol, 2 eq) was added dropwise at 25 °C. The resulting mixture was stirred at 50 °C for 16 h. The reaction mixture 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 (ammonium hydroxide v / v)-ACN]; gradient: 45%-75% B over 10 min), and then lyophilized. 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 was obtained as an off-white solid (0.99 mg, 1.45 μmol, 2.33% yield, 95% purity). LCMS (ESI): calculated m / z [M+H] for C34H37Cl2N6O3: 647.22; found: 647.2. 1H NMR (400 MHz, methanol-d4) δ = 8.89 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.23 (t, J = 2.1 Hz, 1H), 7.70 - 7.59 (m, 3H), 7.24 (s, 1H), 6.86 (s, 1H), 3.91 (s, 3H), 3.67 (br t, J = 5.4 Hz, 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 (br t, 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 of compound 8-61.

[1041] Synthesis of compound 8-60

[1042]

[1043] Compound 8-60 was synthesized by a method similar to Example 8. LCMS (ESI): C34 H 37 Calculated m / z [M+H] for Cl2N6O5: 633.21; Found: 633.2. 1 H NMR (400 MHz, methanol-d4) δ = 8.88 (d, J = 2.0 Hz, 1H), 8.55 - 8.51 (m, 1H), 8.22 (t, J = 2.1 Hz, 1H), 7.66 - 7.63 (m, 1H), 7.62 (d, J = 1.8 Hz, 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 = 7.3 Hz, 2H), 2.64 (br t, J = 4.6 Hz, 2H), 2.53 (br d, J = 7.3 Hz, 2H), 2.50 (s, 2H), 1.60 (s, 6H), 1.14 (t, J = 7.2 Hz, 3H). Figure 101 1H NMR of compound 8 - 60 is shown.

[1044] Synthesis of compound 8 - 63

[1045]

[1046] Compound 8 - 63 was synthesized by a method similar to Example 8. LCMS (ESI): C 36 H 37 Calculated m / z [M+H] for Cl2N6O5F3: 647.22; Found: 647.2. 1 H NMR (400 MHz, methanol-d4) δ = 8.90 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.25 (t, J = 2.0 Hz, 1H), 7.69 - 7.66 (m, 1H), 7.63 (d, J = 1.8 Hz, 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 (br dd, J = 6.8, 9.9 Hz, 2H), 3.13 - 3.07 (m, 2H), 2.91 (br d, J = 1.6 Hz, 2H), 1.89 - 1.76 (m, 2H), 1.70 (s, 6H), 1.04 (t, J = 7.4 Hz, 3H). Figure 1H NMR of compound 8 - 63 is shown.

[1047] Synthesis of compound 8 - 58

[1048]

[1049] 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 TEA (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 H2O and extracted with 20 mL (10 mL * 2) of EtOAc. 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 μm; mobile phase: [water (FA)-ACN]; gradient: 60%-90% B over 10 min), then lyophilized. 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 was obtained as a white solid (27.2 mg, 35.60 μmol, 26.94% yield, 96% purity, FA). LCMS (ESI): calculated m / z [M + H] for C34H34Cl2N6O5F3: 687.18; found: 687.1. 1H NMR (400 MHz, methanol-d4) δ = 8.93 (d, J = 1.8 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.32 (t, J = 1.9 Hz, 1H), 7.66 - 7.60 (m, 3H), 7.24 (s, 1H), 6.88 (s, 1H), 3.92 (s, 3H), 3.72 (t, J = 5.1 Hz, 2H), 3.15 - 3.07 (m, 4H), 2.87 - 2.78 (m, 4H), 2.64 (s, 2H), 1.59 (s, 6H). ​ Nuclear magnetic resonance of compound 8-58 is shown.

[1050] Reaction Scheme 19

[1051]

[1052] Synthesis of 2,2-dimethyloxazolidine

[1053]

[1054] A mixture of 2-aminoethan-1-ol (50 mg, 818.56 μmol, 49.41 μL, 1 equiv) i...

Claims

1. A follicle-stimulating hormone (FSH) modulating compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein, R 1 is a C1-C 5 alkyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; a C1-C 5 alkenyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; a C3-C 5 heteroaryl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; a C6 aryl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3-C8 cycloalkyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3-C8 cycloalkenyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3-C8 cycloalkynyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkenyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkynyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or a C1-C 5 alkynyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; Y is -OC(R 4 )2-; Z is -OR 4 ; -N(R 4 )2; -SR 4 ; -OH; C1-C6 fluoroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -O-(C1-C6 fluoroalkyl) which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C1-C 5 heteroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkenyl which is unsubstituted or substituted by 1, 2, 1, 4 or 5 groups selected from R 16 ; C3-C8 cycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heteroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heteroalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heteroalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or C3-C 5 alkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; R 2 is a C1-C6 fluoroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -O-(C1-C6 fluoroalkyl) which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or -OCH2CH3; R 3 is hydrogen; halogen; C1-C6 fluoroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -O-(C1-C6 fluoroalkyl) which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -OH; C1-C 5 heteroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C3-C 5 heteroaryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C6 aryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or C1-C 5 alkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; Each R 4 is independently hydrogen; a halogen; a C1-C6 fluoroalkyl group that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; -O-(C1-C6 fluoroalkyl) that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; -OH; a C1-C 5 heteroalkyl group that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; a C1-C 5 alkyl group that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; a C1-C 5 alkenyl group that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; a C3-C 5 heteroaryl group that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; a C6 aryl group that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; a C3-C8 cycloalkyl group that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; a C3-C8 cycloalkenyl group that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; a C3-C8 cycloalkynyl group that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; a heterocycloalkyl group that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; a heterocycloalkenyl group that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; a heterocycloalkynyl group that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 5 ; or a C1-C 5 alkynyl group that is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from R 16 ; Each R 5 is independently deuterium, a 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)OR 6 , -C(=O)N(R 6 )2, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C7 cycloalkyl group, a substituted or unsubstituted C2-C7 heterocycloalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; wherein Each R 6 is independently hydrogen, deuterium, a substituted or unsubstituted C1-C4 alkyl group, -CD3, a substituted or unsubstituted C1-C4 haloalkyl group, a substituted or unsubstituted C1-C4 heteroalkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C2-C5 heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

2. An FSH modulating compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein, R 1 is a C1-C 5 alkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; a C1-C 5 alkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; a C3-C 5 heteroaryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; a C6 aryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3-C8 cycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3-C8 cycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3-C8 cycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or a C1-C 5 alkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; Y is -O-, -S-, -S(=O)-, -S(=O)2-, -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 -; Z is -OR 4 ; -N(R 4 )2; -SR 4 ; C1-C6 fluoroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -O-(C1-C6 fluoroalkyl) which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -OH; C1-C 5 heteroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkenyl which is unsubstituted or substituted by 1, 2, 1, 4 or 5 groups selected from R 16 ; C3-C8 cycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or C3-C 5 alkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; R is hydrogen; halogen; C1-C6 fluoroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -O-(C1-C6 fluoroalkyl) which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -OH; C1-C 5 heteroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C3-C 5 heteroaryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C6 aryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or C1-C 5 alkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; R 2 is -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -CF3, -OCF3, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R or -N(R)2; R 3 is hydrogen; a halogen; C1-C6 fluoroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -O-(C1-C6 fluoroalkyl) which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -OH; C1-C 5 heteroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C3-C 5 heteroaryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C6 aryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or C1-C 5 alkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; Each R 4 is independently hydrogen; a halogen; a C1-C6 fluoroalkyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -O-(C1-C6 fluoroalkyl) which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -OH; a C1-C 5 heteroalkyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; a C1-C 5 alkyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; a C1-C 5 alkenyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; a C3-C 5 heteroaryl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; a C6 aryl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3-C8 cycloalkyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3-C8 cycloalkenyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3-C8 cycloalkynyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkenyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkynyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or a C1-C 5 alkynyl group which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; Each R 5 is independently deuterium, a 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)OR 6 , -C(=O)N(R 6 )2, an unsubstituted C1-C6 alkyl group, an unsubstituted C2-C6 alkenyl group, an unsubstituted C2-C6 alkynyl group, an unsubstituted C1-C6 alkoxy group, an unsubstituted C3-C7 cycloalkyl group, an unsubstituted C2-C7 heterocycloalkyl group, an unsubstituted aryl group, and an unsubstituted heteroaryl group; wherein Each R 6 independently is hydrogen, halogen, deuterium, unsubstituted C1-C4 alkyl, -CD3, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 heteroalkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted C2-C5 heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

3. An FSH modulating compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein, R 1 is a C1-C 5 alkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; a C1-C 5 alkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; a C3-C 5 heteroaryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; a C6 aryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3-C8 cycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3-C8 cycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3-C8 cycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or a C1-C 5 alkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; Y is -O-, -S-, -S(=O)-, -S(=O)2-, -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-, -S(=O)C(R 4 )2-, -C(R 4 )2S(=O)-, -S(=O)2C(R 4 )2-, -C(R 4 )2S(=O)2-, -C(R 4 )2-C(R 4 )2- or -CR 4 =CR 4 -; Z is -O-tert-butyl; R is hydrogen; halogen; C1-C6 fluoroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -O-(C1-C6 fluoroalkyl) which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -OH; C1-C 5 heteroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C3-C 5 heteroaryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C6 aryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or C1-C 5 alkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; R 2 is -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -CF3, -OCF3, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R or -N(R)2; R 3 is hydrogen; halogen; C1-C6 fluoroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -O-(C1-C6 fluoroalkyl) which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -OH; C1-C 5 heteroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C3-C 5 heteroaryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C6 aryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or C1-C 5 alkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; Each R 4 is independently hydrogen; halogen; C1-C6 fluoroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -O-(C1-C6 fluoroalkyl) which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; -OH; C1-C 5 heteroalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C1-C 5 alkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C3-C 5 heteroaryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; C6 aryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3-C8 cycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or C1-C 5 alkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; Each R 5 is independently deuterium, a 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)OR 6 , -C(=O)N(R 6 )2, an unsubstituted C1-C6 alkyl group, an unsubstituted C2-C6 alkenyl group, an unsubstituted C2-C6 alkynyl group, an unsubstituted C1-C6 alkoxy group, an unsubstituted C3-C7 cycloalkyl group, an unsubstituted C2-C7 heterocycloalkyl group, an unsubstituted aryl group, and an unsubstituted heteroaryl group; wherein Each R 6 independently is hydrogen, halogen, deuterium, unsubstituted C1-C4 alkyl, -CD3, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 heteroalkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted C2-C5 heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

4. A compound according to any one of claims 1 - 3, wherein R 3 is a C3 - C 5 heteroaryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 ; a C6 aryl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3 - C8 cycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3 - C8 cycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3 - C8 cycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or a heterocycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 .

5. The compound according to any one of claims 1-3, wherein R 3 is C3-C 5 unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 16 heteroaryl.

6. The compound according to any one of claims 1-5, wherein R 3 is selected from and their substituents.

7. The compound according to any one of claims 1-6, wherein R 3 is selected from and their substituents.

8. The compound according to any one of claims 1-7, wherein R 3 is selected from 9. The compound according to any one of claims 1-8, wherein R 3 is 10. A compound according to any one of claims 1 - 8, wherein R 3 is 11. The compound according to any one of claims 1-8, wherein R 3 is 12. A compound according to any one of claims 1 - 8, wherein R 3 is 13. The compound according to any one of claims 1-8, wherein R 3 is 14. A compound according to any one of claims 1 - 8, wherein R 3 is 15. The compound according to any one of claims 1-8, wherein R 3 is 16. A compound according to any one of claims 1 - 8, wherein R 3 is 17. The compound according to any one of claims 1-8, wherein R 3 is 18. The compound according to any one of claims 1 - 8, wherein R 3 is 19. The compound according to any one of claims 2-18, wherein R 2 is - halogen, -OR, -SR, -CN, -NO2, -CF3, -OCF3 or -C(=O)CH3.

20. The compound according to any one of claims 2-18, wherein R 2 is -OCH3, -SCH3, -CN, -NO2, -CF3 or -OCF3.

21. The compound according to any one of claims 2-19, wherein R 2 is -OCH3, -SCH3 or -OCF3.

22. The compound according to any one of claims 2-21, wherein R 2 is -SCH3.

23. The compound according to any one of claims 1-21, wherein R 2 is -OCF3.

24. The compound according to any one of claims 1-19, wherein R 2 is -CF3.

25. The compound according to any one of claims 1-19, wherein R 2 is -OCH2CH3.

26. The compound according to any one of claims 2-21, wherein R 2 is -OCH3.

27. A compound according to any one of claims 1-26, wherein R 1 is a C3-C 5 heteroaryl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 16 ; a C6 aryl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3-C8 cycloalkyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3-C8 cycloalkenyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; a C3-C8 cycloalkynyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; a heterocycloalkenyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ; or a heterocycloalkynyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from R 5 .

28. A compound according to any one of claims 1-27, wherein R 1 is an unsubstituted C6 aryl or a C6 aryl substituted with 1, 2, 3, 4 or 5 groups selected from R 5 ​ 29. A compound according to any one of claims 1-27, wherein R 1 is C3-C 5 unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 16 heteroaryl.

30. A compound according to any one of claims 1-27, wherein R 1 is selected from and their substituents.

31. A compound according to any one of claims 1 - 28 or 30, wherein R 1 is selected from and their substituents.

32. A compound according to any one of claims 1-28 or 30-31, wherein R 1 is 33. A compound according to any one of claims 1 - 28 or 30 - 31, wherein R 1 is 34. A compound according to any one of claims 1-28 or 30-31, wherein R 1 is 35. A compound according to any one of claims 1 - 28 or 30 - 31, wherein R 1 is 36. A compound according to any one of claims 1-28 or 30-31, wherein R 1 is 37. A compound according to any one of claims 1-28 or 30-31, wherein R 1 is 38. A compound according to any one of claims 1-28 or 30-31, wherein R 1 is 39. A compound according to any one of claims 1-28 or 30-31, wherein R 1 is 40. A compound according to any one of claims 1-28 or 30-31, wherein R 1 is 41. A compound according to any one of claims 1-28 or 30-31, wherein R 1 is 42. A compound according to any one of claims 3 - 41, wherein 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-, -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 -.

43. A compound according to any one of claims 3 - 42, wherein 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 )2-.

44. The compound according to any one of claims 3-43, wherein Y is -O-, -S-, -NH-, -OCH2-, -SCH2-, -CH2O-, -CH2S-, -CH2-, -S(=O)CH2-, -CH2S(=O)-, -S(=O)2CH2-, -CH2S(=O)2-.

45. The compound according to any one of claims 2-44, wherein Y is -O-.

46. The compound according to any one of claims 2-44, wherein Y is -S-.

47. The compound according to any one of claims 2-44, wherein Y is -S(=O)-.

48. The compound according to any one of claims 2-44, wherein Y is -S(=O)2-.

49. A compound according to any one of claims 2 - 44, wherein Y is -S(=O)C(R 4 )2-.

50. A compound according to any one of claims 2 - 44, wherein Y is -C(R 4 )2S(=O)-.

51. A compound according to any one of claims 2 - 44, wherein Y is -S(=O)2C(R 4 )2-.

52. A compound according to any one of claims 2 - 44, wherein Y is -C(R 4 )2S(=O)2-.

53. The compound according to any one of claims 2-44, wherein Y is -S(=O)CH2-.

54. The compound according to any one of claims 2-44, wherein Y is -CH2S(=O)-.

55. The compound according to any one of claims 2-44, wherein Y is -S(=O)2CH2-.

56. The compound according to any one of claims 2-44, wherein Y is -CH2S(=O)2-.

57. The compound according to any one of claims 2-44, wherein Y is -NR 4 -.

58. A compound according to any one of claims 3 - 44, wherein Y is -OC(R 4 )2-.

59. A compound according to any one of claims 2 - 44, wherein Y is -SC(R 4 )2-.

60. The compound according to any one of claims 2-44, wherein Y is -C(R 4 )2O-.

61. A compound according to any one of claims 2-44, wherein Y is -C(R 4 )2S-.

62. The compound according to any one of claims 2-44, wherein Y is -C(R 4 )2NR 4 -.

63. A compound according to any one of claims 2-44, wherein Y is -C(R 4 )2-.

64. The compound according to any one of claims 2-44, wherein Y is -C(R 4 )2-C(R 4 )2-.

65. A compound according to any one of claims 2-44, wherein Y is -CR 4 =CR 4 -.

66. The compound according to any one of claims 2-44, wherein Y is -NH-.

67. The compound according to any one of claims 2-44, wherein Y is -OCH2-.

68. The compound according to any one of claims 2-44, wherein Y is -SCH2-.

69. The compound according to any one of claims 2-44, wherein Y is -CH2O-.

70. The compound according to any one of claims 2-44, wherein Y is -CH2S-.

71. A compound according to any one of claims 2 - 44, wherein Y is -CH2NR 4 -.

72. The compound according to any one of claims 2-44, wherein Y is -CH2-.

73. The compound according to any one of claims 2-44, wherein Y is -CH2-CH2-.

74. The compound according to any one of claims 2-44, wherein Y is -CH=CH-.

75. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is -OR 4 ; -N(R 4 )2; -SR 4 ; -CF3; -OCF3; -OH; C3 - C8 cycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3 - C8 cycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; C3 - C8 cycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; heterocycloalkenyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 ; or heterocycloalkynyl which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from R 5 .

76. A compound according to any one of claims 1-2 or 4-75, wherein Z is -OR 4 , -N(R 4 )2, -SR 4 , -CF3, -OCF3, or selected from 77. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is -OR 4 , -N(R 4 )2, -SR 4 .

78. A compound according to any one of claims 1 - 2 or 4 - 74 or 77, wherein Z is -OR 4 , -N(R 4 )2, -SR 4 , and at least one R 4 of Z is selected from 79. A compound according to any one of claims 1 - 2 or 4 - 74 or 77 - 78, wherein Z is -OR 4 or -SR 4 , and the R of Z 4 is 80. The compound according to any one of claims 1-2 or 4-74, wherein Z is selected from 81. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 82. The compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 83. A compound according to any one of claims 1-2 or 4-74, wherein Z is 84. The compound according to any one of claims 1-2 or 4-74, wherein Z is 85. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 86. A compound according to any one of claims 1-2 or 4-74, wherein Z is 87. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 88. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 89. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 90. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 91. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 92. A compound according to any one of claims 1-2 or 4-74, wherein Z is 93. The compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 94. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 95. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 96. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 97. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 98. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 99. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 100. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 101. The compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 102. The compound according to any one of claims 1-2 or 4-74, wherein Z is 103. The compound according to any one of claims 1-2 or 4-74, wherein Z is 104. The compound according to any one of claims 1-2 or 4-74, wherein Z is 105. A compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 106. The compound according to any one of claims 1 - 2 or 4 - 74, wherein Z is 107. The compound according to any one of claims 1-106, wherein R 1 or R 3 is substituted by a halogen.

108. The compound according to any one of claims 1-107, wherein R 1 or R 3 is substituted with chlorine.

109. The compound according to any one of claims 1-108, wherein R 1 or R 3 is substituted with fluorine.

110. The compound according to any one of claims 1-109, R 1 or R 3 is substituted with C1-C4 heteroalkyl.

111. The compound according to any one of claims 1-110, wherein at least one R within Z 4 is selected from 112. The compound according to any one of the preceding claims, wherein, When the compound is administered to a subject, the compound selectively modulates FSH and substantially does not modulate thyroid-stimulating hormone (TSH).

113. The compound according to any one of the foregoing claims, wherein the compound is an FSH agonist.

114. A compound according to any one of the preceding claims, wherein the compound has a selectivity for FSH that is at least 3-fold (e.g., at least 3, 5, 10, 20, 50, or 100-fold) that of TSH.

115. A compound according to any one of the preceding claims, wherein the in vitro or in vivo EC of FSH agonist 50 is not more than about 100 nM (e.g., not more than 100 nM, 50 nM, 10 nM, 5 nM, 1 nM or 500 pM).

116. A compound according to any one of the preceding claims, wherein the compound has a structure selected from the following: 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 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, 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.

117. A method of treating a disease or condition, comprising administering to a subject in need thereof a compound according to any one of the preceding claims.

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

119. The method according to claim 117, wherein the disease or condition is Turner syndrome.

120. The method according to claim 117, wherein the disease or condition is Klinefelter syndrome.

121. The method according to claim 117, wherein the disease or condition is primary ovarian insufficiency (POI).

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

123. A pharmaceutical composition comprising a compound according to any one of claims 1-116 or a pharmaceutically acceptable salt or 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 1-116 or a pharmaceutically acceptable composition according to claim 123.

125. A method of treating a condition or disease, comprising administering to a subject in need thereof a compound according to any one of claims 1-116, 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. Use of a compound according to any one of claims 1-116, 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 treating a condition or disease.

127. A kit comprising: a. A compound according to any one of claims 1-116, 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; and b. Instructions for use.

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