IL322905A - Small molecule fsh receptor modulators - Google Patents

Description

WO 2024/184461 PCT/EP2024/056026 SMALL MOLECULE FSH RECEPTOR MODULATORS FIELD

[001]The present disclosure is in the field of pharmaceutical compounds and compositions and therapeutic methods of their use. In particular, the present disclosure is in the field of follicle- stimulating hormone (FSH) receptor modulators and their use.

BACKGROUND

[002]Gonadotropins serve important functions in several physiological processes including metabolism, temperature regulation, and reproduction. Gonadotropins act on specific gonadal cell types to initiate ovarian and testicular cell differentiation and steroidogenesis. The gonadotropin FSH (follicle-stimulating hormone) is released from the anterior pituitary under the influence of gonadotropin-releasing hormone and estrogens. FSH is a heterodimeric glycoprotein hormone that shares structural similarities with luteinizing hormone (LH), human chorionic gonadotropin (hCG) and thyroid-stimulating hormone (TSH), all of which are proteins (28-38 kDa) composed of a common a-subunit non-covalently bound to a distinct p-subunit that confers receptor binding specificity. See, e.g, Ulloa-Aguirre, A., et al., Front Endocrinol (Lausanne), 2018, 9:707. FSH, LH, and TSH are produced in the pituitary gland, while hCG is produced primarily by the placenta. The cellular receptor for FSH (FSHR) is expressed on testicular Sertoli cells and ovarian granulosa cells. See, e.g., Anderson, R.C., et al., Endocr Rev, 2018, 39(6):911-937.

[003]In the female, FSH plays a pivotal role in the stimulation of follicle development and maturation. Binding of FSH to FSHR initiates an increase in the level of the intracellular second messenger adenosine 3', 5'-monophosphate (cAMP), which stimulates aromatase induction that catalyzes the conversion of androstenedione to estradiol within the ovary, enabling follicle growth. See, e.g., Donadeu, F.X. andM. Ascoli, Endocrinology, 2005, 146(9):3907-16.

[004]FSHR activation also stimulates the expression of LH receptors on granulosa cells, allowing them to respond to the preovulatory LH surge. In the male, FSH is expressed on the Sertoli cells of the testis and plays a key role in stimulating spermatogenesis. Prepubertally, FSH WO 2024/184461 PCT/EP2024/056026 is responsible for Sertoli cell proliferation and in adulthood FSH stimulates spermatogonial proliferation and can support spermatogenesis to the round spermatid stage.

[005]The FSH receptor is a class A member of the G-coupled protein (GPCR) class of receptors, belonging to the subfamily of glycoprotein hormone receptors, which also includes luteinizing hormone/ choriogonadotropin receptor (LHCGR) and thyroid stimulating hormone receptor (TSHR). See, e.g, Ulloa-Aguirre, supra. Hydropathicity plots of the amino acid sequences of these receptors reveal three general domains: a hydrophilic amino-terminal region, considered to be the amino-terminal extracellular domain; seven hydrophobic segments of membrane- spanning length, considered to be the transmembrane domain; and a carboxy-terminal region that contains potential phosphorylation sites (serine, threonine, and tyrosine residues), considered to be the carboxyterminal intracellular or cytoplasmic domain. The glycoprotein hormone receptor family is distinguished from other G protein-coupled receptors, such as the 3-2-adrenergic, rhodopsin, and substance K receptors, by the large size of the hydrophilic amino-terminal domain, which is involved in hormone binding.

[006]Annually in the U.S. there are 2.4 million couples experiencing infertility that are potential candidates for treatment. FSH, either extracted from urine or produced by recombinant DNA technology, is a parenterally-administered protein product used by specialists for ovulation induction and for controlled ovarian stimulation. Whereas ovulation induction is directed at achieving a single follicle to ovulate, controlled ovarian stimulation is directed at aspirating multiple oocytes for use in various in-vitro assisted reproductive technologies, e.g., in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). See, e.g., ESHRE guideline: Ovarian Stimulation for IVF/ICSI, (October 2019). FSH is also used clinically to treat male hypogonadism and male infertility, e.g., some types of failure of spermatogenesis. See, e.g., Behre, H.M., Front Endocrinol (Lausanne), 2019, 10:322.

[007]FSHR is a highly specific target in the ovarian follicle growth process in the female and is almost exclusively expressed in the ovary. However, the use of FSH is limited by its high cost, lack of oral dosing, and the need for extensive monitoring by specialist physicians. Hence, WO 2024/184461 PCT/EP2024/056026 identification of a non-peptidic small molecule substitute for FSH that could potentially be developed for oral administration is desirable.

[008]FSH and small molecule FSH receptor modulators may be used to treat diseases, disorders, and conditions such as female infertility, male infertility, hypogonadism, and failure of spermatogenesis. Small molecule FSH agonists have been disclosed in, e.g., WO 2002/09706, WO 2009/098283, WO 2010/136438, U.S. Patent No. 6,653,338, US Patent No. 8,431,564, WO 2011/012600, WO 2014/209978, and WO 2015/196759. One small molecule FSH receptor modulator, MK-8389, was evalulated in clinical trials, but did not reach approval. See, e.g., Gerrits, M.G.F. et al., Fertility and Sterility Vol. 105, No. 4, April 2016. There remains a need for small molecule FSH receptor modulators that selectively activate FSHR.

SUMMARY

[009]In one aspect, provided herein is a compound of Formula (A) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is -NRf Rg, wherein (i) Rf and Rg together with the nitrogen to which they are attached form a 4- to 8-memberedheterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4 groups, wherein each Rgroup is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to substituents (e.g. 1 to 6, or 1 to 5 substituents) independently selected from C3-Ccycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the WO 2024/184461 PCT/EP2024/056026 atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; or (ii) Rf is C1-C6 alkyl; and Rg is C1-C6 alkyl substituted with 1 to 4 R4c groups, wherein each R4c group is independently selected from halogen, hydroxy, and nitrile; R2 is selected from C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-C3 alkyl)-S02CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6 alkyl)- NR5a R5b; phenyl; C4-C6 cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl; Xis CR20orN; R20 is selected from H, halogen, nitrile, C1-C6 alkyl, and C1-C6 haloalkyl; R3 is selected from -C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or WO 2024/184461 PCT/EP2024/056026 partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11 and R12 together form a double bond, and R10 and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl;wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0010]In some embodiments, R1 is -NRf Rg, wherein: (i) Rf and Rg together with the nitrogen to which they are attached form a 4- to 8-memberedheterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4 groups, wherein each R4 WO 2024/184461 PCT/EP2024/056026 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; or (ii) Rf is C1-C6 alkyl; and Rg is C1-C6 alkyl substituted with 1 to 4 R4c groups, wherein each R4c group is independently selected from halogen, hydroxy, and nitrile.

[0011]In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 4-membered heterocycloalkyl ring optionally containing additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl.

[0012]In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 5-membered heterocycloalkyl ring optionally containing additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl.

[0013]In some embodiments, R1 is , wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the WO 2024/184461 PCT/EP2024/056026 atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl.

[0014]In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 6-membered heterocycloalkyl ring optionally containing additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl.

[0015]In some embodiments, R1 is -NRf Rg, wherein Rf is C1-C6 alkyl; and Rg is C1-C6 alkyl substituted with 1 to 4 R4c groups, wherein each R4c group is independently selected from halogen, hydroxy, and nitrile.

[0016]In some embodiments, R2 is C1-C6 alkyl or C1-C6 alkenyl. In some embodiments, Ris C1-C6 haloalkyl. In some embodiments, R2 is C1-C6 hydroxyalkyl. In some embodiments, Ris phenyl optionally substituted with 1 to 4 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl. In some embodiments, R2 is 4-fluorophenyl. In some embodiments, R2 is C4-C6 cycloalkyl optionally substituted with 1 to R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl. In some embodiments, R2 is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1- C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl. In some embodiments, R2 is 3,3-difluorocyclobutyl, 5-fluoropyridin-2-yl, 2-thiophenyl, 5-thiazolyl, or 1,3,4-thiadiazolyl. -ר- WO 2024/184461 PCT/EP2024/056026

[0017]In some embodiments, X is CR20. In some embodiments, X is N.

[0018]In another aspect, provided herein is a compound of Formula (B) Formula (B) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-Calkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; Het is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 to 4 R5 groups independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl; R3 is selected from -C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from:-8- WO 2024/184461 PCT/EP2024/056026 (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0019]In some embodiments, Het is a 5-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with WO 2024/184461 PCT/EP2024/056026 1 to 4 R5 groups independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-Chaloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-Calkyl. In some embodiments, Het is a 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with to 4 R5 groups independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-Chaloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-Calkyl.

[0020]In another aspect, provided herein is a compound of Formula (C) Formula (C) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is ^-'J, wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-Calkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; R3 is selected from C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl WO 2024/184461 PCT/EP2024/056026 ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; WO 2024/184461 PCT/EP2024/056026 wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0021]In another aspect, provided herein is a compound of Formula (D) Formula (D) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is , wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1- C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; R3 is selected from C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; m is 0, 1,2, 3, or 4; WO 2024/184461 PCT/EP2024/056026 each R5 is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-Chaloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1- C3 alkyl; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are WO 2024/184461 PCT/EP2024/056026 attached, form a 3- to 6-membered ring, , and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl;wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0022]In another aspect, provided herein is a compound of Formula (E) Formula (E) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is , wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-Calkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; R3 is selected from C(O)NHR6, -SO2-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; Aik is C1-C6 alkyl or C1-C6 alkenyl; R6 is selected from:-14- WO 2024/184461 PCT/EP2024/056026 (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl;wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0023]In another aspect, provided herein is a compound of Formula (F) WO 2024/184461 PCT/EP2024/056026 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is -NRf Rg, wherein (i) Rf and Rg together with the nitrogen to which they are attached form a 4- to 8-memberedheterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4 groups, wherein each Rgroup is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1- C3 alkyl; or (i) Rf is C1-C6 alkyl; and Rg is C1-C6 alkyl substituted with 1 to 4 R4c groups, wherein each R4c group is independently selected from halogen, hydroxy, and nitrile; R2 is selected from C1-C6 alkyl; C1-C6 alkenyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-Calkyl)-SO2CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6 alkyl)-NR 5a R5b; phenyl; C4-C6 cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl; WO 2024/184461 PCT/EP2024/056026 R3 is selected from -C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to WO 2024/184461 PCT/EP2024/056026 7 independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11 and R12 together form a double bond, and R10 and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

R׳R4 Fn J [0024]In some embodiments, R1 is , wherein each R4 is independently selected fromnitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from R4^ R4b J-n jC3-C6 cycloalkyl, hydroxy, and halogen. In some embodiments, R1 is k/J , wherein R4a is C1-C6 alkyl and R4b is selected from nitrile and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen. In some R4? R4b . Hn Jembodiments, R1 is k-^ , wherein R4b is C1-C6 alkyl and R4a is selected from nitrile and C1- C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy, and halogen.

[0025]In some embodiments, R3 is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6- membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(0)NH2. In some embodiments, R3 is 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heteroaryl ring contains WO 2024/184461 PCT/EP2024/056026 to 4 ring nitrogens, and wherein the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2. In some embodiments, R3 is tetrazole, pyrazole, imidazole, oxazole, or pyridine, wherein R3 may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2. In some embodiments, R3 is - C(O)NHR6.

[0026]In some embodiments, R6 is (CR7R8)n C(O)NRdRe. In some embodiments, each of Rand R8 is independently selected from H and C1-C3 alkyl. In some embodiments, R7 and Rtogether with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen.

[0027]In some embodiments, R6 is C1-C6 alkyl optionally substituted with nitrile or 5- or 6- membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy. In some embodiments, R6 is C1-C6 alkyl optionally substituted with nitrile or tetrazole. In some embodiments, R6 is phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6- membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to 7 independently selected halogens. In some embodiments, R6 is cyclopropane optionally substituted with nitrile or is 19yclobutene optionally substituted with nitrile.

[0028]In some embodiments, each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, any two of R10, R11, R12, and R13, WO 2024/184461 PCT/EP2024/056026 together with the carbon atom(s) to which they are attached, form a 3 - to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl.

[0029]In another aspect, provided herein is a compound of Formula (F) R R20 Formula (F) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6- membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; R2 is selected from C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-C3 alkyl)-S02CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6 alkyl)- NR5a R5b; phenyl; C4-C6 cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl; R20 is selected from H, halogen, nitrile, C1-C6 alkyl, and C1-C6 haloalkyl; WO 2024/184461 PCT/EP2024/056026 R3 is selected from -C(O)NHR6, -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and WO 2024/184461 PCT/EP2024/056026 each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11 and R12 together form a double bond, and R10 and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0030]In another aspect, provided herein is a compound of Formula (1) Formula (1) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 3 R4 groups, wherein each R4 group is independently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen; R2 is selected from C1-C6 alkyl; C1-C6 haloalkyl; phenyl; and 5- to 6-membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 or 2 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; R3 is selected from C(O)NHR6 and 5- to 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6- WO 2024/184461 PCT/EP2024/056026 membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl, WO 2024/184461 PCT/EP2024/056026 wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0031]In another aspect, provided herein is a compound selected from Table 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another aspect, provided herein is a compound selected from Table 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0032]In another aspect, provided herein are salts, hydrates, solvates, analogs, conjugates, isomers, polymorphs, esters, prodrugs, metabolites, complexes, co-crystals, intermediates, modifications and derivatives of the compounds, stereoisomers, and tautomers described herein.

[0033]In another aspect, provided herein is a pharmaceutical composition comprising the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein, and a pharmaceutically acceptable carrier.

[0034]In another aspect, provided herein is a method of modulating follicle-stimulating hormone receptor (FSHR) activity in a subject, comprising administering to a subject in need thereof the compound disclosed herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or the composition disclosed herein.

[0035]In another aspect, provided herein is a method of modulating follicle-stimulating hormone receptor (FSHR) activity in a biological sample, comprising contacting the biological sample with the compound disclosed herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or the composition disclosed herein.

[0036]In another aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound disclosed herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or the composition disclosed herein. In some embodiments, the disease or disorder is selected from hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngiomas, combined pituitary hormone deficiency, fertile eunuch syndrome, abnormal WO 2024/184461 PCT/EP2024/056026 beta subunit of LH, abnormal beta subunit of FSH, mass lesions, pituitary adenomas, cysts, metastatic cancer to the sella (breast in women, lung and prostate in men), infiltrative lesions, hemochromatosis, sarcoidosis, histiocytosis, lymphoma, lymphocytic hypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, hypothyroidism, intentional (iatrogenic) secondary hypogonadism, empty sella, pituitary infarction, Sheehan syndrome, anorexia nervosa, congenital adrenal hyperplasia, and disorders related to GnRH deficiency.

[0037]In another aspect, provided herein is a method for treating a fertility disorder in a female or male subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a composition as disclosed herein. The method may be a method for stimulating follicular development, a method for ovulation induction, a method of controlled ovarian hyperstimulation, a method of controlled ovarian stimulation, a method of assisted reproductive technology (ART) (including in vitro fertilization), a method of treating male hypogonadism, or a method of treating male infertility, including failure of spermatogenesis.

[0038]In another aspect, provided herein is a compound as disclosed herein or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a composition disclosed herein, for use in modulating follicle-stimulating hormone receptor (FSHR) activity in a subject, or for use in in treating a disease or disorder in a subject in need thereof, such as a disease or disorder selected from hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngiomas, combined pituitary hormone deficiency, fertile eunuch syndrome, abnormal beta subunit of LH, abnormal beta subunit of FSH, mass lesions, pituitary adenomas, cysts, metastatic cancer to the sella (breast in women, lung and prostate in men), infiltrative lesions, hemochromatosis, sarcoidosis, histiocytosis, lymphoma, lymphocytic hypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, hypothyroidism, intentional (iatrogenic) secondary hypogonadism, empty sella, pituitary infarction, Sheehan syndrome, anorexia nervosa, congenital adrenal hyperplasia, and disorders related to GnRH deficiency, or for use in treating a fertility disorder in a subject in need thereof, such as for stimulating follicular development, ovulation induction, controlled WO 2024/184461 PCT/EP2024/056026 ovarian hyperstimulation, controlled ovarian stimulation, assisted reproductive technology (ART) (including in vitro fertilization), treating male hypogonadism, or treating male infertility, including failure of spermatogenesis.

[0039]In another aspect, provided herein is the use of a compound as disclosed herein, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a composition disclosed herein, in the preparation of a medicament for modulating follicle-stimulating hormone receptor (FSHR) activity in a subject, or for treating a disease or disorder in a subject in need thereof, such as a disease or disorder selected from hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngiomas, combined pituitary hormone deficiency, fertile eunuch syndrome, abnormal beta subunit of LH, abnormal beta subunit of FSH, mass lesions, pituitary adenomas, cysts, metastatic cancer to the sella (breast in women, lung and prostate in men), infiltrative lesions, hemochromatosis, sarcoidosis, histiocytosis, lymphoma, lymphocytic hypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, hypothyroidism, intentional (iatrogenic) secondary hypogonadism, empty sella, pituitary infarction, Sheehan syndrome, anorexia nervosa, congenital adrenal hyperplasia, and disorders related to GnRH deficiency, or for treating a fertility disorder in a subject in need thereof, such as for stimulating follicular development, ovulation induction, controlled ovarian hyperstimulation, controlled ovarian stimulation, assisted reproductive technology (ART) (including in vitro fertilization), treating male hypogonadism, or treating male infertility, including failure of spermatogenesis.

DETAILED DESCRIPTION DEFINITIONS

[0040]Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which the present disclosure pertains, unless otherwise defined.

[0041]As used herein, the singular forms "a," "an," and "the" and the like designate both the singular and the plural, unless expressly stated to designate the singular only.

WO 2024/184461 PCT/EP2024/056026

[0042]As used herein, the term "about" means that the stated parameter is not limited to the exact number stated. As used herein, "about" will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, "about" will mean up to plus or minus 10% of the particular term. As used herein, ranges are to be construed as shorthand for each and every value falling within the range, and each separate value should be understood to be expressly disclosed herein.

[0043]The phrase “consisting essentially of ’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. When “consisting essentially of ’ is used to refer to compositions with only one active agent disclosed herein, the compositions cannot include any additional active agents that are not otherwise recited. When “consisting essentially of ’ is used to refer to combinations of active agents disclosed herein, the combinations cannot include any additional active agents that are not otherwise recited.

[0044]As used herein, “pharmaceutically acceptable salt ” refers to a salt of a compound that does not cause significant irritation to a patient to which it is administered and does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. Typically, but not necessarily unless otherwise stated, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term “pharmaceutically acceptable salts ” refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present disclosure may comprise acid addition salts. Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, WO 2024/184461 PCT/EP2024/056026 phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium, and valerate salts. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this disclosure and these should be considered to form a further aspect of the present technology.

[0045]Where compounds disclosed herein have one or more chiral centers, they may exist as, be provided or formulated as, or be used as, a racemate or as individual enantiomers. It should be noted that all such stereoisomers and mixtures thereof are included in the scope of the present disclosure. Thus, the illustration of a chiral center without a designation of R or S signifies that the scope of the disclosure includes the R isomer, the S isomer, racemic mixtures of the isomers, and mixtures where one isomer is present in greater abundance than another.

[0046]Where processes for the preparation of compounds disclosed herein give rise to mixtures of stereoisomers, such isomers may be separated by conventional techniques such as preparative chiral chromatography. The compounds may be prepared in racemic form or individual enantiomers may be prepared by stereoselective synthesis or by resolution. The compounds may be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d- tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides followed by chromatographic separation and removal of the chiral auxiliary.

[0047]As used herein, “aryl ” refers to a carbocyclic (all carbon) ring that is fully aromatized. An “aryl ” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When an aryl group is a fused ring system, then the ring that is connected to the rest of the molecule is fully aromatized. The other ring(s) in the fused ring system may or may not be fully aromatized. Examples of aryl groups include, without limitation, the radicals of benzene, naphthalene and azulene. Additional non-limiting examples include: WO 2024/184461 PCT/EP2024/056026

[0048]As used herein, “heteroaryl ” refers to a ring that is fully aromatized and contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur in the ring. In some examples, a heteroaryl ring may comprise an oxo group directly appended to a ring carbon, the oxo group forming part of the aromatized system. A “heteroaryl ” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When a heteroaryl group is a fused ring system, then the ring that is connected to the rest of the molecule is fully aromatized. The other ring(s) in the fused ring system may or may not be fully aromatized. Examples of heteroaryl rings include, without limitation, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, 2-pyridonyl, pyridazine, pyrimidine, pyrazine and triazine. As described herein, in some examples, the heteroaryl group may be substituted. In other words, the heteroaryl group may comprise one or more substituents on the heteroaromatic ring. When a heteroaryl group is substituted, any hydrogen atom(s) may be replaced with the substituent(s) provided that valencies are satisfied. In some cases, the heteroaryl group may be substituted at the heteroatom, e.g., a N-containing heteroaryl group may be an N-substituted heteroaryl group (such as a N-substituted 2-pyridonyl group).

[0049]As used herein, “alkyl ” refers to a straight or branched chain fully saturated (no double or triple bonds) hydrocarbon group. An alkyl group of the presently disclosed compounds may comprise from 1 to 20 carbon atoms. An alkyl group herein may have 1 to 4 carbon atoms, 1 to carbon atoms, 1 to 6 carbon atoms, 1 to 7 carbon atoms, 1 to 8 carbon atoms, 1 to 9 carbon atoms, to 10 carbon atoms, 1 to 11 carbon atoms, 1 to 12 carbon atoms, 1 to 13 carbon atoms, 1 to carbon atoms, or 1 to 15 carbon atoms. As used herein, a C1-C6 alkyl represents an alkyl group having 1 to 6 carbon atoms, a C1-C4 alkyl represents an alkyl group having 1 to 4 carbon atoms and a C1-C4 alkyl represents an alkyl group having 1 to 3 carbon atoms, etc. Examples of alkyl groups include, without limitation, methyl, ethyl, //-propyl, isopropyl, //-butyl, z-butyl, sec-butyl, /-butyl, amyl, Z-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.

WO 2024/184461 PCT/EP2024/056026

[0050]As used herein, “cycloalkyl ” refers to a completely saturated (no double bonds) hydrocarbon ring. Cycloalkyl groups of the presently disclosed compounds may range from C3 to C5, C3 to C6, C3 to C7, or C3 to C8. As used herein, a C3-C5 cycloalkyl represents a cycloalkyl group containing 3 to 5 carbon atoms and a C3-C6 cycloalkyl represents a cycloalkyl group containing to 6 carbon atoms.

[0051]As used herein, “heterocycloalkyl ” refers to a ring having in the ring system one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. The ring may also contain one or more double bonds provided that the ring is not fully aromatized. A “heterocycloalkyl ” ring as defined herein can be a stable 3- to 18-membered ring (which includes a 3- to 5-membered or 3- to 6-membered ring) that consists of carbon atoms and from one to five ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0052]As used herein, “alkoxy ” refers to an alkyl group, as defined above, appended to the parent molecular moiety through an oxy group, -O-. As used herein, a C1-C6 alkoxy represents an alkoxy group containing 1 to 6 carbon atoms and a C1-C3 alkoxy represents an alkoxy group containing 1 to 3 carbon atoms. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy etc.

[0053]As used herein, "haloalkyl" refers to an alkyl group, as defined above, in which one or more of the hydrogen atoms thereon has been replaced with a halogen atom (e.g. F, Cl, Br or 1). As used herein, “C1-C6 haloalkyl ” represents an alkyl group containing 1 to 6 carbon atoms, in which one or more hydrogens thereon has been replaced with a halogen atom.

[0054]As used herein, “haloalkoxy ” refers to an alkoxy group, as defined herein, in which one or more of the hydrogen atoms thereon has been replaced with a halogen atom (e.g. F, Cl, Br or I). As used herein, “C1-C3 haloalkoxy ” represents a haloalkoxy group containing 1 to 3 carbon atoms.

[0055]As used herein, unless otherwise stated, “independently selected ” indicates that each one of a designated group is selected independently from a subsequent list of species.

WO 2024/184461 PCT/EP2024/056026

[0056]As used herein, and unless otherwise stated, where a group is described as being optionally substituted, one or more hydrogen atoms on the group may each independently be replaced with a substituent, provided valencies are satisfied.

[0057]It is to be understood that, in any compound of the presently disclosed compounds having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be R or S. In addition, it is to be understood that, in any compound of the presently disclosed compounds having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z.

[0058]It is to be understood that the disclosure of a compound herein inherently includes the disclosure of a tautomer thereof, if applicable. For instance, the disclosure of: r x، N ° (wherein Rx is H) also includes the disclosure of: and vice versa, even if only one of the two structures is disclosed.

[0059]Throughout the present disclosure, when a compound is illustrated or named, it is to be understood that isotopically enriched analogs of the compound are also contemplated and encompassed by the disclosure. For example, a compound may have a deuterium incorporated instead of a hydrogen, or a carbon- 13 instead of carbon with natural isotopic distribution. The isotopic enrichment may be in one location on the compound, i.e., only one hydrogen is replaced by a deuterium, or in more than one location, i.e., two or more or all or a plurality less than all hydrogens are replaced by deuterium. For example, in some embodiments, 1 to 10 hydrogens are replaced by deuterium. The present disclosure also encompasses compounds where all similar atoms are replaced by a less common isotope, for example, a perdeutero compound where all hydrogen atoms are replaced by deuterium. The isotopically enriched compounds may be useful, WO 2024/184461 PCT/EP2024/056026 for example, when obtaining NMR spectra or when making use of an isotope effect in managing the kinetics of the reaction the compound is undergoing.

[0060]Throughout the present disclosure, when a compound is illustrated or named, it is to be understood that salts, hydrates, solvates, analogs, conjugates, isomers, polymorphs, esters, prodrugs, metabolites, complexes, co-crystals, intermediates, modifications, and derivatives thereof are contemplated and encompassed by the disclosure.

[0061]The term “pharmaceutical composition ” refers to a mixture of one or more compounds disclosed herein with another pharmaceutically acceptable excipient, such as one or more pharmaceutically acceptable diluents or carriers or one or more other pharmaceutically acceptable excipients known in the art. Formulating a compound in a pharmaceutical composition may facilitate administration of the compound to an organism, e.g., the subject to be treated. The specific components of a pharmaceutical composition may depend on and vary with the intended route of administration.

[0062]As used herein, the terms “patient ” and “subject ” refer to a vertebrate, such as but not limited to a mammal (including a human), bird, fish, or reptile, that has been or will be the object of treatment, observation, or experiment. “Subject ” and “patient ” may be used interchangeably. Mammals include, but are not limited to, humans, mice, rodents, rats, simians, farm animals, dogs, cats, sport animals, and pets. The methods described herein may be useful in human therapy and/or veterinary/animal husbandry applications. Without being limiting, the discussion that follows is written with reference to adult human patients.

[0063]As used herein, the terms “therapeutically effective amount ” and “effective amount ” are used interchangeably and refer to an amount that provides the specific intended pharmacological effect in a patient in need of treatment. It is emphasized that a therapeutically effective amount will not always be effective in treating the conditions described herein in a given patient, even though such amount is deemed to be a therapeutically effective amount by those of skill in the art. Exemplary therapeutically effective amounts are provided herein with reference to adult human patients. The therapeutically effective amount may vary depending upon WO 2024/184461 PCT/EP2024/056026 characteristics of the patient being treated, the condition being treated, and the severity of the condition, for example.

COMPOUNDS

[0064]In one aspect, disclosed herein is a compound of Formula (A) R2 Formula (A) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is -NRf Rg, wherein (i) Rf and Rg together with the nitrogen to which they are attached form a 4- to 8-memberedheterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4 groups, wherein each Rgroup is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to 13 substituents (e.g. to 6, or 1 to 5 substituents) independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; or (ii) Rf is C1-C6 alkyl; and Rg is C1-C6 alkyl substituted with 1 to 4 R4c groups, wherein each R4c group is independently selected from halogen, hydroxy, and nitrile; R2 is selected from C1-C6 alkyl; C1-C6 alkenyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-Calkyl)-S02CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6 alkyl)-NR 5a R5b; phenyl; C4-C6 cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, WO 2024/184461 PCT/EP2024/056026 wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl; Xis CR20orN; R20 is selected from H, halogen, nitrile, C1-C6 alkyl, and C1-C6 haloalkyl; R3 is selected from -C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: (i) -(CR7R8)״C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and WO 2024/184461 PCT/EP2024/056026 (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11 and R12 together form a double bond, and R10 and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0065]In another aspect, disclosed herein is a compound of Formula (A) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is -NRf Rg, wherein (i) Rf and Rg together with the nitrogen to which they are attached form a 4- to 8-memberedheterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from WO 2024/184461 PCT/EP2024/056026 oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4 groups, wherein each Rgroup is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; or (ii) Rf is C1-C6 alkyl; and Rg is C1-C6 alkyl substituted with 1 to 4 R4c groups, wherein each R4c group is independently selected from halogen, hydroxy, and nitrile; R2 is selected from C1-C6 alkyl; C1-C6 alkenyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-Calkyl)-SO2CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6 alkyl)-NR 5a R5b; phenyl; C4-C6 cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl; Xis CR20orN; R20 is selected from H, halogen, nitrile, C1-C6 alkyl, and C1-C6 haloalkyl; R3 is selected from -C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein WO 2024/184461 PCT/EP2024/056026 n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11 and R12 together form a double bond, and R10 and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0066]In some embodiments, X is CR20. In some embodiments, X is N.

WO 2024/184461 PCT/EP2024/056026

[0067]In another aspect, disclosed herein is a compound of Formula (F) R20 Formula (F) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; R2 is selected from C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-C3 alkyl)- SO2CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl) optionally substituted with 1 to 13 halogens; -(C1- C6 alkyl)-NR 5a R5b; phenyl; C4-C6 cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl; R20 is selected from H, halogen, nitrile, C1-C6 alkyl, and C1-C6 haloalkyl; R3 is selected from -C(O)NHR6, -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from WO 2024/184461 PCT/EP2024/056026 oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected WO 2024/184461 PCT/EP2024/056026 from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11 and R12 together form a double bond, and R10 and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0068]In another aspect, disclosed herein is a compound of Formula (1) Formula (1) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 3 R4 groups, wherein each R4 group is independently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen; R2 is selected from C1-C6 alkyl; C1-C6 haloalkyl; phenyl; and 5- to 6-membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 or 2 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; R3 is selected from C(O)NHR6 and 5- to 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6- membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl; R6 is selected from: WO 2024/184461 PCT/EP2024/056026 (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl;wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0069]In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 4-membered heterocycloalkyl ring optionally containing WO 2024/184461 PCT/EP2024/056026 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to substituents (e.g. 1 to 6, or 1 to 5 substituents) independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1- C3 alkyl.

[0070]In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 4-membered heterocycloalkyl ring optionally containing additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl.

[0071]In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 4-membered heterocycloalkyl ring optionally containing additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 3 R4 groups, wherein each R4 group is independently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen.

[0072]In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 5-membered heterocycloalkyl ring optionally containing additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to substituents (e.g. 1 to 6, or 1 to 5 substituents) independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are WO 2024/184461 PCT/EP2024/056026 attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1- C3 alkyl. In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 5-membered heterocycloalkyl ring optionally containing additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl. In some embodiments, Ris -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 5- membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy, and halogen.

[0073]In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 5-membered heterocycloalkyl ring optionally containing additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 3 R4 groups, wherein each R4 group is independently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen.

J [0074]In some embodiments, R1 is , wherein R1 is substituted with 1 to 4 R4 groups,wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to 13 substituents (e.g. 1 to 6, or 1 to substituents) independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl. In some embodiments, R1 WO 2024/184461 PCT/EP2024/056026 Hn Jis wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1- . JC3 alkyl. In some embodiments, R1 is , wherein R1 is substituted with 1 to 4 R4 groups,wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; ; and each R4a and R4b is independently selected Fn Jfrom C1-C3 alkyl. In some embodiments, R1 is , wherein R1 is substituted with 1 to 4 R4groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, and Ci-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 Hn Jcycloalkyl, hydroxy, and halogen. In some embodiments, R1 is , wherein R1 is substituted with 2 to 4 R4 groups, wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring and each remaining R4 group, if present, is independently selected from halogen, hydroxy, nitrile, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen.

[0075]In some embodiments, R1 is , wherein R1 is substituted with 1 to 3 R4 groups,wherein each R4 group is independently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen.

[0076]In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 6-membered heterocycloalkyl ring optionally containing additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, WO 2024/184461 PCT/EP2024/056026 hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to substituents (e.g. 1 to 6, or 1 to 5 substituents) independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1- C3 alkyl. In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 6-membered heterocycloalkyl ring optionally containing additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl. In some embodiments, Ris -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 6- membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy, and halogen; and each R4a and R4b is independently selected from C1-C3 alkyl. In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 6-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 2 to R4 groups, wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring and each remaining R4 group, if present, is independently selected from halogen, hydroxy, nitrile, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen. In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 6-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group WO 2024/184461 PCT/EP2024/056026 is independently selected from halogen, hydroxy, nitrile, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen.

[0077] In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 6-membered heterocycloalkyl ring optionally containing additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 3 R4 groups, wherein each R4 group is independently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen.

[0078] In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 7-membered heterocycloalkyl ring optionally containing additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to substituents (e.g. 1 to 6, or 1 to 5 substituents) independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1- C3 alkyl. In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 7-membered heterocycloalkyl ring optionally containing additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl.

[0079] In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 8-membered heterocycloalkyl ring optionally containing additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, WO 2024/184461 PCT/EP2024/056026 hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to substituents (e.g. 1 to 6, or 1 to 5 substituents) independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1- C3 alkyl. In some embodiments, R1 is -NRf Rg, wherein Rf and Rg together with the nitrogen to which they are attached form a 8-membered heterocycloalkyl ring optionally containing additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl.

[0080]In some embodiments, R1 is -NRf Rg, wherein Rf is C1-C6 alkyl; and Rg is C1-C6 alkyl substituted with 1 to 4 R4c groups, wherein each R4c group is independently selected from halogen, hydroxy, and nitrile.

In some embodiments, R1 is [0081] WO 2024/184461 PCT/EP2024/056026 CNN X-CF! 3. In some embodiments, R11ן OHis

[0082]In some embodiments, R2 is C1-C6 alkyl. In some embodiments, R2 is C1-C4 alkyl. In some embodiments, R2 is C1-C3 alkyl. In some embodiments, R2 is C1-C6 alkenyl. In some embodiments, R2 is C1-C6 alkyl or C1-C6 alkenyl. In some embodiments, R2 is

[0083]In some embodiments, R2 is C1-C6 haloalkyl. In some embodiments, R2 is C1-Chaloalkyl. In some embodiments, R2 is C1-C3 haloalkyl.

[0084]In some embodiments, R2 is C1-C6 hydroxyalkyl. In some embodiments, R2 is C1-Chydroxyalkyl. In some embodiments, R2 is C1-C3 hydroxyalkyl.-48- WO 2024/184461 PCT/EP2024/056026

[0085]In some embodiments, R2 is phenyl optionally substituted with 1 to 4 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1- C3 alkyl. In some embodiments, R2 is phenyl optionally substituted with 1 or 2 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy.

[0086]In some embodiments, R2 is phenyl optionally substituted with 1 or 2 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-Chaloalkyl, and C1-C3 alkoxy. In some embodiments, R2 is 4-fluorophenyl.

[0087]In some embodiments, R2 is C4-C6 cycloalkyl optionally substituted with 1 to 4 Rgroups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1- C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl. In some embodiments, R2 is C4-C6 cycloalkyl optionally substituted with 1 or R5 groups, wherein each R5 group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy.

[0088]In some embodiments, R2 is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl. In some embodiments, R2 is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 or 2 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-Chaloalkyl, and C1-C3 alkoxy.

WO 2024/184461 PCT/EP2024/056026

[0090]In some embodiments, R2 is a 5- to 6-membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 or 2 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy. In some embodiments, R2 is a 5- membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 or 2 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy. In some embodiments, R2 is a 6-membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 or 2 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy. In some embodiments, R2 is 2- thiophene.

WO 2024/184461 PCT/EP2024/056026

[0092]In another aspect, disclosed herein is a compound of Formula (B) Formula (B) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-Calkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; Het is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 to 4 R5 groups independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl; R3 is selected from -C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the WO 2024/184461 PCT/EP2024/056026 phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring; WO 2024/184461 PCT/EP2024/056026 wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0093]In another aspect, disclosed herein is a compound of Formula (IF) Formula (IF) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein Fn JR1 is , wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1- C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; Het is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 to 4 R5 groups independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl; R3 is selected from -C(O)NHR6, -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: WO 2024/184461 PCT/EP2024/056026 (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0094]In another aspect, disclosed herein is a compound of Formula (11) WO 2024/184461 PCT/EP2024/056026 Formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is , wherein R1 is substituted with 1 to 3 R4 groups, wherein each R4 group isindependently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from hydroxy and halogen; Het is a 5- to 6-membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 or 2 R5 groups independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; R3 is selected from C(O)NHR6 and 5- to 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6- membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; WO 2024/184461 PCT/EP2024/056026 (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl;wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0095]In some embodiments, Het is a 5-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with to 4 R5 groups independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-Chaloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-Calkyl. In some embodiments, Het is a 5-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with to 4 R5 groups independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy.

[0096]In some embodiments, Het is a 5-membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with WO 2024/184461 PCT/EP2024/056026 1 or 2 R5 groups independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and . .yx (VC1-C3 alkoxy. In some embodiments, Het is "—" , N , or N N ת ן some . embodiments, Het is N N ת ן some embodiments, Het is " or N N

[0097]In some embodiments, Het is a 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with to 4 R5 groups independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-Chaloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-Calkyl. In some embodiments, Het is a 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with to 4 R5 groups independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy.

[0098]In some embodiments, Het is a 6-membered heteroaryl ring containing 1 or 2 ringheteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with or 2 R5 groups independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy. In some embodiments, Het is

[0099]In another aspect, disclosed herein is a compound of Formula (C) Formula (C) WO 2024/184461 PCT/EP2024/056026 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is , wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-Calkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; R3 is selected from C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and WO 2024/184461 PCT/EP2024/056026 nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[00100]In another aspect, disclosed herein is a compound of Formula (Ila ’) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein Formula (Ila ’) WO 2024/184461 PCT/EP2024/056026 R1 is , wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1- C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; R3 is selected from C(O)NHR6, -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the WO 2024/184461 PCT/EP2024/056026 heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl;wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[00101]In another aspect, disclosed herein is a compound of Formula (11a) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein Fn JR1 is , wherein R1 is substituted with 1 to 3 R4 groups, wherein each R4 group isindependently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from hydroxy and halogen; R3 is selected from C(O)NHR6 and 5- to 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6- WO 2024/184461 PCT/EP2024/056026 membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; WO 2024/184461 PCT/EP2024/056026 wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[00102]In another aspect, disclosed herein is a compound of Formula (D) Formula (D) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is , wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1- C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; R3 is selected from C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; m is 0, 1,2, 3, or 4; WO 2024/184461 PCT/EP2024/056026 each R5 is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-Chaloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1- C3 alkyl; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are WO 2024/184461 PCT/EP2024/056026 attached, form a 3- to 6-membered ring, , and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[00103]In another aspect, disclosed herein is a compound of Formula (IIP) Formula (IIP) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1- C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; R3 is selected from C(O)NHR6, -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; m is 0, 1,2, 3, or 4; WO 2024/184461 PCT/EP2024/056026 each R5 is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-Chaloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1- C3 alkyl; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are WO 2024/184461 PCT/EP2024/056026 attached, form a 3- to 6-membered ring, , and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl;wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[00104]In another aspect, disclosed herein is a compound of Formula (III) Formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is , wherein R1 is substituted with 1 to 3 R4 groups, wherein each R4 group isindependently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from hydroxy and halogen; R3 is selected from C(O)NHR6 and 5- to 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6- membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl; m is 0, 1, or 2; each R5 is independently selected from halogen; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; WO 2024/184461 PCT/EP2024/056026 each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl;wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[00105]In another aspect, disclosed herein is a compound of Formula (E) WO 2024/184461 PCT/EP2024/056026 Formula (E) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-Calkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; R3 is selected from C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; Aik is C1-C6 alkyl or C1-C6 alkenyl; R6 is selected from: (i) -(CR7R8)״C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or WO 2024/184461 PCT/EP2024/056026 partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[00106]In some embodiments, Aik is C1-C6 alkyl. In some embodiments, Aik is C1-C6 alkenyl.

[00107]In another aspect, disclosed herein is a compound of Formula (IV’) In some embodiments, Aik is WO 2024/184461 PCT/EP2024/056026 Formula (IV’) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1- C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; R3 is selected from C(O)NHR6, -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; Aik is C1-C6 alkyl; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; WO 2024/184461 PCT/EP2024/056026 each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl;wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[00108] In another aspect, disclosed herein is a compound of Formula (IV) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein Formula (IV) WO 2024/184461 PCT/EP2024/056026 R1 is , wherein R1 is substituted with 1 to 3 R4 groups, wherein each R4 group isindependently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from hydroxy and halogen; R3 is selected from C(O)NHR6 and 5- to 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6- membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl; Aik is C1-C6 alkyl; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, and wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently -73- WO 2024/184461 PCT/EP2024/056026 selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl;wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[00109]In another aspect, disclosed herein is a compound of Formula (F) R2 Formula (F) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is -NRf Rg, wherein (i) Rf and Rg together with the nitrogen to which they are attached form a 4- to 8-memberedheterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4 groups, wherein each Rgroup is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; or (i) Rf is C1-C6 alkyl; and Rg is C1-C6 alkyl substituted with 1 to 4 R4c groups, wherein each R4c group is independently selected from halogen, hydroxy, and nitrile; WO 2024/184461 PCT/EP2024/056026 R2 is selected from C1-C6 alkyl; C1-C6 alkenyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-Calkyl)-SO2CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6 alkyl)-NR 5a R5b; phenyl; C4-C6 cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl; R3 is selected from -C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: (i) -(CR7R8)n C(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and WO 2024/184461 PCT/EP2024/056026 (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11 and R12 together form a double bond, and R10 and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[00110]In another aspect, disclosed herein is a compound of Formula (A) Formula (A) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is -NRf Rg, wherein (i) Rf and Rg together with the nitrogen to which they are attached form a 4- to 8-memberedheterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from WO 2024/184461 PCT/EP2024/056026 oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4 groups, wherein each Rgroup is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to 13 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; or (ii) Rf is C1-C6 alkyl; and Rg is C1-C6 alkyl substituted with 1 to 4 R4c groups, wherein each R4c group is independently selected from halogen, hydroxy, and nitrile; R2 is selected from C1-C6 alkyl; C1-C6 alkenyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-Calkyl)-SO2CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6 alkyl)-NR 5a R5b; phenyl; C4-C6 cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5a R5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl; Xis CR20orN; R20 is selected from H, halogen, nitrile, C1-C6 alkyl, and C1-C6 haloalkyl; and R3 is 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heteroaryl ring contains to 4 ring nitrogens, and wherein the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11 and R12 together form a double bond, and R10 and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; WO 2024/184461 PCT/EP2024/056026 wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[00111]As stated above, for each of Formulas (A), (B), (C), (D), (E), and (F), R1 is or may be Hn Jrepresented as , wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1- C3 alkyl.

[00112]As stated above, for each of Formulas (F), (IF), (Ila ’), (HF) and (IV’), R1 is or may be Fn Jrepresented as J, wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R4b, -SR4a , -S(O)2R4a , and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1- C3 alkyl.

[00113]As stated above, for each of Formulas (1), (II), (Ila), (III) and (IV), R1 is or may be Jrepresented as י wherein R1 is substituted with 1 to 3 R4 groups, wherein each R4 group isindependently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen.

[00114]In some embodiments, R1 may be a pyrrolidinyl ring (as shown above) that may be substituted with two R4 groups. By way of example, the pyrrolidinyl ring may be substituted with at least two R4 groups on an atom adjacent the nitrogen atom. For example, the pyrrolidinyl group may comprise two R4 groups in a geminal substitution pattern (e.g., each R4 group may be appended to the same atom on the pyrrolidinyl ring).

WO 2024/184461 PCT/EP2024/056026

[00115]As such, in some embodiments of any of Formulas (A), (B), (C), (D), (E), and (F), R1R4r 4 may be represented as , in which two R4 groups are appended to a carbon atom adjacentthe nitrogen atom. In some embodiments of any of Formulas (F), (IF), (Ila ’), (IIF), and (IV’), R1 R4r 4 8 may be represented as , in which two R4 groups are appended to a carbon atom adjacentthe nitrogen atom. In some embodiments of any of Formulas (I), (II), (Ila), (III) and (IV), R1 may R4 04 & be represented as , j n which two R4 groups are appended to a carbon atom adjacent thenitrogen atom. At least one of the R4 groups may be C1-C6 alkyl. At least one of the R4 groups may be selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen.

R4aR4b Fn J [00116]By way of example only, R1 may be represented as ,wherein R4a is C1-C6alkyl (such as methyl); and R4b is selected from nitrile and C1-C6 alkyl optionally substituted with to 4 substituents independently selected from hydroxy and halogen. Representative examples of suitable R4b groups include, but are not limited to, nitrile, methyl, ethyl, CH2OH, CH(OH)CH3, and CH(OH)CF3.

R4aR4b J [00117]By way of example only, R1 may be represented as ,wherein R4b is C1-C6alkyl (such as methyl); and R4a is selected from nitrile and C1-C6 alkyl optionally substituted with to 4 substituents independently selected from hydroxy and halogen. Representative examples of suitable R4a groups include, but are not limited to, nitrile, methyl, ethyl, CH2OH, CH(OH)CH3, and CH(OH)CF3.

WO 2024/184461 PCT/EP2024/056026 R4' R4b Fn J [00118]In some embodiments, R1 may be represented as , wherein R4a and R4b areas defined above.

[00119]In some embodiments of any one or more of Formulas (A), (B), (C), (D), (E), (F), (F), (IF), (Ila ’), (IIF), (IV’), (I), (II), (Ila), (III) and (IV), R3 is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2. In some embodiments, R3 is tetrazole, pyrazole, imidazole, oxazole, or pyridine, wherein R3 may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-Calkyl, C1-C3 haloalkyl, and -C(O)NH2.

[00120]In some embodiments of any one or more of Formulas (I), (II), (Ila), (III) and (IV), Ris a 5- to 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl. In some embodiments, R3 is pyrazole, imidazole, oxazole, pyridonyl (e.g., 2-pyridonyl), or pyridine, wherein R3 may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl. Where the heteroaryl ring comprises a ring nitrogen atom, the substituent may be bonded directly to the nitrogen atom. By way of example only, R3 may be aN-(C1-C3 alkyl) pyridonyl group.

[00121]In some embodiments of any one or more of Formulas (A), (B), (C), (D), (E), (F), (F), (IF), (Ila ’), (IIF), (IV’), (I), (II), (Ila), (III) and (IV), R3 is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring nitrogens, wherein the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1- C3 haloalkyl, and -C(0)NH2. In some embodiments, R3 is a tetrazolyl, optionally substituted with C1-C3 alkyl, e.g. a methyl-substituted tetrazolyl ring.

WO 2024/184461 PCT/EP2024/056026

[00122]As stated above, in some embodiments of Formulas (A), (B), (C), (D), (E), and (F), Ris -C(O)NHR6. In some embodiments of any one or more of Formulas (F), (IF), (Ila ’), (IFF) and (IV’), R3 is -C(O)NHR6. In some embodiments of any one or more of Formulas (I), (II), (Ila), (III) and (IV), R3 is -C(O)NHR6.

[00123]In some embodiments, R6 is (CR7R8)n C(O)NRdRe.

[00124] In some embodiments, n is 1. In some embodiments, n is 2.

[00125]In some embodiments, each of R7 and R8 is independently selected from H and C1-Calkyl. In some embodiments, R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen.

[00126]In some embodiments, Rd and Re are both C1-C3 alkyl. In some embodiments, Rd and Re are both methyl.

WO 2024/184461 PCT/EP2024/056026

[00128]In some embodiments, R6 is C1-C6 alkyl optionally substituted with nitrile or 5- or 6- membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy. In some embodiments, R6 is C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy. In some embodiments, R6 is C1-C6 alkyl optionally substituted with nitrile. In some embodiments, R6 is a 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy. In some embodiments, R6 is pyrazolyl, oxazolyl, imidazolyl, pyridinyl, or 2-pyridonyl, each of which may be optionally substituted with 1 to WO 2024/184461 PCT/EP2024/056026 substituents independently selected from halogen, C1-C3 alkyl, and C1-C3 haloalkyl. Where the heteroaryl ring comprises a ring nitrogen atom, the substituent may be bonded directly to the nitrogen atom.

[00129]In some embodiments, R6 is C1-C6 alkyl optionally substituted with nitrile or tetrazole. By way of example only, R6 may be a C1-C3 alkyl (such as a C3 alkyl) optionally substituted with nitrile or tetrazole.

[00130]In some embodiments, R6 is phenyl, a 3- to 6-membered saturated or partially unsaturated ring, or a 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with one or more independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens. In some embodiments, R6 is phenyl, a 3- to 6-membered saturated or partially unsaturated ring, or a 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens. In some embodiments, R6 is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and Ci- C3 alkyl optionally substituted with one or more independently selected halogens. In some embodiments, R6 is a 3- to 6-membered saturated or partially unsaturated ring optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently WO 2024/184461 PCT/EP2024/056026 selected halogens. In some embodiments, R6 is cyclopropane optionally substituted with nitrile or is cyclobutane optionally substituted with nitrile. In some embodiments, R6 is a 5- to 6-membered heteroaryl ring, wherein the ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens. Representative examples include but are not limited to, pyridonyl (e.g., 2-pyridonyl) which may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens. In some examples, R6 may be 2-pyridonyl optionally substituted with a C1-C3 alkyl (e.g., methyl), further optionally wherein the 2-pyridonyl is substituted at the nitrogen atom with a C1-C3 alkyl (e.g., methyl)

[00131]In some embodiments of any one or more of Formulas (A), (B), (C), (D), (E), and (F), each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, each of R10, R11, R12, and R13 is hydrogen. In some embodiments, two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6- membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-Chaloalkyl. In some embodiments, two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a cyclopropyl ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl.

[00132]In some embodiments of any one or more of Formulas (F), (IF), (Ila ’), (IFF) and (IV’), each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, each of R10, R11, R12, and R13 is hydrogen. In some embodiments, two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6- membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-Chaloalkyl. In some embodiments, two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a cyclopropyl ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl.

WO 2024/184461 PCT/EP2024/056026

[00133]In some embodiments of any one or more of Formulas (1), (II), (Ila), (III) and (IV), each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, each of R10, R11, R12, and R13 is hydrogen. In some embodiments, two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6- membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-Chaloalkyl.

[00134]In some embodiments of Formula (A), R11 and R12 together form a double bond, and R10 and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments of Formula (F), R11 and R12 together form a double bond, and R10 and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl.

[00135]The presently disclosed compounds were and can be synthesized using the general synthetic procedures set forth in reaction schemes below. The carrying out of each individual illustrated step is within the skill of an ordinary artisan guided by this disclosure, who also knows how to modify the synthetic procedures of the below schemes to synthesize the full scope of the compounds disclosed herein. The synthetic procedure for individual compounds is provided in the Examples section, below.

[00136]In another aspect, disclosed herein is a compound selected from Table 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[00137] Table 1 Compd No. Name 4-1 [8-methoxy-9-(l-methylpyrazol-3-yl)-l-thiazol-5-yl-5,6-dihydropyrrolo[2,l-a]isoquinolin- 3-yl]-[(2S)-2-methyl-2-[(17?)-2,2,2-trifluoro-l-hydroxyethyl]pyrrolidin-l-yl]methanone 4-2 (l-(5-fluoropyridin-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-l- hydroxyethyl)pyrrolidin- 1 -yl)methanone WO 2024/184461 PCT/EP2024/056026 4-3 (A)-8-methoxy-5-methyl-3-((A)-2-methyl-2-((5)-2,2,2-trifluoro-l-hydroxyethyl) pyrrolidine- 1-carbonyl)-N-( 1-methyl-2-oxo-1 ,2-dihydropyri din-3-yl)- 1-(2,2,2-tri flu oroethyl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxamide 6-1 (35)-4-[8-methoxy-9-( 1-methylpyrazol-3-yl)- 1-(2-thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3 -carbonyl] -3 -methyl -morpholine-3 -carbonitrile 6-2 (2A)-1-[8-methoxy-9-( 1-methylpyrazol-3-yl)- 1-thiazol-5-yl-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 6-3 (/?)-!-(1-(1-hydroxy -2-methylpropan-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5, 6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile 6-4 (A)-l-(l-(2,2-difluoropropyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile 6-5 (A)-l-(l-(2,2-difluoropropyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile 6-6 (7?)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile 6-7 (/?)-!-(l-(5-fluoropyri din-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5, 6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile 6-8 (A)-l-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile 7-1 (2A)-l-[8-methoxy-9-oxazol-2-yl-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 7-2 4-[3 -[(2A)-2-[( 1A)-1 -hydroxyethyl] -2-methyl-pyrrolidine- 1 -carbonyl] -8-methoxy- 1 -(2- thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-9-yl]-6-methyl-17f-pyridin-2-one 7-3 (2A)-2-[(lA)-l-hydroxyethyl]-2-methyl-pyrrolidin-l-yl]-[8-methoxy-9-oxazol-2-yl-l-(2- thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]methanone 7-4 3-[3-[(27?)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-!-(4-fluorophenyl)-8-methoxy-5, 6- dihydropyrrolo[2, 1 -a]isoquinolin-9-yl]pyridine-2-carbonitrile 7-5 3-[3-[(2A)-2-[(lA)-l-hydroxyethyl]-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l-propyl-5,6-dihydropyrrolo[2, 1 -a]isoquinolin-9-yl]pyridine-2-carbonitrile WO 2024/184461 PCT/EP2024/056026 7-6 [8-methoxy-9-(2-methyltetrazol-5-yl)-l -(2-thienyl )-5,6-dihydropyrrolo[2,l -a] isoquinol in- 3-yl]-[(2//)-2-methyl-2-[( 1 .S)-2,2,2-trilluoro-l -hydroxy-ethyl]pyrrol id in- 1 -yl] methanone 7-7 (2A)-l-[9-(17/-imidazol-2-yl)-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 7-8 (2A)-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 7-9 (2A)-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-propyl-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 7-10 [(2A)-2-[(lA)-l-hydroxyethyl]-2-methyl-pyrrolidin-l-yl]-[8-methoxy-9-(2-methyltetrazol- 5-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]methanone 7-11 (2A)-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 7-12 [(5A)-8-methoxy-5-methyl-9-(2-methyltetrazol-5-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l- a] isoquinol in-3-yl]-[(2.S')-2-methyl-2-[( 1 /? )-2,2,2-tri fluoro- 1 -hydroxy-ethyl ]pyrrol id in- 1 - yl]methanone 7-13 [(5A)-8-methoxy-5 -methyl-9-(2-methyltetrazol-5 -yl)- 1 -thiazol-5 -yl-5 ,6-dihydropyrrolo[2,l -،/]isoquinolin-3-yl]-[(2/?)-2-methyl-2-[( I.S')-2,2,2-trifluoro-1 -hydroxy- ethyl]pyrrolidin-l -yl]methanone 7-14 (2A)-1-[8-methoxy-9-(2-methyltetrazol-5-yl)- 1-thiazol-5-yl-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 7-15 (A)-3-(3-(2-cyano-2-methylpyrrolidine-l-carbonyl)-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,l-a]isoquinolin-9-yl)-5-(trifluoromethyl)picolinonitrile 7-16 (A)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile 7-17 (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(l,3,4-thiadiazol-2-yl)-5,6- dihydropyrrolo[2, 1 -a] isoquinol i n-3-yl )((.S')-2-methyl-2-((/? )-2,2,2-tri fluoro- 1 - hydroxyethyl)pyrrolidin- 1 -yl)methanone 7-18 (/?)-!-(1-(3,3-di fluorocyclobutyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5, 6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile WO 2024/184461 PCT/EP2024/056026 7-19 (R)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(thiophen-2-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile 7-20 (A)-l-(l-(5-fluoropyridin-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile 7-21 (A)-l-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile 7-22 ((A)-8-methoxy-5-methyl-9-(2-methyl-2H-tetrazol-5-yl)-l-(thiophen-2-yl)-5,6- dihydropyrrolo[2,l-a]isoquinolin-3-yl)((R)-2-methyl-2-((5)-2, 2,2-trifluoro-l- hydroxyethyl)pyrrolidin- 1 -yl)methanone 7-23 5-((R)-8-methoxy-5-methyl-3-((R)-2-methyl-2-((5)-2,2,2-trifluoro-l-hydroxyethyl)pyrrolidine-l-carbonyl)-! -(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l- a] i soquinolin- 9 -yl)nico tinamide 7-24 3-((R)-8-methoxy-5-methyl-3-((R)-2-methyl-2-((5)-2,2,2-trifluoro-l-hydroxyethyl)pyrrolidine-l -carbonyl)-! -(2,2,2-trifluoroethyl)-5,6-dihy dropyrrolo[2, 1 - a] i soquinolin- 9 -yl)picolinonitrile 7-25 ((R)-8-methoxy-5-methyl-9-(2-methyl-2H-tetrazol-5-yl)-l-(2,2,2-trifluoroethyl)-5,6- dihydrop yrrolo[2,l-a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2, 2,2-trifluoro-1- hydroxyethyl)pyrrolidin- 1 -yl)methanone 7-26 ((la/?,9bR)-8-methoxy-7-(2-methyl-2H-tetrazol-5-yl)-5-(thiophen-2-yl)-la,9b-dihydro-lH- cyclopropa[c]pyrrolo[2,l-a]isoquinolin-3-yl)((R)-2-methyl-2-((5)-2, 2,2-trifluoro-l- hydroxyethyl)pyrrolidin- 1 -yl)methanone 7-27 [(2R)-2-[(lR)-l-hydroxyethyl]-2-methyl-pyrrolidin-l-yl]-[8-methoxy-9-(2-methyltetrazol- 5-yl)-l-thiazol-5-yl-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]methanone 7-28 [8-methoxy-9-(2-methyltetrazol-5-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinolin- 3-yl]-[(2S)-2-methyl-2-[(17?)-2,2,2-trifluoro-l-hydroxy-ethyl]pyrrolidin-l-yl]methanone 8-1 (2R)-1 -[8-methoxy-9-( 1 -methylpyrazol-3 -yl)- 1 -(2-thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 8-2 (2R)-l-[8-methoxy-9-(17/-pyrazol-3-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carbonyl] -2 -methyl -pyrrolidine-2 -carbonitrile WO 2024/184461 PCT/EP2024/056026 8-3 (2R)-l-[l-(4-fh1orophenyl)-8-methoxy-9-(l-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 8-4 (2A)-1 -[8-methoxy-9-( 1 -methylpyrazol-3 -yl)- 1 -propyl-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 8-5 4-[3 -[(2R)-2-[( 17?)-1 -hydroxyethyl] -2-methyl-pyrrolidine- 1 -carbonyl] -8-methoxy- 1 -propyl-5,6-dihydropyrrolo[2,l-a]isoquinolin-9-yl]-l-methyl-pyridin-2-one 8-6 [(2A)-2-[(lA)-l-hydroxyethyl]-2-methyl-pyrrolidin-l-yl]-[8-methoxy-9-(17/-pyrazol-3-yl)- l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]methanone 8-7 6-[8-methoxy-3-[(2/?)-2-methyl-2-[( I.S')-2,2,2-tri fluoro- 1 -hydroxy-ethyl ]pyrrol id ine-l - carbonyl]-! -(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-9-yl]-177-pyridin-2-one 8-8 4-[3 -[(2R)-2-[( 17?)-1 -hydroxyethyl] -2-methyl-pyrrolidine- 1 -carbonyl] -8-methoxy- 1 -(2- thienyl)-5,6-dihydropyrrolo[2, 1 -a] isoqui nol i n-9-yl]- 1 -methyl -pyri din-2 -one 8-9 3-[3-[(27?)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l -(2,2,2-tri fluoroethyl)-5,6-dihydropyrrolo[2, 1 -a]isoquinolin-9-yl]pyridine-2-carbonitrile 8-10 [(5A)-8-methoxy-5 -methyl-9-( 1 -methylpyrazol-3-yl)- 1 -thiazol-5 -yl-5 ,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]-[(2A)-2-methyl-2-[(15)-2,2,2-trifluoro-l-hydroxy- ethyl]pyrrolidin-l -yl]methanone 8-11 (A)-l-(8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-l-(thiophen-2-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile 8-12 (A)-l-((5'*)-8-methoxy-6-methyl-9-(l-methyl-lH-pyrazol-3-yl)-l-(thiophen-2-yl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile 8-13 ((A)-8-methoxy-5 -methyl-9-( 1 -methyl- 1 H-pyrazol-3 -yl)- 1 -(thiophen-2-yl)-5,6-dihydropyrr olo[2,l-a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-l-hydroxyethyl)pyrrolidin- -yl)methanone8-14 ((R)-2-((R)-l -hydroxyethyl)-2-methylpyrrolidin-l -yl)((5)-8-methoxy-5-methyl-9-(l - methyl-lH-pyrazol-3-yl)-l-(thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3- yl)methanone 8-15 ((1 a/?,9bR)-8-methoxy-7-( 1-methyl- 1 H-pyrazol-3-yl)-5 -(thiophen-2-yl)-1 a,9b-dihydro- 1H- cyclopropa[c]pyrrolo[2,l-a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2, 2,2-trifluoro-l- hydroxyethyl)pyrrolidin- 1 -yl)methanone WO 2024/184461 PCT/EP2024/056026 8-16 (8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-l-(l,3,4-thiadiazol-2-yl)-5,6- dihydropyrrolo[2,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2, 2,2-tri fluoro- 1- hydroxyethyl)pyrrolidin- 1 -yl)methanone 9-1 [(2R)-2-[(lR) -1 -hydroxyethyl J-2-methyl-pyrrol id in- 1 -yl]-[9-( 1 /7-imidazol-2-yl )-8- methoxy-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]methanone 9-2 (2R)-l-[9-(17/-imidazol-2-yl)-8-methoxy-l-(2-thienyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile -1 Af-(l-cyanocyclobutyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l-(2- thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide -2 N-( 1 -cyano- 1 -methyl-ethyl)-3 -[(2R)-2-cyano-2-methyl-pyrrolidine- 1 -carbonyl] -1 -(4- fluorophenyl)-8-methoxy-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide -3 3-[(2R)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-l-(4-fluorophenyl)-8-methoxyW-(2- oxo-17/-pyridin-3-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide -4 3-[(2R)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-l-(4-fluorophenyl)-8-methoxyW-(l- methyl-2-oxo-3-pyridyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide -5 3-[(2R)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-A f-(2-oxo-17/-pyridin-3-yl)--propyl-5,6-dihydropyrrolo[2, 1 -a] isoquinol ine-9-carboxam ide -6 3-[(2R)-2-cyano-2-methyl-pyrrolidine- 1 -carbonyl]-8-methoxy-A L( 1 -methyl -2-oxo-3 - pyridyl)-!-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide -7 N-( 1 -cyano- 1 -methyl-ethyl)-3 -[(2R)-2-[( 1R)-1 -hydroxyethyl] -2-methyl-pyrrolidine- 1 - carbonyl]-8-methoxy- 1 -propyl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxamide -8 A^-(l -cyanocyclobutyl)-3-[(2R)-2-[(lR)-l -hydroxyethyl]-2-methyl-pyrrolidine-l -carbonyl]- 8-methoxy- 1 -propyl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxamide -9 N-( 1 -cyano- 1 -methyl-ethyl)-3 -[(2R)-2-cyano-2-methyl-pyrrolidine- 1 -carbonyl] -8-methoxy- -propyl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxamide -10 Af-[2-(dimethylamino)-2-oxo-ethyl]-3-[(2R)-2-(hydroxymethyl)-2-methyl-pyrrolidine-l- carbonyl]-8-methoxy- 1 -(2-thienyl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxamide -11 3-(2,2-dimethylpyrrolidine-l-carbonyl)-8-methoxy-A ?-(17/-tetrazol-5-ylmethyl)-l-(2- thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide WO 2024/184461 PCT/EP2024/056026 -12 3-[(2A)-2-cyano-2-methyl-pyrrolidine- 1 -carbonyl]-8-methoxy-N-( 1 -methyl -2-oxo-3 - pyridyl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide -13 3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-7V-(2-oxo-17/-pyridin-3-yl)--(2-thienyl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxamide -14 A^-(l -cyano-1 -methyl-ethyl)-8-methoxy-3-[(2A)-2-methyl-2-[(15)-2,2,2-trifluoro-l - hydroxy-ethyl]pyrrolidine-l-carbonyl]-! -(2-thienyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-9-carboxamide -15 A^-(l -cyanocyclobutyl)-3-[(2A)-2-[(lA)-l -hydroxyethyl]-2-methyl-pyrrolidine-l -carbonyl]- 8-methoxy-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide -16 N-( 1 -cyano- 1 -methyl-ethyl)-3 -[(2A)-2-[( 1A)-1 -hydroxyethyl] -2-methyl-pyrrolidine- 1 - carbonyl]-8-methoxy- 1 -(2-thienyl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxamide -17 N-( 1 -cyanocyclobutyl)- 1 -(4-fluorophenyl)-3 -[(2A)-2-[( 1A)-1 -hydroxyethyl] -2-methyl- pyrrolidine- 1 -carbonyl] -8 -metho xy-5 ,6-dihydropyrrolo [2,1 -a]isoquinoline-9 -carboxamide -18 N-(l -cyano-l -methyl-ethyl)-l -(4-fluorophenyl)-3-[(2A)-2-[(lA)-l -hydroxyethyl]-2-methyl- pyrrolidine- 1 -carbonyl] -8 -metho xy-5 ,6-dihydropyrrolo [2,1 -a]isoquinoline-9 -carboxamide -19 N-( 1 -cyanocyclopropyl)-8-methoxy-3 -[(2A)-2-methyl-2-[( 1 S)-2,2,2-trifluoro- 1 -hydroxy- ethyl]pyrrolidine-l-carbonyl]-! -(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9- carboxamide -20 N-( 1 -cyanocyclopropyl)-3-[(2A)-2-[( 1A)-1 -hydroxyethyl] -2-methyl-pyrrolidine- 1 - carbonyl]-8-methoxy- 1 -(2-thienyl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxamide -21 8-methoxyW-(l-methyl-2-oxo-3-pyridyl)-3-[(2A)-2-methyl-2-[(15)-2, 2,2-trifluoro-l- hydroxy-ethyl]pyrrolidine-l-carbonyl]-l-(2-thienyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-9-carboxamide -22 Af-(l-cyanocyclobutyl)-8-methoxy-3-[(2A)-2-methyl-2-[(15)-2,2,2-trifluoro-l-hydroxy- ethyl]pyrrolidine-l-carbonyl]- 1-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9- carboxamide -23 A^-(l -cyanocyclobutyl)-3-[(2A)-2-[(lA)-l -hydroxyethyl]-2-methyl-pyrrolidine-l -carbonyl]- 8-methoxy-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide -24 N-( 1 -cyanocyclobutyl)-3-[(2A)-2-cyano-2-methyl-pyrrolidine- 1 -carbonyl] -1 -(4- fluorophenyl)-8-methoxy-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide WO 2024/184461 PCT/EP2024/056026 -25 Af-(3-cyanooxetan-3-yl)-8-methoxy-3-[(2A)-2-methyl-2-[(15)-2,2,2-trifluoro-l-hydroxy- ethyl]pyrrolidine-l-carbonyl]-! -(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9- carboxamide -26 7V-(3 -cyanooxetan-3 -yl)-3 -[(2A)-2-[(lA)-1 -hydroxyethyl] -2-methyl-pyrrolidine- 1 - carbonyl]-8-methoxy- 1 -(2-thienyl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxamide -27 N-( 1 -cyano- 1 -methyl-ethyl)-3 -[(2A)-2-cyano-2-methyl-pyrrolidine- 1 -carbonyl] -8-methoxy- -(2-thienyl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxamide -28 3-[(2A)-2-cyano-2-methyl-pyrrolidine- 1 -carbonyl] -N־V(3R*)-3 -cyanotetrahydro furan-3 -yl] -8-methoxy-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide -29 3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-7V-[(3,S'*)-3-cyanotetrahydrofuran-3-yl]- 8-methoxy-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide -30 3-[(2A)-2-cyano-2-methyl-pyrrolidine- 1 -carbonyl] -^-(3 -cyanooxetan-3 -yl)-8-methoxy- 1 - (2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide -31 A^-(l-cyanocyclopropyl)-3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l- (2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide -32 Af-(l-cyanocyclobutyl)-3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l- propyl-5,6-dihydropyrrolo[2, 1 -a] isoqui nol ine-9-carboxam ide -33 3-[(2A)-2-cyano-2-methyl-pyrrolidine- 1 -carbonyl] -7V-(3 -cyanooxetan-3 -yl)-8-methoxy- 1 - propyl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxamide -34 3-[(2A)-2-cyano-2-methyl-pyrrolidine- 1 -carbonyl] -7V-(3 -cyanooxetan-3 -yl)-8-methoxy- 1 - (2-thienyl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxamide -35 Af-(l-cyanocyclobutyl)-3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l- thiazol-5-yl-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide -36 (A)-3-(2-cyano-2-methylazetidine-l-carbonyl)-8-methoxy-N-(l-methyl-2-oxo-l,2- dihydropyridin-3-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9- carboxamide -37 (A)-3-(2-cyano-2-methylazetidine-l-carbonyl)-8-methoxy-N-(2-oxo-1,2-dihydropyridin-3- yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide WO 2024/184461 PCT/EP2024/056026 -38 N-(l-cyanocyclobutyl)-8-methoxy-3-((S)-2-methyl-2-((R)-2, 2,2-trifluoro-1-hydroxy ethyl) pyrrolidine- 1-carbonyl)-! -(1,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9- carboxamide -39 (R)-3-(2-cyano-2-methylazetidine-l-carbonyl)-N-(l-cyanocyclobutyl)-8-methoxy-l- (thiophen-2 -yl)-5 ,6-dihydropyrrolo [2,1 -a] isoquinoline-9 -carboxamide -40 (5'*)-N-(l-cyanocyclobutyl)-3-((R)-2-((R)-l-hydroxyethyl)-2-methylpyrrolidine-l- carbonyl)-8-methoxy-6-methyl-l-(thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9- carboxamide -41 (5'*)-3-((R)-2-cyano-2-methylpyrrolidine-l-carbonyl)-N-(l-cyanocyclobutyl)-8-methoxy-6- methyl-l-(thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide -42 (R)-N-(l -cyanocyclobutyl)-3 -((R)-2-((R)-1 -hydroxyethyl)-2-methylpyrrolidine- 1 -carbonyl)-8-methoxy-5-methyl-l-(thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9- carboxamide -43 (R)-N-(l-cyanocyclobutyl)-8-methoxy-5-methyl-3-((R)-2-methyl-2-((S)-2,2,2-trifluoro-l- hydroxyethyl)pyrrolidine- 1 -carbonyl)- 1 -(thiophen-2-yl)-5,6-dihydropyrrolo[2, 1 -a] i soquinoline -9 -carboxamide -44 (S)-N-( 1 -cyanocyclobutyl)-3 -((R)-2-((R)-1 -hydroxyethyl)-2-methylpyrrolidine- 1 -carbonyl)-8-methoxy-5-methyl-l-(thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9- carboxamide -45 (4S)-N-(l-cyanocyclobutyl)-7-methoxy-4-methyl-3-((R)-2-methyl-2-((S)-2, 2,2-trifluoro-l- hydroxyethyl)pyrrolidine- 1 -carbonyl)- 1 -(thiophen-2-yl)-3a,5 -dihydro-4H- cyclopenta[a]naphthalene-8-carboxamide -46 (S)-3-((R)-2-cyano-2-methylpyrrolidine-l-carbonyl)-N-(l-cyanocyclobutyl)-8-methoxy-5- methyl-l-(thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide -47 (R)-N-(l-cyanocyclobutyl)-8-methoxy-5-methyl-3-((R)-2-methyl-2-((S)-2,2,2-trifluoro-l- hydroxyethyl)pyrrolidine-l-carbonyl)-! -(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l- a] i soquinoline -9 -carboxamide -48 (laR,9bR)-N-(l-cyanocyclobutyl)-8-methoxy-3-((R)-2-methyl-2-((S)-2,2,2-trifluoro-l- hydroxyethyl)pyrrolidine- 1 -carbonyl)-5 -(thiophen-2-yl)-1 a,9b-dihydro- 1H- cyclopropa[c]pyrrolo[2, 1 -a] isoquinoline-7 -carboxamide WO 2024/184461 PCT/EP2024/056026 11-1 Af-[2-(dimethylamino)-2-oxo-ethyl]-3-[(2S)-2-ethyl-2-methyl-pyrrolidine-l-carbonyl]-8- methoxy- 1 -(2-thienyl )-5,6-dihydropyrrolo[2, 1 -a] isoquinol ine-9-carboxamide 13-1 [(2A)-2-[(lA)-l-hydroxyethyl]-2-methyl-pyrrolidin-l-yl]-[8-methoxy-9-(l-methylpyrazol- 3-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]methanone 13-2 [8-methoxy-9-(l-methylpyrazol-3-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinolin- 3-yl]-[(2/?)-2-methyl-2-[( 1 .Sy 2,2,2-tri fluoro- 1 -hydroxy-ethyl] pyrrol id in- 1 -yljmethanone 13-3 [ (27?)-2-[(lS)-l-hydroxyethyl]-2-methyl-pyrrolidin-l-yl]-[8-methoxy-9-(l-methylpyrazol-3-yl)-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]methanone 13-4 [l-(4-fluorophenyl)-8-methoxy-9-(l-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,l- a]isoquinolin-3-yl]-[(25)-2-methyl-2-[(lA)-2,2,2-trifluoro-l-hydroxy-ethyl]pyrrolidin-l- yl]methanone13-5 [l-(4-fluorophenyl)-8-methoxy-9-(l-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,l- a]isoquinolin-3 -yl] -[(2A)-2-[( 1 .S')-1 -hydroxyethyl] -2 -methyl-pyrrolidin- 1 -yl]methanone 13-6 [l-(4-fluorophenyl)-8-methoxy-9-(l-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,l- a]isoquinolin-3 -yl] -[(2A)-2-[( 1R)-1 -hydroxyethyl] -2-methyl-pyrrolidin-1 -yl] methanone 13-7 [l-(4-fluorophenyl)-8-methoxy-9-(l-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3 -yl] -[(2S)-2-[(l 5)-1 -hydroxyethyl] -2-methyl-pyrrolidin- 1 -yl] methanone 13-8 [(2S)-2-[(lS)-l-hydroxyethyl]-2-methyl-pyrrolidin-l-yl]-[8-methoxy-9-(l-methylpyrazol- 3-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]methanone 13-9 [l-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a] isoquinol in-3-yl]-[(2.S')-2-methyl-2-[( 1 /? )-2,2,2-tri fluoro- 1 -hydroxy-ethyl ]pyrrol id in- 1 - yljmethanone 13-10 [l-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinolin-3 -yl] -[(2S)-2-[(l 5*)-1 -hydroxypropyl] -2-methyl-pyrrolidin- 1 -yljmethanone 13-11 [l-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3 -yl] -[(2S)-2-[(l 5)-1 -hydroxyethyl] -2-methyl-pyrrolidin- 1 -yljmethanone 13-12 (R *)-2-(R *)-cyclopropyl(hydroxy)methyl)-2-methylpyrrolidin-l -yl)(l -(4-fluorophenyl)-8- methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3- yl)methanone WO 2024/184461 PCT/EP2024/056026 18-1 (A)-3-(2-cyano-2-methylpyrrolidine-l-carbonyl)-N-(2-cyanopropan-2-yl)-8-methoxy-l- (2,2,2 -trifluoroethyl)-5 ,6-dihydropyrrolo [2,1 -a]isoquinoline-9 -carboxamide 18-2 Af-(l-cyanocyclobutyl)-3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l- (2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide 18-3 3-[(2A)-2-[( 1A)-1 -hydroxyethyl] -2-methyl-pyrrolidine- 1 -carbonyl] -8-methoxy-TV-( 1 - methyl-2-oxo-3-pyridyl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9- carboxamide 18-4 3-[(2A)-2-cyano-2-methyl-pyrrolidine- 1 -carbonyl]-8-methoxy-.V-( 1 -methyl -2-oxo-3 - pyridyl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide 18-5 3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-7V-(2-oxo-17/-pyridin-3-yl)--(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxamide 18-6 3-[(2A)-2-cyano-2-methyl-pyrrolidine- 1 -carbonyl] -N-J3R *)-3 -cyanotetrahydro furan-3 -yl] -8-methoxy-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide 18-7 3-[(27?)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-A^-[(3S'*)-3-cyanotetrahydro furan-3-yl]-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide -1 [l-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinolin-3-yl]-[(2A or 5)-4,4-difluoro-2-methyl-2-[(lA or S)-l-hydroxyethyl]pyrrolidin- 1 -yl] methanone 24-1 A^-(l -cyanocyclobutyl)-3-[(2A)-2-[(lA)-l -hydroxyethyl]-2-methyl-pyrrolidine-l -carbonyl]- 8-methoxy-l-thiazol-5-yl-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide 24-2 Af-(l-cyanocyclobutyl)-8-methoxy-3-[(27?)-2-methyl-2-[(lS)-2,2,2-trifluoro-l-hydroxy- ethyl]pyrrolidine-l-carbonyl]-l-thiazol-5-yl-5,6-dihydropyrrolo[2,l-a]isoquinoline-9- carboxamide -1 (27?*-2-ethyl-l-[8-methoxy-9-(l-methylpyrazol-3-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carbonyl]pyrrolidine-2-carbonitrile 26-1 rcl-(2R, 3 S)-3-hydroxy- 1 -[8-methoxy-9-(2-methyltetrazol-5-yl)-l -propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 26-2 re/-(2A,35)-l-[l-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-3-hydroxy-2-methyl-pyrrolidine-2- carbonitrile WO 2024/184461 PCT/EP2024/056026 32-1 (15*,6A*)-2-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-azabicyclo[4.2.0]octane-l-carbonitrile 32-2 (lS,5S)-2-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carbonyl)-5-methyl-2-azabicyclo[3.2.0]heptane-l-carbonitrile 33-1 (2A,45)-4-hydroxy-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-propyl-5,6-dihydropyrro- lo[2,l-a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 34-1 (2A,45)-l-[l-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-4-hydroxy-2-methyl-pyrrolidine-2- carbonitrile

[00138]In another aspect, disclosed herein is a compound selected from Table 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

WO 2024/184461 PCT/EP2024/056026

[00139] Table 2 Example Name 1(2R,4S)-4-hydroxy- 1 -(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 1 -(thiophen- 2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine- 2-carbonitrile 2(R)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(thiophen-2-yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile 3(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-3 ,3,3-trifluoro- 1- hydroxypropyl)pyrrolidin- 1 -yl)methanone 4(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3, 3,3-trifluoro- 1- hydroxypropyl)pyrrolidin- 1 -yl)methanone (S)-N-(2-cyano-4, 4,4-trifluorobutan-2-yl)-8-methoxy-N-methyl-9-(2-methyl- 2H-tetrazol-5-yl)-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3- carboxamide 6(2R,4S)-l-(l-(3,3-difluorocyclobutyl)-8-methoxy-9-(2-methyl-2H-tetr azol-5- yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-4-hydroxy-2- methylpyrrolidine-2-carbonitrile WO 2024/184461 PCT/EP2024/056026 7(R)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2,2,2-trifluoroethyl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile 8(8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-l-(thiophen-2-yl)-5, 6-dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2, 2,2-tri fluoro- 1- hydroxy ethyl)pyrrolidin- 1 -yl)methanone 9(8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-l-(thiophen-2-yl)-5, 6- dihydroimidazo[5 ,1 a]isoquinolin-3 -yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro- 1 - hydroxyethyl)pyrrolidin-1 -yl) methanone (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2, 2,2-tri fluoro- 1- hydroxy ethyl)pyrrolidin- 1 -yl)methanone 11(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2, 2,2-tri fluoro- 1- hydroxy ethyl)pyrrolidin- 1 -yl)methanone 12(R)-3-(2-cyano-2-methylpyrrolidine- 1 -carbonyl)-8-methoxy-N-(l -methyl-2- oxo- 1,2-dihydropyridin-3-yl)- 1 -(thiophen-2-yl)-5,6-dihydroimidazo[5, 1 - a]isoquinoline-9-carboxamide WO 2024/184461 PCT/EP2024/056026 13(R)-3-(2-cyano-2-methylpyrrolidine- 1 -carbonyl)-8-methoxy-N-(2-oxo- 1,2- dihydropyridin-3 -yl)- 1 -(thiophen-2-yl)-5,6-dihydroimidazo[5, 1 - a]isoquinoline-9-carboxamide 14(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 1 -propyl-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3, 3,3-tri fluoro- 1- hydroxypropyl)pyrrolidin- 1 -yl)methanone ((S)-2-((R)-1,2-dihydroxy-2-methylpropyl)-2-methylpyrro lidin- 1 -yl)( 1 -(4- fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2, 1 -a] isoquinolin- 3 -yl)methanone 16(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-3,3,3-trifluoro-l- hydroxypropyl)pyrrolidin- 1 -yl)methanone 17(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-l- hydroxypropyl)pyrrolidin- 1 -yl)methanone 18(R)-3-(2-cyano-2-methylazetidine-l-carbonyl)-8-methoxy-N-(l-methyl-2-oxo- 1,2-dihydropyridin-3-yl)- 1 -propyl-5,6-dihydropyrrolo[2, 1 -a] isoquinoline-9- carboxamide WO 2024/184461 PCT/EP2024/056026 19(R)-3-(2-cyano-2-methylazetidine- 1 -carbonyl)-8-methoxy-N-(2-oxo- 1,2- dihydropyridin-3-yl)-1 -propyl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9- carboxamide (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6-dihydroimidazo[5,l- a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-l-hydroxy ethyl)pyrrolidin- 1 -yl)methanone 21(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6-dihydroimidazo[5,l- a]isoquinolin-3-yl) ((R)-2-methyl-2-((S)-2,2,2-trifluoro-l-hydroxy ethyl)pyrrolidin- 1 -yl)methanone 22(R)-3-(2-cyano-2-methylazetidine- 1 -carbonyl)- 1 -isobutyl-8-methoxy-N-(2- oxo- 1,2-dihydropyridin-3-yl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9- carboxamide 23(R)-3-(2-cyano-2-methylazetidine- 1 -carbonyl)- 1 -isobutyl-8-methoxy-N-(l - methyl-2-oxo-1 ,2-dihydropyridin-3-yl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline- 9-carboxamide 24(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-l- hydroxypropyl)pyrrolidin- 1 -yl)methanone WO 2024/184461 PCT/EP2024/056026 (R)-3-(2-cyano-2-methylazetidine-l-carbonyl)-8-methoxy-N-(l-methyl-2-oxo- 1,2-dihydropyridin-3-yl)- 1 -(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide 26(l-(4-fluorophenyl)-8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-5, 6- dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2, 2,2-tri fluoro- 1- hydroxy ethyl)pyrrolidin- 1 -yl)methanone 27(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2, 2,2-tri fluoro- 1- hydroxy ethyl)pyrrolidin- 1 -yl)methanone 28(R)-3-(2-cyano-2-methylpyrrolidine- 1 -carbonyl)- 1 -(4-fluorophenyl)-8- methoxy-N-(l-methyl-2-oxo-l,2-dihydropyridin-3-yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-9-carboxamide 29(l-(3,5-difluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo [2,1 -a] isoquinolin- 3 -yl)((S)-2-methyl-2-((S)-3 ,3,3 -trifluoro- 1 - hydroxypropyl)pyrrolidin- 1 -yl)methanone {(S)-2-[(S)-3,3,3-trifluoro- 1 -hydroxypropyl]-2-methyl- 1 -pyrrolidinyl} {11- methoxy-12-(2-methyl-2H-tetraazol-5-yl)-3-(2-thienyl)-6-azatricyclo[7.4.0.0 2,6]trideca-l(13),2,4,9,l l-pentaen-5-yl} methanone WO 2024/184461 PCT/EP2024/056026 31(R)-1 -(8-methoxy-9-(l -methyl- lH-pyrazol-3-yl)-1 -(thiophen-2-yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile 32(R)-1 -(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 1 -(2-methylprop- 1 -en- 1 -yl)- 5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carbonitrile 33(S)-3-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4- carbonitrile 34(S)-3-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4- carbonitrile (R)-1 -(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 1 -propyl-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile 36(R)-1-(8-methoxy-9-(l-methyl- lH-pyrazol-3-yl)-1-(2,2, 2-trifluoroethyl)-5, 6- dihydroimidazo[5 ,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile WO 2024/184461 PCT/EP2024/056026 37(R)-l-(l-(3,3-difluorocyclobutyl)-8-methoxy-9-(l-methyl- lH-pyrazol-3-yl)- 5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile 38(S)-3-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4- carbonitrile 39(R)-l-(l-(4-fluorophenyl)-8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-5, 6- dihydroimidazo[5 ,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile 40(R)-l-(l-(4-fluorophenyl)-8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-5, 6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carbonitrile 41(R)-l-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5 ,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile 42(R)-l-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carbonitrile 43(R)-3-(3 -(2-cyano-2-methylpyrrolidine- 1 -carbonyl)- 1 -(4-fluorophenyl)-8- methoxy-5,6-dihydroimidazo[5,l-a]isoquinolin-9-yl)picolinonitrile WO 2024/184461 PCT/EP2024/056026 44(R)-3-(3 -(2-cyano-2-methylazetidine- 1 -carbonyl)- 1 -(4-fluorophenyl)-8- methoxy-5,6-dihydroimidazo[5,l-a]isoquinolin-9-yl)picolinonitrile 45(R)-l-(9-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-8-methoxy-l-(thiophen-2-yl)- 5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile (R)-8-methoxy-5-methyl-3-((R)-2-methyl-2-((S)-2,2,2-trifluoro-l-hydroxyethyl)pyrrolidine- 1 -carbonyl)-N-( 1 -methyl-2-oxo-1 ,2-dihydropyridin- 3-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9- carboxamide 473-((R)-3-((2R,4S)-2-cyano-4-hydroxy-2-methylpyrrolidine-l-carbonyl)-8- methoxy-5-methyl- 1 -(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-9-yl)picolinonitrile 48(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 1 -(2-methylprop- 1 -en- 1 -yl)-5,6- dihydropyrrolo [2,1 -a] isoquinolin- 3 -yl)((S)-2-methyl-2-((S)-3 ,3,3 -trifluoro- 1 - hydroxypropyl)pyrrolidin- 1 -yl)methanone 49(2R,4S)-4-hydroxy-l-(l-isobutyl-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile WO 2024/184461 PCT/EP2024/056026 50(S)-N-(2-cyano-4, 4,4-trifluorobutan-2-yl)-8-methoxy-N-methyl-9-(2-methyl- 2H-tetrazol-5-yl)- 1 -(2-methylprop- 1 -en- 1 -yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carboxamide 51(S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)- 1 -(2,2-diflu oropropyl)-8-methoxy- N-methyl-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamide 52(S)-N-(2-cyano-4, 4,4-trifluorobutan-2-yl)-8-methoxy-N-methyl-9-(2-methyl- 2H-tetrazol-5-yl)- 1 -(1,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo [2,1- a]isoquinoline-3-carboxamide 53(S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-l-(5-fluoropyridin-2-yl)-8-methoxy-N-methyl-9-(2-methyl-2H- 1,2,3-triazol-4-yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carboxamide 54((R)-1 -(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 1 -(2-methylprop- 1 -en- 1 -yl)- 5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile 55(l-(tert-butyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3, 3,3-trifluoro- 1- hydroxypropyl)pyrrolidin- 1 -yl)methanone WO 2024/184461 PCT/EP2024/056026 56(R)-l-(l-isobutyl-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile 57(R)-l-(l-(3,3-difluorocyclobutyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile 58(1 -isobutyl-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3, 3,3-tri fluoro- 1- hydroxypropyl)pyrrolidin- 1 -yl)methanone 59(l-(tert-butyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-l- hydroxypropyl)pyrrolidin- 1 -yl)methanone 60(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-2,2,2-trifluoro-l- hydroxy ethyl)pyrrolidin- 1 -yl)methanone 61(2R,4S)-l-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-4-hydroxy-2- methylpyrrolidine-2-carbonitrile WO 2024/184461 PCT/EP2024/056026 ACTIVITY OF THE COMPOUNDS 62(R)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2-methylallyl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carbonitrile

[00140]As noted above, the compounds disclosed herein have activity as FSHR modulators. This activity may be assessed by any suitable FSHR interaction assay, such as a cAMP accumulation assay as illustrated in the examples, and the other assays outlined below and illustrated in the examples. The compounds disclosed herein may show EC50 values of less than 1000 nM, less than or equal to 500 nM, less than or equal to 100 nm, less than or equal to 10 nM, or less than or equal to I nM, wherein the EC50 is the effective concentration of a compound at which 50% of the maximum response of that that would be obtained with FSH is observed.

[00141]Glycoprotein hormone receptors, FSHR, TSHR and LHR/LHCGR predominantly activate Gas class of intracellular G proteins, resulting in cAMP accumulation. The Homogeneous Time Resolved Fluorescence (HTRF) assay illustrated in the examples is based on competition between native cAMP produced by cells and cAMP labeled with the dye d2 (red acceptor) for binding to a cryptate labeled antibody (Europium donor). The specific energy transfer signal is inversely proportional to the concentration of cAMP in the standard or sample. See, e.g., Nataraja, S.G., et al., Frontiers in Endocrinology. 2015, 6:142.

[00142]Another assay uses the immortalized rat steroidogenic granulosa cell line, GFSHR-17, which stably expresses the FSH Receptor and is responsive to FSH stimulation with human FSH. See, e.g., Keren-Tai, I., et al., Molecular and Cellular Endocrinology, 1993, 95:Rl-R10. This engineered cell line lacks the aromatase found in primary granulosa cells required for conversion of androgen precursors to estrogens. However it shows a robust progesterone response which can serve as a surrogate to verify the activity of FSHR agonists. It can be used in a cell-based assay to evaluate the ability of compounds to activate FSHR in GFSHR-17 cells by measuring progesterone released into the supernatant, such as by using a progesterone HTRF kit from Cisbio. A ratiometric WO 2024/184461 PCT/EP2024/056026 HTRF read-out has been established to assess agonist activity of compounds and is described in the examples below.

[00143]The activity of the compounds described herein as agonists of the FSHR can be investigated using a modification of the classic FSH bioassay (Steelman-Pohley) which is based on the increase in ovarian weight in immature female rats. See Steelman, S.L. and F.M. Pohley, Endocrinology, 1953, 53(6):604-16. It is well-documented that activation of the FSHR in females stimulates granulosa cells of the ovarian follicles to proliferate and induce the expression of aromatase and luteinizing hormone receptor. See, e.g., Donadeu, F.X. and M. Ascoli, Endocrinology, 2005, 146(9):3907-16. Proper granulosa cell expansion and gene expression is essential to induce steroid synthesis and secretion to allow the follicle to respond to the preovulatory luteinizing hormone surge, which triggers ovulation of the oocytes contained within follicles into the oviduct where they can be fertilized. Therefore, it is reasonable to measure ovarian weight gain as a function of granulosa cell expansion, the number of ovulated oocytes as a function of follicle maturation, and uterine weight as a function of estradiol synthesis and secretion.

[00144]In some embodiments, a compound as disclosed herein selectively activates FSHR as compared to, for example, TSHR. This selective activity may be assessed by any suitable FSHR/TSHR assay comparing the potency in cAMP accumulation specific to the individual receptors, such as an assay illustrated in the examples (assessing selectivity based on EC50 ratios).

[00145]In some embodiments, a compound as disclosed herein selectively activates FSHR as compared to, for example, luteinizing hormone receptor. This selective activity may be assessed by any suitable FSHR/LHR assay comparing the potency in cAMP accumulation specific to the individual receptors, such as an assay illustrated in the examples(assessing selectivity based on EC50 ratios).

[00146]In some embodiments, a compound as disclosed herein exhibits at least 5-fold greater selectivity for FSHR than for TSHR. This includes at least 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-fold, or more, greater selectivity for follicle-stimulating hormone receptor than for thyroid-stimulating hormone WO 2024/184461 PCT/EP2024/056026 receptor. A compound as disclosed herein may exhibit about 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-fold greater selectivity for follicle-stimulating hormone receptor than for thyroid-stimulating hormone receptor.

[00147]In some embodiments, a compound as disclosed herein exhibits at least 5-fold greater selectivity for FSHR than for luteinizing hormone receptor. This includes at least 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-fold, or more, greater selectivity for follicle-stimulating hormone receptor than for luteinizing hormone receptor. A compound as disclosed herein may exhibit about 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-fold greater selectivity for follicle-stimulating hormone receptor than for luteinizing hormone receptor.

SYNTHESIS OF THE COMPOUNDS

[00148]In another aspect there is provided a method of manufacture of any one of the compounds disclosed herein. The presently disclosed compounds were and can be synthesized using the general synthetic procedures set forth in Schemes A-D below. The carrying out of each individual illustrated step is within the skill of an ordinary artisan guided by this disclosure, who also knows how to modify the synthetic procedures of the below schemes to synthesize the full scope of the compounds disclosed herein. Definitions for R1, R2, R3, R6, R10, R11 R12, R13, Rf , and WO 2024/184461 PCT/EP2024/056026 Rg are as provided in the formulas described herein. The synthetic procedure for individual compounds is disclosed in the Examples section below.

[00149] Scheme A A-1 A-6

[00150]As shown in Scheme A, compound A-1 (which may be synthesized as described in Method 1 below) was converted to oxalyl amide A-2. Cyclization of intermediate compound A-provided intermediate compound A-3. Subsequent saponification to intermediate compound A-followed by coupling with amine HNRf Rg resulted in intermediate compound A-5. Metal-mediated coupling of intermediate compound A-5 led to intermediate compound A-6, which after ester hydrolysis provided intermediate compound A-7. Coupling of compound A-7 with amine H2NRafforded compound A-8 (compounds as disclosed herein).

WO 2024/184461 PCT/EP2024/056026

[00151] Scheme B

[00152]Scheme B illustrates metal-mediated conversion of compound B-1 to a boronate ester which is then reacted with R3X (X = Cl, Br, 1, or OTf) to compound B-3 (a compound as disclosed herein) through another metal-mediated conversion.

[00153] Scheme C R2 B-1 B-3

[00154]Scheme C illustrates metal-mediated conversion of compound B-1 with an R3-boronate ester to compound B-3 (a compound as disclosed herein).

[00155] Scheme D HNRfR9 -ill- WO 2024/184461 PCT/EP2024/056026

[00156]Scheme D illustrates amide coupling of compound D-1 with amine HNRf Rg to arrive at compound B-3 (a compound as disclosed herein).

PHARMACEUTICAL COMPOSITIONS

[00157]In another aspect, disclosed herein are pharmaceutical compositions comprising, consisting essentially of, or consisting of a compound as described herein, and one or more pharmaceutically acceptable excipients.

[00158]In another aspect, disclosed herein are pharmaceutical compositions comprising, consisting essentially of, or consisting of a compound of Formulas (I), (II), (Ila), (III), or (IV) as described herein, and one or more pharmaceutically acceptable excipients.

[00159]The compounds may be formulated for administration by any suitable route of administration, such as for example, oral, topical (including transdermal), rectal, vaginal, transmucosal, or intestinal administration; parenteral delivery, including by intramuscular, subcutaneous, or intravenous injection, as well as inhalation, intrathecal, direct intraperitoneal, or intranasal delivery.

[00160]Pharmaceutical compositions as disclosed herein may comprise, as one or more pharmaceutically acceptable excipients, a pharmaceutically acceptable carrier, diluent, disintegrant, sweetening agent, glidant (such as magnesium stearate), flavoring agent, emulsifying agent, suspending agent, stabilizer, isotonic agent, etc. Pharmaceutical compositions as disclosed herein may be formulated into an oral dosage form such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or a topical (including transdermal) or transmucosal dosage form such as liquids, suspensions, emulsions, gels (ointments or the like), or a parenteral dosage form such as liquids, suspensions, emulsions, and freeze-dried powders. Said dosage forms may be formulated in various forms, e.g., a dosage form for single administration or for multiple administrations.

[00161]Exemplary excipients include, without limitation, lactose, polyethylene glycol (PEG), hydrogenated castor oil (HCO), cremophors, carbohydrates, starches (e.g., corn starch), inorganic salts, antimicrobial agents, antioxidants, binders/fillers, surfactants, lubricants (e.g., calcium or WO 2024/184461 PCT/EP2024/056026 magnesium stearate), glidants such as talc, disintegrants, diluents, buffers, acids, bases, film coats, combinations thereof, and the like.

[00162]The amount of any individual excipient in the composition will vary depending on the role of the excipient, the dosage requirements of the active agent, and particular needs of the composition. Generally, however, the excipient will be present in the composition in an amount of from about 1 % to about 99% by weight, such as from about 5% to about 98% by weight, including from about 15 to about 95% by weight of the composition. In general, the amount of excipient present in a composition of the disclosure is selected from the following: about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% by weight.

[00163]A pharmaceutical composition as disclosed herein may include a compound disclosed herein as the only active agent, or may be formulated with other active agents.

[00164]Techniques for formulation and administration of the compounds disclosed herein may be found in “Remington: The Science and Practice of Pharmacy, ” Academic Press, London, United Kingdom, 23rd edition, 2020.

[00165]Pharmaceutical compositions as disclosed herein may be formulated to provide a therapeutically effective amount of a compound as disclosed herein in a reasonable volume or mass of the composition, which may be administered by any effective dosing schedule, such as once a day. Although the exact dosage may be determined on a drug-by-drug (compound-by- compound) basis, for most compounds, some generalizations regarding the dosage can be made. For example, the daily dosage regimen for an adult human patient may be between 0.001 mg and 1000 mg, such as between 0.01 mg and 500 mg, for example from 1 to 200 mg of the compound or pharmaceutically acceptable salt thereof, calculated as the free base or free acid.

METHODS OF TREATMENT

[00166]In another aspect, disclosed herein are methods of modulating follicle-stimulating hormone receptor (FSHR) activity in a subject, comprising, consisting essentially of, or consisting of administering to a subject in need thereof a compound as disclosed herein or a pharmaceutical WO 2024/184461 PCT/EP2024/056026 composition as disclosed herein. In an alternative aspect, disclosed herein are methods of modulating follicle-stimulating hormone receptor activity in a biological sample, comprising contacting the biological sample with a compound or pharmaceutical composition as disclosed herein.

[00167]In another aspect, disclosed herein are methods of treating a disease or disorder in a subject in need thereof, comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a compound as disclosed herein or a pharmaceutical composition as disclosed herein. The disease or disorder may be any for which modulation of FSHR activity is desired, such as one or more of hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngiomas, combined pituitary hormone deficiency, fertile eunuch syndrome, abnormal beta subunit of LH, abnormal beta subunit of FSH, mass lesions, pituitary adenomas, cysts, metastatic cancer to the sella (breast in women, lung and prostate in men), infiltrative lesions, hemochromatosis, sarcoidosis, histiocytosis, lymphoma, lymphocytic hypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, hypothyroidism, intentional (iatrogenic) secondary hypogonadism, empty sella, pituitary infarction, Sheehan syndrome, anorexia nervosa, congenital adrenal hyperplasia, and disorders related to GnRH deficiency.

[00168]In another aspect, disclosed herein are methods for treating a fertility disorder in a male or female subject in need thereof, comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a compound as disclosed herein or a pharmaceutical composition as disclosed herein. Such a method may be for stimulating follicular development, ovulation induction, controlled ovarian hyperstimulation, controlled ovarian stimulation, assisted reproductive technology (ART) (including in vitro fertilization), treating male hypogonadism, or treating male infertility, including failure of spermatogenesis.

[00169]In another aspect, disclosed herein are compounds for use in modulating follicle- stimulating hormone receptor (FSHR) activity in a subject.

[00170]In another aspect, disclosed herein are compounds for use in treating a disease or disorder in a subject in need thereof. The disease or disorder may be any for which modulation of WO 2024/184461 PCT/EP2024/056026 FSHR activity is desired, such as one or more of hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngiomas, combined pituitary hormone deficiency, fertile eunuch syndrome, abnormal beta subunit of LH, abnormal beta subunit of FSH, mass lesions, pituitary adenomas, cysts, metastatic cancer to the sella (breast in women, lung and prostate in men), infiltrative lesions, hemochromatosis, sarcoidosis, histiocytosis, lymphoma, lymphocytic hypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, hypothyroidism, intentional (iatrogenic) secondary hypogonadism, empty sella, pituitary infarction, Sheehan syndrome, anorexia nervosa, congenital adrenal hyperplasia, and disorders related to GnRH deficiency.

[00171]In another aspect, disclosed herein are compounds for use in treating a fertility disorder in a female or male subject in need thereof, such as for stimulating follicular development, ovulation induction, controlled ovarian hyperstimulation, controlled ovarian stimulation, assisted reproductive technology (ART) (including in vitro fertilization), treating male hypogonadism, or treating male infertility, including failure of spermatogenesis.

[00172]In other aspects, disclosed herein are uses of the compounds disclosed herein in the preparation of medicaments for modulating follicle-stimulating hormone receptor (FSHR) activity in a subject, for treating a disease or disorder in a subject in need thereof, such as any one or more listed above, or for treating a fertility disorder in a female or male subject in need thereof, such as for stimulating follicular development, ovulation induction, controlled ovarian hyperstimulation, controlled ovarian stimulation, assisted reproductive technology (ART) (including in vitro fertilization), treating male hypogonadism, or treating male infertility, including failure of spermatogenesis.

[00173]In accordance with any of these methods or uses, the compound or composition may be administered by any suitable route of administration as discussed above, and may be administered in a therapeutically effective amount as discussed above. As also discussed above, the administration may be by any effective dosing schedule, such as once a day, 1 to 4 times per day, once a week, 1 to 4 times per week, once a month, 1 to 4 times month, etc. Although the exact dosage may be determined on a drug-by-drug (compound-by-compound) basis, the daily dosage WO 2024/184461 PCT/EP2024/056026 regimen for an adult human patient may be, for example, between 0.001 mg and 1000 mg, such as between 0.01 mg and 500 mg, for example 1 to 200 mg of the compound or pharmaceutically acceptable salt thereof, calculated as the free base or free acid.

[00174]The present technology, thus generally described, may be further understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present technology.

EXAMPLES

[00175] Analytical LCMS conditions were as follows:

[00176] Analytical Method 1 (Ml):

[00177]Analytical HPLC-MS were performed on a Shimadzu LCMS system using a Kinetex Core shell CIS column (2.1 mm x 50 mm, 5 pm; temperature: 40 °C) and a gradient of 5-100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) over 1.2 min, then 100% B for 0.1 min. A second gradient of 100-5% B was then applied over 0.01 min and held for 0.39 min with an injection volume of 3 pL at a flow rate of 1.2 mL/min. UV spectra were recorded at 2nm using a SPD-M20A PDA detector spectrum range: 200-400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[00178] Analytical Method 2 (M2)

[00179]Analytical uHPLC-MS were performed on a Waters ACQUITY uPLC system using a Waters uPLC® BEH™ CIS column (2.1 mm x 50 mm, 1.7 pm; temperature 40 °C) and a gradient of 5-100% B (A= 0.1% formic acid in water: B= 0.1% formic acid in acetonitrile) over 1.1 min, then 100% B for 0.25 min. A second gradient of 100-5% B was then applied over 0.05 min and held for 0.1 min with an injection volume of 1 pL at a flow rate of 0.9 mL/min. UV spectra were recorded at 215 nm on a Waters ACQUITY PDA with a spectrum range of 200-400 nm. Mass spectra were obtained using a Waters SQD (MSQI) or Waters ACQUITY QDA (MSQ2, MSQ4). Data were integrated and reported using Waters MassLynx and OpenLynx software.

WO 2024/184461 PCT/EP2024/056026

[00180] Analytical Method 3 (M3):

[00181]Analytical uHPLC-MS were performed on a Waters ACQUITY uPLC system using Waters uPLC® BEH™ Cl 8 column (2.1 mm x 30 mm, 1.7 pm; temperature 40 °C) and a gradient of 5-100% B (A = 2 mM ammonium bicarbonate, buffered to pH 10, B: acetonitrile) over 0.min, then 100% B for 0.1 min. A second gradient of 100-5% B was then applied over 0.05 min and held for 0.1 min with an injection volume of 1 pL at a flow rate of 1 mL/min. UV spectra were recorded 215 nm Waters ACQUITY PDA spectrum range of 200-400 nm. Mass spectra were obtained using a Waters Quattro Premier XE. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[00182] Analytical Method 4 (M4):

[00183]Analytical uHPLC-MS were performed on a Waters ACQUITY uPLC system using a Phenomenex Kinetex-XB Cl8 column (2.1 mm x 100 mm, 1.7 pm; temperature: 40 °C) and a gradient of 5-100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) over 5.3 min, then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min with an injection volume of 1 pL at flow rate of 0.6 mL/min. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector spectrum range: 200-400 nm, ELS data was collected using a Waters ACQUITY ELS detector (where fitted). Mass spectra were obtained using a Waters SQD (MSQI) or Waters ACQUITY QDA (MSQ2, MSQ4). Data were integrated and reported using Waters MassLynx and OpenLynx software.

[00184] Analytical Method 5 (M5):

[00185]Analytical uPLC-MS were performed on a Waters ACQUITY uPLC system using a Waters uPLC® BEH™ C18 column (2.1 mm x 100 mm, 1.7 pm column; temperature: 40°C) and a gradient of 5-100% B (A= 2 mM ammonium bicarbonate, buffered to pH 10; B = acetonitrile) over 5.3 min, then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min with an injection volume of 1 pL and at flow rate of 0.6 mL/min. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector Spectrum range: 200-400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector WO 2024/184461 PCT/EP2024/056026 (MS 16) or a Waters SQD2 (MSQ5). Data were integrated and reported using Waters MassLynx and OpenLynx software.

[00186] Analytical Method 6 (M6):

[00187]Analytical uPLC-MS were performed on a Waters ACQUITY uPLC system using a Phenomenex Kinetex Core-Shell C8 column (50 x 2.1mm, 5 pm column; temperature: 40°C) and a gradient of 5-100% B (A= 0.1% formic acid in water; B= 0.1% formic acid in acetonitrile) over 1.83 min, then 100% B for 0.42 min. A second gradient of 100-5% B was then applied over 0.min and held for 0.54 min with an injection volume of 3 pL and at flow rate of 1.2 mL/min. UV spectra were recorded at 215 nm using a SPD-M20A PDA detector spectrum range: 200-400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[00188] Analytical Method 7 (M7):

[00189]Analytical HPLC-MS were performed on a Waters LCMS systems using a Waters uPLC CORTEX C8 column (2.1 mm x 100 mm, 1.6 pm; temperature: 40 °C) and a gradient of 5- 100% B (A= 0.1% formic acid in water; B= 0.1% formic acid in acetonitrile) over 5.3 min, then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min with an injection volume of I pL at a flow rate of 0.6 mL/min. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector spectrum range: 200-400 nm, ELS data was collected using a Waters ACQUITY ELS detector (where fitted). Mass spectra were obtained using a Waters SQD or Waters ACQUITY QDa. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[00190] Analytical Method 8 (M8):

[00191]Analytical HPLC-MS were performed on a Waters LCMS systems using a Waters uPLC CORTEX C8 column (2.1 mm x 50 mm, 1.6 pm; temperature: 40 °C) and a gradient of 5- 100% B (A= 0.1% formic acid in water; B= 0.01% formic acid in acetonitrile) over 1.1 min, then 100% B for 0.3 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 0.28 min with an injection volume of I pL at a flow rate of 0.9 mL/min. UV spectra were recorded WO 2024/184461 PCT/EP2024/056026 at 215 nm using a Waters ACQUITY PDA detector spectrum range: 200-400 nm, ELS data was collected using a Waters ACQUITY ELS detector (where fitted). Mass spectra were obtained using a Waters SQD or Waters ACQUITY QDa. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[00192] Analytical Method 9 (M9):

[00193]Analytical HPLC-MS were performed on a Waters LCMS systems using a Waters CSH CIS column (2.1 mm x 100 mm, 1.7 pm; temperature: 40 °C) and a gradient of 5-100% B (A= mM ammonium acetate, buffered to pH 7; B= acetonitrile) over 5.3 min, then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min with an injection volume of I pL at a flow rate of 0.6 mL/min. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector spectrum range: 200-400 nm, ELS data was collected using a Waters ACQUITY ELS detector (where fitted). Mass spectra were obtained using a Waters SQD or Waters ACQUITY QDa. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[00194] Analytical Method 10 (M10):

[00195]Analytical (Ml4) uHPLC-MS were performed on a Waters ACQUITY uPLC system using a Waters uPLC® BEH™ Cl 8 column (2.1 mm x 30 mm, 1.7 pm; temperature 40 °C) and a gradient of 1-100% B (A= 2 mM ammonium bicarbonate, buffered to pH 10; B = acetonitrile) over 1.1 min, then 100% B for 0.25 min. A second gradient of 100-1% B was then applied over 0.05 min and held for 0.4 min with an injection volume of 1 pL at a flow rate of 1.0 mL/min. UV spectra were recorded at 215 nm on a Waters ACQUITY PDA with a spectrum range of 200-4nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector (MS 16) or a Waters SQD2 (MSQ5). Data were integrated and reported using Waters MassLynx and OpenLynx software.

WO 2024/184461 PCT/EP2024/056026

[00196] Analytical Method 11 (Mil): Instrument: Shimadzu LC-20AD&MS 2020;Column: Kinetex C18 2.6 pm, 2.1 *30mm; Column temperature: 40°C Gradient Ratio: Mobile phase A (MPA) H2O+0.04 % (v/v) TFAMobile phase B (MPB)Flow rate: 1.0 mL/minACN+0.02 % (v/v) TFA Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000 Time(min) 0.01 3.00 3.50 3.51 4.30MPA (%) 95 5 5 95 95MPB (%) 5 95 95 5 5

[00197] Analytical Method 12 (M12): Instrument: Shimadzu LC-20AD&MS 2020;Column: Kinetex CIS 2.6 pm, 2.1 *30mm; Column temperature: 40°CMobile phase A (MPA) H20+0.04% (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 1.5 mL/minGradient Ratio:Time(min) 0.01 0.70 1.15 1.16 1.50MPA (%) 95 5 5 95 95MPB (%) 5 95 95 5 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[00198] Analytical Method 13 (M13): Instrument: Shimadzu LC-20AD&MS 2020;Column: HALO CIS 5.0 pm, 3.0*30mm; Column temperature: 40°CMobile phase A (MPA) H20+0.04% (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 1.0 mL/min (0.01-3.0 min) 1.2 mL/min (3.01-3.5 min) WO 2024/184461 PCT/EP2024/056026 Gradient Ratio: Time (min) 0.01 2.5 3.0 3.01 3.5MPA (%) 95 5 5 95 95MPB (%) 5 95 95 5 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[00199] Analytical Method 14 (M14): Instrument: Shimadzu LC-20AD&MS 2020;Column: HALO Cl 8 2.7 pm,' 3.0*30mm; Column temperature: 40°CMobile phase A (MPA) H20+0.04% (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 1.5 mL/minGradient Ratio:Time(min) 0.01 0.70 1.15 1.16 1.50MPA (%) 95 5 5 95 95MPB (%) 5 95 95 5 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[00200] Analytical Method 15 (M15): Instrument: Shimadzu LC-20AD XR&MS 2020;Column: HALO C18 5 pm, 3.0*30mm; Column temperature: 40°CMobile phase A (MPA) H20+0.04% (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 2.0 mL/min (0.00-0.9 min)Gradient Ratio: Time (min) 0.00 0.50 0.90MPA (%) 90 0 0MPB (%) 10 100 100Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[00201] Analytical Method 16 (M16): Instrument: Shimadzu LC-20AD&MS 2020;Column: Xbridge-C18 2.1 *30mm 5 pm; Column temperature: 40°C WO 2024/184461 PCT/EP2024/056026 Mobile phase A (MPA) H2O+10mM NH4HCO3Mobile phase B (MPB) AcetonitrileFlow rate: 1.5 mL/minGradient Ratio:Time(min) 0.01 0.70 1.16 1.50MPA (%) 95 5 5 95MPB (%) 5 95 95 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[00202] Analytical Method 17 (Ml7): Instrument: Waters Arc&Qda;Column: HALO 2.7 pm C18 90A 30x3.0mm; Column temperature: 40°CMobile phase A (MPA) HO+0.04 % (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 1.0 mL/min (0.01-4.00 min)Gradient Ratio:Time(min) 0.01 3.00 3.50 3.51 4MPA (%) 95 5 5 95 95MPB (%) 5 95 95 5 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1200

[00203] Analytical Method 18 (Ml8): Instrument: Shimadzu LC-30AD&MS 2020;Column: InfinityLab Poroshell 120 SB-C18 2.7 pm 3.0*30mm; Column temperature: 40°CMobile phase A (MPA) HO+0.04 % (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 1.5 mL/min (0.01-1.50 min)Gradient Ratio:Time(min) 0.01 0.70 1.16 1.50MPA (%) 95 5 5 95 WO 2024/184461 PCT/EP2024/056026 MPB (%) 5 95 95 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[00204] Analytical Method 19 (Ml9): Instrument: Shimadzu LC-30AD&MS 2020;Column: InfinityLab Poroshell 120 SB-C18 2.7 pm 3.0*30mm; Column temperature: 40°CMobile phase A (MPA) HO+0.04 % (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 1.5 mL/min (0.01-1.50 min)Gradient Ratio:Time(min) 0.01 0.70 1.16 1.50MPA (%) 95 5 5 95MPB (%) 5 95 95 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-20

[00205] Analytical Method 20 (M20): Instrument: Shimadzu LC-20AD&MS 2020;Column: Kinetex EVO Cl8 30*2.1mm, 5 pm; Column temperature: 40°CMobile phase A (MPA) HO+0.04 % (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 1 mL/min (0.01-3.00 min)-1.2 mL/min (3.01-3.50 min)Gradient Ratio:Time(min) 0.01 2.50 3.00 3.01MPA (%) 95 5 5 95MPB (%) 5 95 95 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[00206] Analytical Method 21 (M21): Instrument: Shimadzu LC-20AD XR&MS 2020;Column: HALO C18 3.0*30mm, 5pm; Column temperature: 40°CMobile phase A (MPA) H2O+0.04 % (v/v) TFA WO 2024/184461 PCT/EP2024/056026 Mobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 1.5 mL/min (0.00-1.30 min)Gradient Ratio:Time(min) 0.01 0.8 1.30MPA (%) 90 0 0MPB (%) 10 100 100Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[00207] .Analytical Method 22 (M22): Instrument:Shimadzu LC-20AD XR&MS 2020;Column: HALO C18 5pm, 3.0*30mm; Column temperature: 40°CMobile phase A (MPA) HO+0.04 % (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 1.50 mL/minGradient Ratio:Time(min) 0 0.70 1.30MPA (%) 95 5 5MPB (%) 5 95 95Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-500

[00208] Analytical Method 23 (M23): Instrument: Shimadzu LC-20AD XR&MS 2020;Column: HALO C18 5 pm, 3.0*30mm; Column temperature: 40°CMobile phase A (MPA) H20+0.04% (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 2.0 mL/min (0.00-0.9 min)Gradient Ratio: Time (min) 0.00 0.50 0.90MPA (%) 90 0 0MPB (%) 10 100 100Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000 WO 2024/184461 PCT/EP2024/056026

[00209] Analytical Method 24 (M24): Instrument: Agilent 1260 & 6125B;Column: Xbridge Cl8 2.1 *50mm, 5 pm; Column temperature: 40°CMobile phase A (MPA) H2O+10mM NH4HCO3Mobile phase B (MPB) AcetonitrileFlow rate: 0.8 mL/minGradient Ratio:Time(min) 0.00 0.40 3.40 3.85 3.86 4.50MPA (%) 95 95 5 5 95 95MPB (%) 5 5 95 95 5 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[00210] Analytical Method 25 (M25): Instrument: Shimadzu 20AB&MS 2020;Column: Xbridge Cl8 2.1 *50mm, 5pm; Column temperature: 40°CMobile phase A (MPA) H2O+10 mMOL/L NH4HCO3Mobile phase B (MPB) 100%ACNFlow rate: 1.0 mL/minGradient Ratio:Time(min) 0.01 3.00 3.50 3.51 4.30MPA (%) 95 5 5 95 95MPB (%) 5 95 95 5 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[00211] Analytical Method 26 (M26): Instrument: Shimadzu LC-20AB&MS 2020;Column: Xbridge-C18 2.1*50mm 5um; Column temperature: 40°CMobile phase A (MPA) HO+10 mM NH4HCO3Mobile phase B (MPB) AcetonitrileFlow rate: 1.0 mL/min (0.01-3.01 min, 1.2 mL/min (3.02-3.50 min) WO 2024/184461 PCT/EP2024/056026 Gradient Ratio:Time(min) 0.01 2.50 3.00 3.01 3.5MPA (%) 95 5 5 95 95MPB (%) 5 95 95 5 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[00212] Analytical Method 27 (M27): Instrument: Shimadzu 20AB&MS 2020;Column: Xbridge C18 2.1*50mm, 5pm; Column temperature: 40°CMobile phase A (MPA) H2O+10 mMOL/L NH4HCO3Mobile phase B (MPB)Flow rate: 1.0 mL/minGradient Ratio:Time(min) 0.01 3.00 100%ACN 3.50 3.51 4.30 4.30MPA (%) 95 5 5 95 95 95MPB (%) 5 95 95 5 5 5Detection: 220 nm & 254 nm; MS Mode: Negative; MS Range: 100-2000

[00213] Analytical Method 28 (M28): Instrument: Agilent 1260 & 6125B;Column: Luna-C18 (2) 2.0*50mm, 5pm; Column temperature: 40°CMobile phase A (MPA) Mobile phase B (MPB) Flow rate: 1.0 mL/min H2O+0.04 % (v/v) TFAACN+0.02 % (v/v) TFA Gradient Ratio:Time (min) 0.00 0.40 3.00 4.00 4.01 4.50MPA (%) 95 95 5 5 95 95MPB (%) 5 5 95 95 5 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000 WO 2024/184461 PCT/EP2024/056026

[00214] Analytical Method 29 (M29): Instrument: Shimadzu LC-20AD XR&MS 2020;Column: HALO CIS 5pm, 3.0*30mm; Column temperature: 40°CMobile phase A (MPA) HO+0.04 % (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 1.50 mL/minGradient Ratio:Time(min) 0 0.70 1.30MPA (%) 90 0 0MPB (%) 10 100 100Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-1500

[00215] Analytical Method 30 (M30): Instrument: Shimadzu LC-20AD XR&MS 2020;Column: HALO CIS 5pm, 3.0*30mm; Column temperature: 40°CMobile phase A (MPA) HO+0.04 % (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 2.0 mL/min (0.00-0.9 min)Gradient Ratio:Time(min) 0 0.5 0.90MPA (%) 90 0 0MPB (%) 10 100 100Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[00216] Analytical Method 31 (M31): Instrument: Shimadzu LC-20AD XR&MS 2020;Column: HALO CIS 3.0*30mm, 5pm; Column temperature: 40°CMobile phase A (MPA) HO+0.04 % (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 1.5 mL/min (0.00-1.30 min) WO 2024/184461 PCT/EP2024/056026 Gradient Ratio:Time(min) 0.01 0.8 1.30MPA (%) 90 0 0MPB (%) 10 100 100Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[00217] Analytical Method 32 (M32): Instrument: Shimadzu LC-20AD XR&MS 2020;Column: HALO C18 5pm, 3.0*30mm; Column temperature: 40°CMobile phase A (MPA) HO+0.04 %(v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 2.0 mL/min (0.00-0.9 min)Gradient Ratio:Time(min) 0 0.5 0.90MPA (%) 90 0 0MPB (%) 10 100 100Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[00218] Analytical Method 33 (M33): Instrument: Shimadzu LC-20AD XR&MS 2020;Column: HALO C18 5pm, 3.0*30mm; Column temperature: 40°CMobile phase A (MPA) HO+0.04 % (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 2.0 mL/min (0.00-0.9 min)Gradient Ratio:Time(min) 0 0.5 0.90MPA (%) 90 0 0MPB (%) 10 100 100Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000 WO 2024/184461 PCT/EP2024/056026

[00219] Analytical Method 34 (M34): Instrument: Agilent 1260 & 6125B;Column: Luna-C18 (2) 2.0*50mm,5 pm; Column temperature: 40°CMobile phase A (MPA) HO+0.04 % (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 1.0 mL/minGradient Ratio:Time(min) 0.00 0.40 3.00 4.00 4.01 4.50MPA (%) 95 95 5 5 95 95MPB (%) 5 5 95 95 5 5Detection: 220 nm&254nm; MS Mode: Positive; MS Range: 100-1000

[00220] Analytical Method 35 (M35): Instrument: Agilent 1200 & 6110A;Column: Luna-C18 (2) 2.0*50mm, 5pm; Column temperature: 40°CMobile phase A (MPA) H2O+0.04 % (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 1.0 mL/minGradient Ratio:Time(min) 0.00 0.40 3.00 4.00 4.01 4.50MPA (%) 95 95 5 5 95 95MPB (%) 5 5 95 95 5 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[00221] Analytical Method 36 (M36): Instrument: Agilent 1200 & 6130;Column: Xbridge-C18 2.1*50mm 5pm; Column temperature: 40°CMobile phase A (MPA) HO+10 mM NH4HCO3Mobile phase B (MPB) AcetonitrileFlow rate: 0.8 mL/min WO 2024/184461 PCT/EP2024/056026 Gradient Ratio:Time(min) 0.00 0.40 3.40 3.85 3.86 4.50MPA (%) 95 95 5 5 95 95MPB (%) 5 5 95 95 5 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[00222] Analytical Method 37 (M37): Instrument: Agilent 1200 & 6110A;Column: Luna-C18 (2) 2.0*50mm,5pm; Column temperature: 40°CMobile phase A (MPA) HO+0.04 % (v/v) TFAMobile phase B (MPB) ACN+0.02 % (v/v) TFAFlow rate: 1.0 mL/minGradient Ratio:Time(min) 0.00 0.40 3.00 4.00 4.01 4.50MPA (%) 95 95 5 5 95 95MPB (%) 5 5 95 95 5 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[00223] Analytical Method 38 (M38): Instrument: Shimadzu LC-20AD&MS 2020;Column: Gemini Cl8 2.0*50mm, 5 pm; Column temperature: 40°CMobile phase A (MPA) Mobile phase B (MPB) Flow rate: 1.0 mL/minGradient Ratio: H20+10mM NH4HCO3Acetonitrile Time(min) 0.01 2.50 3.00 3.01 3.50MPA (%) 95 5 5 95 95MPB (%) 5 95 95 5 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000 WO 2024/184461 PCT/EP2024/056026

[00224] Analytical Method 39 (M3 9): Instrument: Agilent 1200 HPLC MSD: 1956A single quadrupole MSDColumn: Luna C18, 2.0*50mm, 5pm; Column temperature: 40°CMobile phase A (MPA) 0.04%TFA in H2OMobile phase B (MPB) 0.02%TFA in ACNFlow rate: 1.0 mL/minGradient Ratio:Time(min) 0.01 0.40 3.00 4.00 4.01 4.50MPA (%) 95 95 5 5 95 95MPB (%) 5 5 95 95 5 5Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[00225] Analytical Method 40 (M40):

[00226]All the analysis were performed using an Agilent G1956A LC/MSD quadrupole coupled to an Agilent 1100 series liquid chromatography (LC) system consisting of a binary pump with degasser, autosampler, thermostated column compartment and diode array detector. The mass spectrometer (MS) was operated with an atmospheric pressure electro-spray ionization (API-ES) source in positive ion mode. The capillary voltage was set to 3000 V, the fragmentor voltage to V and the quadrupole temperature was maintained at 100°C. The drying gas flow and temperature values were 12.0 L/min and 350 °C, respectively. Nitrogen was used as the nebuliser gas, at a pressure of 35 psig. Data acquisition was performed with Agilent Chemstation software. [00227]Analysis were earned out on a YMC pack ODS-AQ C18 column (50 mm long x 4.mm I.D.; 3 pm particle size) at 35 °C, with a flow rate of 2.6 mL/min. A gradient elution was performed from 95% (Water + 0.1% Formic acid)/5% Acetonitrile to 5% (Water + 0.1% Formic acid)/95% Acetonitrile in 4.8 min; the resulting composition was held for 1.0 min; from 5% (Water + 0.1% formic acid)/95% Acetonitrile to 95% (Water + 0.1% formic acid)/5% Acetonitrile in 0.min. The injection volume was 2 pL. Acquisition ranges were set to 190-400 nm for the UV-PDA detector and 100-1400 m/z for the MS detector.

WO 2024/184461 PCT/EP2024/056026

[00228] Analytical Method 41 (M41): [00229]All the analysis were performed using an Agilent G6224A TOF-LC/MS quadrupole coupled to an Agilent 1290 Infinity series liquid chromatography (LC) system consisting of a binary pump with degasser, autosampler, thermostated column compartment and diode array detector. The TOF-mass spectrometer (TOF-MS) was operated with an atmospheric pressure dual- electro-spray ionization (Dual-ESI) source in positive ion mode. The capillary voltage was set to 3000 V, the fragmentor voltage to 70 V and the quadrupole temperature was maintained at 100°C. The drying gas flow and temperature values were 12.0 L/min and 350 °C, respectively. Nitrogen was used as the nebuliser gas, at a pressure of 35 psig. Data acquisition was performed with MassHunter software.

[00230]Analysis were earned out on a YMC pack ODS-AQ C18 column (50 mm long x 4.mm I.D..; 3 pm particle size) at 35 °C, with a flow rate of 2.6 mL/min. A gradient elution was performed using ISET 2V1.0 Emulated Agilent Pump G1312A V1.0 from 94.51% (Water + 0.1% Formic acid)/5.49% Acetonitrile to 5% (Water + 0.1% Formic acid)/95% Acetonitrile in 4.8 min; the resulting composition was held for 1.0 min; from 5% (Water + 0.1% formic acid)/95% Acetonitrile to 95% (Water + 0.1% formic acid)/5% Acetonitrile in 0.2 min. The injection volume was 4 pL. Acquisition ranges were set to 190-400 nm for the UV-PDA detector and 100-1000 m/z for the TOF-MS detector.

[00231] Analytical Method 42 (M42):

[00232]Analytical HPLC-MS were performed on Agilent 1260 Infinity (Quat. Pump) DAD LC/MS G6120B system using a Thermo Scientific Accucore Cl8 (50 x 4.6 mm, 2.6 pm; temperature: 35 °C) and a gradient From 90% A to 10% A in 1.5 min, held for 0.9 min, to 95% A in 0.1 min (A: 0.1% HCOOH in H2O; B: CH3CN) with an injection volume of 3 pL at a flow rate of 3 mL/min. UV spectra were recorded at 254 nm using a 1260 Infinity II Diode Array Detector HS spectrum range: 200-400 nm. Mass spectra were obtained using a LC/MS G6120B system. Data were integrated and reported using ACD Labs software.

WO 2024/184461 PCT/EP2024/056026

[00233] Analytical Method 43 (M43): [00234]Analytical HPLC-MS were performed on Agilent 1290 Infinity II HPLC DAD LC/MSD G6125C ISET emulating Agilent G4220A system using a Phenomenex Kinetex C18 (x 2.1 mm, 1.7 pm; temperature: 60 °C) and a gradient of from 90% A to 10% A in 2.4 min, held for 0.4 min, to 90% A in 0.2 min (A: 0.1% HCOOH in HO; B: CHCN) with an injection volume of 3 pL at a flow rate of 0.9 mL/min. 254 nm using 1290 Infinity II Diode Array Detector spectrum range: 200-400 nm. Mass spectra were obtained using a LC/MSD G6125C detector. Data were integrated and reported using ACD Labs software.

[00235] Analytical Method 44 (M44):

[00236]Analytical HPLC-MS were performed on Agilent 1290 Infinity II HPLC DAD LC/MSD iQ G6160A using a Phenomenex Kinetex C18 (50 x 2.1 mm, 1.7 pm; Temperature: °C) and a gradient from 90% A to 10% A in 1.6 min, held for 0.4 min, to 90% A in 0.2 min. (A: 0.1% HCOOH in H2O; B: CH3CN) over 2.2 min with an injection volume of 3 pL at a flow rate of 1.2 mL/min. UV spectra were recorded at 254 nm using 1290 Infinity II Diode Array Detector spectrum range: 200-400 nm. Mass spectra were obtained using a LC/MSD iQ G6160A detector. Data were integrated and reported using ACD Labs software.

[00237] Analytical Method a: Instrument: Shimadzu LC-20AD&MS 2020Column:Column temperature:Mobile phase A(MPA)Mobile phase B(MPB)Flow rate:Gradient Ratio: HALO C18 5.0pm,3.0*30mm40°CH20+0.04%(v/v) TFAACN+0.02 %(v/v) TFALOmL/min (0.01-3.0min) 1.2mL/min 0.01-3.5min)Time(min) 0.01 2.5 3.0 3.01 3.5 Detection:MS Mode: MPA(%) 95 5 5 95 95MPB(%) 5 95 95 5 5220 nm 254nm Positive WO 2024/184461 PCT/EP2024/056026 MS Range: 50-2000

[00238] Analytical Method b.

Instrument: Agilent 1260 & 6125BColumn:Column temperature:Mobile phase A(MPA) Mobile phase B(MPB) Flow rate: Luna-C18(2) 2.0*50mm,5pm40°CHO+0.04 %(v/v) TFAACN+0.02 %(v/v) TFA1.0 mL/minGradient Ratio: Time(min) 0.00 0.40 3.00 4.00 4.01 4.50MPA(%) 95 95 5 5 95 95 Detection:MS Mode:MS Range: MPB(%) 5 5 95 95 5 5220 nmPositive100-1000

[00239] Analytical Method c.

Instrument: Shimadzu LC-20AD XR&MS 2020Column:Column temperature:Mobile phase A(MPA)Mobile phase B(MPB)Flow rate:Gradient Ratio: Halo Cl8 3.0*30mm, 5 pm40°CH2O+0.04 %(v/v) TFAACN+0.02 %(v/v) TFA1.5 mL/min (0.00-1.30min)Time(min) 0.01 0.8 1.30 Detection:MS Mode: MPA(%) 90 0 0MPB(%) 10 100 100220 nm 254nmPositive WO 2024/184461 PCT/EP2024/056026 MS Range: 50-2000

[00240] Analytical Method d.

Instrument: Shimadzu LC-20AD XR&MS 2020Column:Column temperature:Mobile phase A(MPA) Mobile phase B(MPB) Flow rate: Halo CIS 3.0*30mm, 5pm40°CHO+0.04 %(v/v) TFAACN+0.02 %(v/v) TFA1.5 mL/min (0.00-1.30min)Gradient Ratio: Time(min) 0.01 0.8 1.30MPA(%) 90 0 0MPB(%) 10Detection: 220 nm 254nmMS Mode: PositiveMS Range: 50-2000

[00241] Analytical Method e.

Instrument: Shimadzu LC-20AD XR&MS 2020Column: HALO CIS 5pm, 3.0*30mmColumn temperature: 40°CMobile phase A(MPA) H2O+0.04 %(v/v) TFAMobile phase B(MPB) ACN+0.02 %(v/v) TFAFlow rate: 2.0 mL/min (0.00-0.9min) 100 100 Gradient Ratio: Time(min) 0 0.5 0.90MPA(%) 90 0 0 Detection:MS Mode: MPB(%)220 nm 254nmPositive 100 100 WO 2024/184461 PCT/EP2024/056026 MS Range: 50-2000

[00242] Analytical Method f.

Instrument: Agilent 1260 & 6125BColumn:Column temperature:Mobile phase A(MPA) Mobile phase B(MPB) Flow rate: Xbridge CIS 2.1*50mm, 5pm40°CH20+10mMNH 4HC03Acetonitrile0.8 mL/minGradient Ratio: Time(min) 0.00 0.40 3.40 3.85 3.86 4.50MPA(%) 95 95 5 5 95 95 Detection:MS Mode:MS Range: MPB(%) 5 5 95 95 5 5220 nm &254 nmPositive100-1000

[00243] Analytical Method g.

Instrument: Shimadzu LC-20AD XR&MS 2020Column:Column temperature:Mobile phase A(MPA)Mobile phase B(MPB)Flow rate:Gradient Ratio: HALO Cl8 5 pm, 3.0*30mm40°CH2O+0.04 %(v/v) TFAACN+0.02 %(v/v) TFA2.0 mL/min (0.00-0.9min)Time(min) 0 0.5 0.90 Detection:MS Mode: MPA(%) 90 0 0MPB(%) 10 100 100220 nm 254nmPositive WO 2024/184461 PCT/EP2024/056026 MS Range: 50-2000

[00244] Analytical Method h.

Instrument: Shimadzu LC-20AB&MS 2020Column:Column temperature:Mobile phase A(MPA)Mobile phase B(MPB)Flow rate:Gradient Ratio: Xtimate C18 2.1*50mm 5 pm40°CH20+10mMNH 4HC03Acetonitrile1.0 mL/min(0.0 1 -3.0 Imin, 1.2mL/min(3 .02-3.50min)Time(min) 0.01 2.50 3.00 3.01 3.5 Detection:MS Mode:MS Range: MPA(%) 95 5 5 95 95MPB(%) 5 95 95 5 5220 254nm Positive 50-2000

[00245] Analytical Method i.

Instrument: Shimadzu LC-20AD XR&MS 2020Column:Column temperature:Mobile phase A(MPA)Mobile phase B(MPB)Flow rate:Gradient Ratio: Halo CIS 3.0*30mm, 5 pm40°CH2O+0.04 %(v/v) TFAACN+0.02 %(v/v) TFA1.5 mL/min (0.00-1.30min)Time(min) 0.01 0.8 1.30 Detection:MS Mode: MPA(%) 90 0 0MPB(%) 10 100 100220 nm 254nmPositive WO 2024/184461 PCT/EP2024/056026 MS Range: 50-2000

[00246] Analytical Method j.

Instrument: Agilent 1260 & 6125BColumn:Column temperature:Mobile phase A(MPA) Mobile phase B(MPB) Flow rate: Luna-C18(2) 2.0*50mm,5pm40°CHO+0.04 %(v/v) TFAACN+0.02 %(v/v) TFA1.0 mL/minGradient Ratio: Time(min) 0.00 0.40 3.00 4.00 4.01 4.50MPA(%) 95 95 5 5 95 95 Detection:MS Mode:MS Range: MPB(%) 5 5 95 95 5 5220 nm&254nmPositive100-1000

[00247] Analytical Method k.

Instrument: Shimadzu LC-20AD XR&MS 2020Column:Column temperature:Mobile phase A(MPA)Mobile phase B(MPB)Flow rate:Gradient Ratio: Tiank Cl8 50*2.1mm, 5pm40°CH20+10mM NH4HCO3AcetonitrilemL/min (0.00-4.5min)Time(min) 0.01 3.5 4.5 Detection:MS Mode: MPA(%) 95 5 5MPB(%) 5 95 95220 nm 254nmPositive WO 2024/184461 PCT/EP2024/056026 MS Range: 50-2000

[00248] Analytical Method 1.

Instrument: Shimadzu LC-20AD XR&MS 2020Column:Column temperature:Mobile phase A(MPA) Mobile phase B(MPB) Flow rate: HALO Cl8 5pm, 3.0*30mm40°CHO+0.04 %(v/v) TFAACN+0.02 %(v/v) TFA2.0 mL/min (0.00-0.9min)Gradient Ratio: Time(min) 0 0.5 0.90MPA(%) 90 0 0MPB(%) 10Detection: 220 nm 254nmMS Mode: PositiveMS Range: 50-2000

[00249] Analytical Method m.

Instrument: Shimadzu LC-20AD XR&MS 2020Column: Halo C18 3.0*30mm, 5pmColumn temperature: 40°CMobile phase A(MPA) H2O+0.04 %(v/v) TFAMobile phase B(MPB) ACN+0.02 %(v/v) TFAFlow rate: 2.0 mL/min (0.00-0.90min) 100 100 Gradient Ratio: Time(min) 0.01 0.5 0.9MPA(%) 90 0 0 Detection:MS Mode: MPB(%)220 nm 254nmPositive 100 100 WO 2024/184461 PCT/EP2024/056026 MS Range: 50-2000

[00250] Analytical Method n.

Instrument: Shimadzu LC-20AD XR&MS 2020Column:Column temperature:Mobile phase A(MPA)Mobile phase B(MPB)Flow rate:Gradient Ratio: TitankC18, 3.0*30mm 5 pm40°CH20+10mMNH 4HC03Acetonitrile1.5 mL/min (0.00-0.90min)Time(min) 0.01 0.5 0.9 Detection:MS Mode:MS Range: MPA(%)MPB(%)220 nm 254nmPositive&Negative50-2000 900100100

[00251] Analytical Method 0.

Instrument: Shimadzu LC-20ADXR&MS 2020Column: Xtimate C18 2.1*50mm,5pmColumn temperature: 40°CMobile phase A(MPA) H20+10mMNH4HC03Mobile phase B(MPB) AcetonitrileFlow rate: 1.0 mL/minGradient Ratio: Time(min) 0.01 2.50 3.00MPA(%) 95 5 5MPB(%) 5 95 95Detection: 220 nm 254 nmMS Mode: Positive WO 2024/184461 PCT/EP2024/056026 MS Range: 50-2000

[00252] Analytical Method p.

Instrument: Agilent 1260 & 6125BColumn:Column temperature:Mobile phase A(MPA) Mobile phase B(MPB) Flow rate: Luna-C18(2) 2.0*50mm,5pm40°CHO+0.04 %(v/v) TFAACN+0.02 %(v/v) TFA1.0 mL/minGradient Ratio: Time(min) 0.00 0.40 3.00 4.00 4.01 4.50MPA(%) 95 95 5 5 95 95 Detection:MS Mode:MS Range: MPB(%) 5 5 95 95 5 5220 nmPositive100-1000

[00253] Analytical Method q.

Instrument: Agilent 1260 & 6125BColumn:Column temperature:Mobile phase A(MPA) Mobile phase B(MPB) Flow rate: Luna-C18(2) 2.0*50mm,5pm40°CH2O+0.04 %(v/v) TFAACN+0.02 %(v/v) TFA1.0 mL/minGradient Ratio: Time(min) 0.00 0.40 3.00 4.00 4.01 4.50MPA(%) 95 95 5 5 95 95 Detection:MS Mode: MPB(%) 5 5 95 95 5 5220 nm&254nmPositive WO 2024/184461 PCT/EP2024/056026 MS Range: 100-1000

[00254] Analytical Method r.

Instrument: Agilent 1200 & 6120BColumn:Column temperature:Mobile phase A(MPA) Mobile phase B(MPB) Flow rate: Xbridge C18 2.1 *50mm,5pm40°CH20+10mMNH 4HC03Acetonitrile0.8 mL/minGradient Ratio: Time(min) 0.00 0.40 3.40 3.85 3.86 4.50MPA(%) 95 95 5 5 95 95 Detection:MS Mode:MS Range: MPB(%) 5 5 95 95 5 5220 nm&254nmPositive100-1000

[00255] Analytical Method s.

Instrument: Agilent 1200 & 6130Column: Xbridge-C18 2.1*50mm 5pmColumn temperature: 40°CMobile phase H20+10mMNH4HC03A(MPA)Mobile phase AcetonitrileB(MPB)Flow rate: 0.8 mL/minGradient Ratio: Time(min) 0.00 0.40 3.40 3.85 3.86 4.50MPA(%) 95 95 5 5 95 95MPB(%) 5 5 95 95 5 5 WO 2024/184461 PCT/EP2024/056026 Detection: 220 nm 254nmMS Mode: PositiveMS Range: 100-1000

[00256] Analytical Method t.

Instrument: Shimadzu LC-20AD&MS 2020Column: Xtimate C18 2.1 *50mm 5 pmColumn 40°Ctemperature:Mobile phase H20+10mMNH 4HC03A(MPA)Mobile phase AcetonitrileB(MPB)Flow rate: 1.0 mL/minGradient Ratio: Time(min) 0.01 2.50 3.00 3.01 3.5MPA(%) 95 5 5 95 95MPB(%) 5 95 95 5 5Detection: ELSD 220 nm 254nmMS Mode: PositiveMS Range: 50-2000

[00257] Analytical Method u.

Instrument: Shimadzu LC-30AD&MS 2020Column: Halo CIS 3.0*30mm, 5 pmColumn 40°Ctemperature:Mobile phase HO+0.04 %(v/v) TFAA(MPA) WO 2024/184461 PCT/EP2024/056026 Mobile phase ACN+0.02 %(v/v) TFAB(MPB)Flow rate: 1 mL/min(0.0 1 -3 .OOmin), 1.2mL/min(3 .01 -3.50min)Gradient Ratio: Time(min) 0.01 2.50 3.00 3.01 3.5 Detection:MS Mode:MS Range: MPA(%) 95 5 5 95 95MPB(%) 5 95 95 5 5ELSD 220 nm 254nmPositive50-2000

[00258] Purification methods were as follows:

[00259] Purification Method 1 (Pl):

[00260]Purifications LC were performed on a Gilson LC system using a Waters Sunfire Ccolumn (30 mm x 100 mm, 10 pM; temperature: rt) and a gradient of 10-95% B (A= 0.1% formic acid in water; B= 0.1% formic acid in acetonitrile) over 14.44 min then 95% B for 2.11 min. A second gradient of 95-10% B was then applied over 0.2 min with an injection volume of 1500 pL at flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.

[00261] Purification Method 2 (P2):

[00262]Purifications LC were performed on a Gilson LC system using a Waters Sunfire Ccolumn (30 mm x 10 mm, 10 pM; temperature: rt) and a gradient of 30-95% B (A= 0.1% formic acid in water; B= 0.1% formic acid in acetonitrile) over 11.00 min then 95% B for 2.10 min. A second gradient of 95-30% B was then applied over 0.2 min with an injection volume of 1500 pL at flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.

[00263] Purification Method 3 (P3):

[00264]Purifications LC were performed on a Gilson LC system using a Waters X-Bridge Ccolumn (30 mm x 100 mm, 10 pM; temperature: rt) and a gradient of 10-95% B (A= 0.2% ammonium hydroxide in water; B= 0.2% ammonium hydroxide in acetonitrile) over 14.44 min WO 2024/184461 PCT/EP2024/056026 then 95% B for 2.11 min. A second gradient of 95-10% B was then applied over 0.2 min with an inj ection volume of 1500 pL at flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.

[00265] Purification Method 4 (P4):

[00266]Purifications LC were performed on a Gilson LC system using a Waters X-Bridge Cl 8 column (30 mm x 10 mm, 10 pM; temperature: rt) and a gradient of 30-95% B (A= 0.2% ammonium hydroxide in water; B= 0.2% ammonium hydroxide in acetonitrile) over 11.00 min then 95% B for 2.10 min. A second gradient of 95-30% B was then applied over 0.21 min with an inj ection volume of 1500 pL at flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.

[00267] Purification Method 5 (P5): Instrument: Gilson 281 semi-preparative HPLC system;Mobile phase: A: H2O (0.04% HC1); B: ACN;Column: Phenomenex Luna C18 100*30mm*3pm;Column temperature: ambient, variable gradient;Flow rate: 25 mL/min;Monitor wavelength: 220 nm & 254 nm

[00268] Purification Method 6 (P6): Instrument: Gilson 281 semi-preparative HPLC system;Mobile phase: A: water (NH4HCO3); B: ACN;Column: Phenomenex C18 80*40mm*3pm;Column temperature: ambient, variable gradient;Flow rate: 25 mL/min;Monitor wavelength: 220 nm & 254 nm

[00269] Purification Method 7 (P7): Instrument: Gilson 281 semi-preparative HPLC system;Mobile phase: A: water (NH4HCO3); B: ACN;Column: Waters Xbridge Prep OBD C18 150*40mm*10pm;-145- WO 2024/184461 PCT/EP2024/056026 Column temperature: ambient, variable gradient;Flow rate: 25 mL/min;Monitor wavelength: 220 nm & 254 nm

[00270] Purification Method 8 (P8): Instrument: Gilson 281 semi-preparative HPLC system;Mobile phase: A: water (NH4HCO3); B: ACN;Column: Waters Xbridge BEH Cl8 100*30mm*10pm;Column temperature: ambient, variable gradient;Flow rate: 25 mL/min;Monitor wavelength: 220 nm & 254 nm

[00271] Purification Method 9 (P9): Instrument: Gilson 281 semi-preparative HPLC system;Mobile phase: A: water (NH4HCO3); B: ACN;Column: Waters Xbridge BEH C18 250*70mm*10pm;Column temperature: ambient, variable gradient;Flow rate: 25 mL/min;Monitor wavelength: 220 nm & 254 nm

[00272] Purification Method 10 (P10): Instrument: Orienda;Mobile phase: A: water+HCl; B: ACNColumn: 4kg Agela Cl8 column;Flow rate: 500 mL/min;

[00273] Purification Method 11 (Pll): Instrument: Waters SFC350 preparative SFC;Mobile phase: A for CO2 and B for EtOH (0.1% NH3H2O); B%=55% isocratic elution modeColumn: DAICEL CHIRALPAK AD (250mm* 50mm, 10 pm);Column temperature: ambient, variable gradient;Flow rate: 200 g/min; WO 2024/184461 PCT/EP2024/056026 Monitor wavelength: 220 nm

[00274] Purification Method 12 (P12): Instrument: Waters SFC350 preparative SFC;Mobile phase: A for CO2 and B for EtOH; B%=20% isocratic elution modeColumn: DAICEL CHIRALCEL OJ (250mm*50mm,10 pm);Column temperature: ambient, variable gradient;Flow rate: 200 g/min;Monitor wavelength: 220 nm

[00275] Purification Method 13 (P13):

[00276]The raw material was purified by using a Jasco System consisting of a CO2 Preparative Pump (PU-4387), a Preparative Pump for organic solvent (PU-4087 with six channel selector), Preparative SFC Autosampler (AS-4358), column oven with four valve selector (CO-4065), a PDA detector (MD-4015), a Back Pressure Regulator (BP-4340), two open-bed collectors (Gilson- 223) and a Julabo recirculating cooler (FL 1201). Data acquisition was performed with ChromNAV 2.04.00 software, equipped with a Phenomenex Lux Amylose- 1 column (250x30mm 5pm, 5 pM; temperature: 35 °C), with a flow rate of 30 mL/min and BPR set at 120 Bar. An isocratic mode elution was performed 60% B (A= CO2; B= 0.1% diethylamine in 2-propanol) in min on a stacked injection mode. Acquisition frequency was set to 220 nm for the PDA detector.

[00277] Purification Method 14 (P14):

[00278]The raw material was purified by using a Jasco System consisting of a CO2 Preparative Pump (PU-4387), a Preparative Pump for organic solvent (PU-4087 with six channel selector), Preparative SFC Autosampler (AS-4358), column oven with four valve selector (CO-4065), a PDA detector (MD-4015), a Back Pressure Regulator (BP-4340), two open-bed collectors (Gilson- 223) and a Julabo recirculating cooler (FL 1201). Data acquisition was performed with ChromNAV 2.03.05 software, equipped with a Phenomenex Lux Amylose- 1 column (250x30mm 5pm, 5 pM; temperature: 35 °C), with a flow rate of 30 mL/min and BPR set at 120 Bar. An isocratic mode elution was performed 55% B (A= CO2; B= 0.1% diethylamine in 2-propanol) in min on a stacked injection mode. Acquisition frequency was set to 220 nm for the PDA detector.-147- WO 2024/184461 PCT/EP2024/056026

[00279] Purification Method 15: Instrument: Gilson 281 semi-preparative HPLC system; Mobile phase: A: H2O (WmM NH4HCO3); B: ACN; Column: Waters Xbridge Prep OBD C18 150*40mm*10pm; Column temperature: ambient; Gradient: 30%-60% B over 8.0 min; Flow rate: 25mL/min; Monitor wavelength: 220&254nm

[00280] Purification Method 16: Instrument: Gilson 281 semi-preparative HPLC system; Mobile phase: A: H2O (lOmM NH4HCO3); B: ACN; Column: Phenomenex Gemini-NX 150*30mm*5pm; Column temperature: ambient; Gradient: 30%-70% B over 20.0 min; Flow rate: 25mL/min; Monitor wavelength: 220&254nm

[00281] Purification Method 17: Instrument: Gilson 281 semi-preparative HPLC system; Mobile phase: A: H2O (0.2% FA)-ACN; B: ACN; Column: Phenomenex Luna Cl8 100*30mm*3pm; mobile phase; Column temperature: ambient; Gradient: 25%-55% B over 8.0 min; Flow rate: 25mL/min; WO 2024/184461 PCT/EP2024/056026 Monitor wavelength: 220&254nm

[00282] Purification Method 18: Instrument: Gilson 281 semi-preparative HPLC system; Mobile phase: A: H2O (WmM NH4HCO3); B: ACN; Column: Agela DuraShell C18 250*70mm*10pm; Column temperature: ambient; Gradient: 80%-95% B over 20.0 min; Flow rate: 25mL/min; Monitor wavelength: 220&254nm

[00283] Purification Method 19: Instrument: Gilson 281 semi-preparative HPLC system; Mobile phase: A: H2O (0.05% NH3H2O+10mM NH4HCO3); B: ACN; Column: Welch Xtimate C18 250* 100mm* 10pm; Column temperature: ambient; Gradient: 40%-70% B over 24.0 min; Flow rate: 25mL/min; Monitor wavelength: 220&254nm

[00284] SFC Purification Method A: Instrument: Auno-600; Mobile phase: A for Heptane and B for EtOH (0.1% NH3H2O); B%=20% isocratic elution mode; Column: DAICEL CHIRALPAK IG (250mm* 50mm, 10 pm) ; Column temperature: 25 °C Flow rate: 130mL/min WO 2024/184461 PCT/EP2024/056026 Monitor wavelength: 200nm

[00285] NMR Conditions

[00286]Unless otherwise stated, 1H NMR spectra were recorded at 500 MHz or 400 MHz on either a Bruker Avance III HD 500 MHz or a Bruker Avance III HD 400 MHz spectrometer respectively. Chemical shifts, 6, are quoted in parts per million (ppm) and are referenced to the residual solvent peak. The following abbreviations are used to denote the multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), pent (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz.

WO 2024/184461 PCT/EP2024/056026

[00287]List of Abbreviations AIBN a,a'-azoisobutyronitrileAc acylAcN acetonitrileAc20 acetic anhydrideAr aromaticaq aqueousBn benzylBOC tertbutoxy carbonylCbz carboxybenzyl groupCDI carbonyldiimidazoleCui copper iodideCV column volumesd doubletDAST diethylaminosulfur trifluorideDCM dichloromethaneDCE 1,2-dichloroethaneDBA dibenzylideneacetoneDIAD diisopropyl azodicarboxylateDIPEA diisopropyl ethylamineDMA A-A-dimethylacetamideDME dimethoxyethaneDMF A-A-dimethylformamideDMSO dimethylsulfoxideDPPA diphenyl phosphoryl azideDPPE ethylenebis(diphenylphosphine)dppb 1,3 -bis(diphenylphosphino)propane WO 2024/184461 PCT/EP2024/056026 dppf 1,1 '-bis(diphenylphosphino)ferrocenedtbpf 1,1 -bis(di-tert-butylphosphino) ferroceneEDCI 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorideESI+ Electrospray ionization under positive ion modeE120 diethyl etherEtOAc or EA ethyl acetateEtOH ethyl alcoholEtONa sodium ethoxideFCC flash column chromatographyh hour(s)HATU (1 -[bis(dimethylamino)methylene]-l//- 1,2,3-triazolo[4,5-6]pyridinium 3- oxide hexafluorophosphateHFIP hexafluoroisopropanolHOAc acetic acidHOBt 1 -hydroxybenzotriazoleHPLC high performance liquid chromatographyi-PrOH isopropyl alcoholKOAc potassium acetateKOH potassium hydroxideLAH lithium aluminum hydrideLCMS liquid chromatography and mass spectrometryLiHMDS lithium bis(trimethylsilyl)amideM+H ion observed by mass spectrometry created by addition of a hydrogen cationmCPBA 3-chloroperbenzoic acidMeCN acetonitrileMeOH methanol WO 2024/184461 PCT/EP2024/056026 Me4tBuXphos 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-l,r ־ biphenylMTBE methyl tert-butyl etherm multipletmin minute(s)mE millilitremol/M mole/molarmmol millimoleN2 nitrogenNBS N-bromo succinimideNH40Ac ammonium acetateNMO 4-methylmorpholine A-oxideNMP 1 -methyl-2-pyrrolidinoneNMR nuclear magnetic resonanceOTf trifluoromethanesulfonatePE petroleum etherPPA polyphosphoric acid qquartetrt room temperatureRT retention times singletSat. saturatedSEC supercritical fluid chromatographySTAB sodium triacetoxy borohydridet tripletTBAE tetrabutyl ammonium fluorideTBAT tetrabutylammonium difluorotriphenylsilicate WO 2024/184461 PCT/EP2024/056026 TBDPS tertbutyl diphenyl silylTBSC1 tert-butylchlorodimethylsilanet-BuOH tert-butanolt-BuOK potassium tert-butoxidet-BuOLi lithium tert-butoxideTCFH N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphateTEA triethylamineTEA 2,2,2-trifluoroacetic acidTFAA trifluoroacetic anhydrideTHF tetrahydrofuranTLC thin layer chromatographyTMS trimethylsilylTMSN3 azidotrimethylsilaneTMSOK potassium trimethylsilanolatepL microliterXPhos Pd G2 chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1,1 '-biphenyl)[2-(2'- amino- 1,1 '-biphenyl)]palladium(II)XPhos Pd G3 (2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1,1 '-biphenyl)[2-(2'-amino- ,l'-biphenyl)]palladium(II) methanesulfonate

[00288]Compounds were named with the aid of OpenEye Scientific software (Lexichem TK).

[00289] Synthetic Method 1

[00290] Scheme for Method 1 WO 2024/184461 PCT/EP2024/056026

[00291] Step 1, Method 1

[00292]Ethyl 2-chloro-2-oxo-acetate (12.0 mL, 105.0 mmol, CAS 4755-77-5) was added to a solution of 7-bromo-6-methoxy-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (20.00 g, 69.mmol) in anhydrous THF (300 mL) and the reaction mixture stirred at rt for l h. The reaction mixture was concentrated in vacuo to give 7-bromo-2-(2-ethoxy-2-oxo-acetyl)-6-methoxy-3,4- dihydro-1H-isoquinoline-1-carboxylic acid as a yellow solid which was used directly in the next step assuming quantitative yield. RT (M2) = 0.75 min, [M+H]+ (ESI+) 386.1 / 388.1.

[00293] Step 2, Method 1

[00294]Pent-l-yne (8.6 mL, 87.4 mmol, CAS 627-19-0) was added to a stirred solution of 7- bromo-2-(2-ethoxy-2-oxo-acetyl)-6-methoxy-3,4-dihydro-l/7-isoquinoline-l-carboxylic acid (26.99 g, 69.9 mmol) in acetic anhydride (207 mL). The reaction mixture was placed into a pre- heated heating block at 140 °C and stirred for 45 min. The reaction mixture was cooled and concentrated in vacuo. The resulting residue was taken up in DCM (200 mL) and stirred with sat. aq. NaHCO3 (100 mL). The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Heptane (200 mL) and diethyl ether (50 mL) were added and the resulting mixture heated at 85 °C for 30 min. A hot filtration was carried out to afford a solid. This solid was dried and ground with a pestle and mortar to give ethyl 9-bromo-8-methoxy-l-propyl-5,6- dihydropyrrolo[2,l-a!]isoquinoline-3-carboxylate (13.90 g, 48% yield) as a brown solid. The filtrate was left overnight at rt and orange crystals formed which were isolated by filtration to give more desired product (3.13 g, 11% yield) as an orange solid. RT (M2) = 1.31 min, [M+H]+ (ES1+) 392.3/394.3; 1HNMR (500 MHz, DMSO) 6 7.68 (s, 1H), 7.16 (s, 1H), 6.78 (s, 1H), 4.(t, J = 6.6 Hz, 2H), 4.21 (q, J= 1A Hz, 2H), 3.88 (s, 3H), 2.99 (t, J= 6.5 Hz, 2H), 2.63 (t, J= 7.Hz, 2H), 1.66 - 1.57 (m, 2H), 1.27 (t, J= 1A Hz, 3H), 0.97 (t, J= 13 Hz, 3H).

WO 2024/184461 PCT/EP2024/056026

[00295]The following analogs were made by analogous method: Structure Name LCMS ״£/Gj p' ethyl 9-bromo-l-(4-fluorophenyl)- 8-methoxy-5,6-dihydropyrrolo[2, 1 -a]isoquinoline- 3-carboxylate RT(M8) = 1.10 min, [M+H]+ (ESI+) 444.1/446.1 .24% V ethyl 9-bromo-8-methoxy-l-thiazol-5-yl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline- 3-carboxylate RT (M3) = 1.10 min, [M+H]+ (ESI+) 433.1/435.1 BXXX»° N ethyl (5/?)-9-bromo-8-mcthoxy-5- methyl-l-thiazol-5-yl-5, 6- dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylate RT (M2) = 1.09 min, [M+H]+ (ESI+) 447.1/449.0 BXXX»° CT ethyl (5/?)-9-bromo-8-mcthoxy-5- methyl- 1 -(2-thienyl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline- 3-carboxylate RT (M2) = 1.32 min, [M+H]+ (ESI+) 446.1/448.1 bXX?n ״°ethyl 9-bromo-8-methoxy-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylate RT (MH) = 2.04 min, [M+H]+ (ESI+) 350.1/352.1 1 Y > /?Br Y 1/ OEt OBn ethyl 1 -(1 -(benzyl oxy)-2- methylpropan-2-yl)-9-bromo-8- methoxy- 5,6-dihydropyrrolo[2, 1 - a]isoquin-oline-3-carboxylate RT(M13) = 2.67 min, [M+H]+ (ESI+) 512.3/514.1 WO 2024/184461 PCT/EP2024/056026 JUUj OEtsVaN ethyl 9-bromo-8-methoxy-l- (l,3,4-thiadiazol-2-yl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylate RT(M14)= 1.13 min, [M+H]+ (ESI+) 434.1/436.0 11 T । 0 BT y_rX- FX F ethyl 9-bromo-l-(3,3-difluorocyclobutyl)-8-methoxy-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carboxylate RT (M22) = 0.97 min, [M+H]+ (ESI+) 440.1/442.1 BrXO ^^LyOEt F ethyl 9-bromo-l-(5-fluoropyridin- 2-yl)-8-methoxy-5,6-dihydropyrrolo[2, 1 -a]isoquinoline- 3-carboxylate RT(M19) = 0.89 min, [M+H]+ (ESI+) 445.2/447.1 ,° XX?N ״ethyl (R*)- 9-bromo-8-methoxy-6- methyl- 1 -(thiophen-2-yl)-5 ,6- dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylate RT (M25) = 3.13 min, [M+H]+ (ESI+) RT = 0.89 min, [M+H]+ (ESI+) 445.2/447.1 /0.h zr °m R JUJ j r^X^^L^0'־Et c> ethyl (R*)- 9-bromo-8-methoxy-6- methyl- 1 -(thiophen-2-yl)-5 ,6- dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylate SEC Method (11) First enantiomer RT (M25) = 0.89 min, [M+H]+ (ESI+) 446.0/447.9Second enantiomer RT (M25) = 1.80 min, [M+H]+ (ESI+) 417.9/419.9 WO 2024/184461 PCT/EP2024/056026 ״ JUck j '0Et ethyl (R*)-9-bromo-8-methoxy-5- methyl- 1 -(thiophen-2-yl)-5 ,6- dihydropyrrolo[2, 1 -a]isoquinoline- 3-carboxylate SFC Method (11) Second enantiomerRT(M15)= 1.08 min, [M+H]+ (ESI+) 444.8/446.1 bXXXjethyl-9 -bromo- 8 -methoxy- 5 - methyl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylate RT (Ml) = 2.07 min, [M+H]+ (ESI+) 364.1/366.1 (RL^/0pO Ri 0 Br ethyl (laR,9bR)-7-bromo-8- methoxy- 5 -(thiophen-2-yl)-1 a,9b- dihydro- 1 H-cyclopropa [c]pyrrolo[2,l-a]isoquinoline-3- carboxylate RT (M22) = 1.02 min, [M+H]+ (ESI+) 444.1/446.1 * Denotes unknown stereochemistry, isolated from a diastereomeric mixture using SFC chromatography

[00296] Synthetic Method 2

[00297] Scheme for Method 2 WO 2024/184461 PCT/EP2024/056026

[00298] Step 1, Method 2

[00299]Potassium hydroxide (7.93 g, 139.0 mmol) was added to a stirred solution of ethyl 9- bromo-8-methoxy-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a!]isoquinohne-3-carboxylate (prepared in accordance with an analogous method to method 1 (steps 1 and 2) using 2-ethynyl-thiophene) (15.00 g, 34.7 mmol) in ethanol (300 mL) and water (100 mL) at 80 °C. After 1 h, the reaction mixture was cooled to rt and concentrated in vacuo. The aqueous residue was acidified to pH l using 1 M aq HCI, and the solid suspended in the aqueous layer was collected by filtration to give 9-bromo-8-methoxy-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-o ؛]isoquinoline-3-carboxylic acid (83% purity, 14.70 g, 87% yield) as a pale brown solid. RT (M2) = 1.03 min, [M+H]+ (ESI+) 402.9/404.9.

[00300] Step 2, Method 2

[00301]DIPEA (30 mL, 173.0 mmol, CAS 7087-68-5), HATH (14.11 g, 37.1 mmol, CAS 148893-10-1) and (2R)-2-methylpyrrolidine-2-carboxamide hydrochloride (4.89 g, 29.7 mmol, CAS 1262381-66-7) were added to a stirred solution of 9-bromo-8-methoxy-l-(2-thienyl)-5,6- dihydropyrrolo[2,l-،2]isoquinoline-3-carboxylic acid (10.00 g, 24.7 mmol) in DCM (400 mL) at rt. The reaction mixture was stirred overnight and then diluted with DCM and water. The layers were separated, the organic passed through a phase separator and then concentrated in vacuo to yield the crude product as a brown oil. The crude was purified by FCC (silica, eluting with 0-100% EtOAc in heptane, then 0-20% MeOH in EtOAc). The product containing fractions were concentrated in vacuo to give (2R)-l-[9-bromo-8-methoxy-l-(2-thienyl)-5,6-dihydropyrrolo[2,l- o ؛]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carboxamide (10.27 g, 77% yield) as a pale brown foam. RT (M2) = 1.00 min, [M+H]+ (ESI+) 514.2/516.2; 1H NMR (400 MHz, DMSO) 8.16 (s, 1H), 7.57 (dd, J=5.2, 1.2 Hz, 1H), 7.45 (s, 1H), 7.18-7.10 (m, 2H), 7.07 (dd,J=3.4, 1.2 Hz, 1H), 6.82 (s, 1H), 6.66 (s, 1H), 4.24-4.20 (m, 1H), 3.96 - 3.91 (m, 1H),3.86 (s, 3H),3.- 3.74 (m, 1H), 3.69 - 3.57 (m, 1H), 3.20 - 3.09 (m, 1H), 3.05 - 2.97 (m, 1H), 2.10 - 2.02 (m, 1H), 1.89 - 1.84 (m, 3H), 1.53 (s, 3H).

WO 2024/184461 PCT/EP2024/056026

[00302]The following analogs were made by analogous method: Structure Name LCMS X 1 1 oTAXH =Br XJ^N-Xa [9-bromo-8-methoxy- 1 -(2-thienyl)-5 ,6- dil1־ydropyrrolo[2,l -،/] isoquinol in-3-yl]- [(2،S)-2-ethyl-2-methyl-pyrrolidin- 1 - yl] methanone RT (M2) = 1.min, [M+H]+ (ESI+) 499.1/501.1 B J? - OHBr^px u[9-bromo-8-methoxy- 1 -(2-thienyl)-5 ,6- dihydropyrrolo[2,l -،/] isoquinol in-3-yl]- [(27?)-2-(hydroxymethyl)-2-methyl- pyrrolidin- 1 -yl] methanone RT (M2) = 0.min, [M+H]+ (ESI+) 501.2/ 503.2 ״XXA 7.

CT [9-bromo-8-methoxy- 1 -(2-thienyl)-5 ,6- dihydropyrrolo[2,l -،/] isoquinol in-3-yl]- (2,2-dimethylpyrrolidin- 1 -yl)methanone RT (M2) = 1.min, [M+H]+ (ESI+) 485.1 / 487.1 XJ،n x f - O _Br ^^x yX ja xxnh 2 ^/־־־^ (2/?)-1 -(9-bromo-8-methoxy- 1 -propyl- 5,6-dihydropyrrolo[2,l-،2]isoquinoline- 3-carbonyl)-2-methyl-pyrrolidine-2- carboxamide RT (M2) = 0.min, [M+H]+ (ESI+) 474.2 / 476.2 /OxXXJUx /Nx J - OBr ^^X JLA)J ^nh 2 f' (27?)-1 -[9-bromo- 1 -(4-fluorophenyl)-8- methoxy-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl]-2-methyl- pyrrolidine-2-carboxamide RT (M2) = 0.min, [M+H]+ (ESI+) 526.0/528.0 BrXX،N^ , QHN— FZ [9-bromo- 1 -(4-fluorophenyl)-8- methoxy-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-3-yl]-[(27?)-2-[(lR)-l- hydroxyethyl]-2-methyl-pyrrolidin- 1 - yl] methanone RT (M3) = 0.min, [M+H]+ (ESI+) 527.3/529.3 WO 2024/184461 PCT/EP2024/056026 /°XVXjL/N j - °Br X yX זעnh 2 ؛؛־؟ M Xf F (27?)-1 -[9-bromo-8-methoxy- 1 -(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl]-2-methyl- pyrrolidine-2-carboxamide RT (M3) = 0.min, [M+H]+ (ESI+) 514.1/516.1/O^X^XXX N /? - OH؛؛ Br x yx—/ n — [9-bromo-8-methoxy- 1 -(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-3-yl]-[(27?)-2-[(17?)-l- hydroxyethyl]-2-methyl-pyrrolidin- 1 - yl] methanone RT (M3) = 1.min, [M+H]+ (ESI+) 515.3/517.3 1O^x/xaX j H% tC N [(27?)-2-[(17?)-l-hydroxyethyl]-2- methyl-pyrrolidin- 1 -yl]-[8-methoxy-9- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-thiazol-5-yl-5,6-dihydropyrrolo[2, 1 -a]isoquinolin-3 - yl] methanone RT (M2) = 0.min, [M+H]+ (ESI+) 516.1/518.1 1Ox/X/XTil oHQ FAX״n // , __ z_FX yX '-./ F X/ nX F N (9-bromo-8-methoxy-l-thiazol-5-yl-5,6- dihydropyrrolo[2, 1 -a]isoquinolin-3 -yl)- [(27?)-2-methyl-2-[(l lS)-2,2,2-trifluoro- -hydroxy-ethyl]pyrrolidin- 1 - yl] methanone RT (M2) = 0.min, [M+H]+ (ESI+) 570.0/572.0 /0x/X/X1 I O oXL /X N //in 0r^7X XXXX ^־־^nh 2V ° (27?)-1 -(9-bromo-8-methoxy- 1 -thiazol- 5-yl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carbonyl)-2-methyl- pyrrolidine-2-carboxamide RT (M2) = 0.min, [M+H]+ (ESI+) 515.1/517.1 WO 2024/184461 PCT/EP2024/056026 ^0x^x/XjOC N /? . PH8^)LP'nVPfF [9-bromo-8-methoxy- 1 -(2-thienyl)-5 ,6- dil1־ydropyrrolo[2,l -،/] isoquinol in-3-yl]- [(2S)-2-methyl-2-[(lR)-2,2,2-trifluoro- -hydroxy-ethyl]pyrrolidin- 1 - yl] methanone RT (M2) = 1.min, [M+H]+ (ESI+) 569.1/571.1 /XJC/N J? _ 01_| NHcf3 (R)-1 -(9-bromo-8-methoxy- 1 -(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carboxamide RT(M13) = 1.min [M+H]+ (ESI+) 500.3/502.0 /0x^X^XN J = |H2 /-F (R)-1 -(1 -(2,2-difluoropropyl)-8- methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 5,6-dihydropyrrolo[2, 1 -a] isoquinoline- 3-carbonyl)-2-methylpyrrolidine-2- carboxamide RT (M29) = 0.min [M+H]+ (ESI+) 514.1 ,Ox^xZ^nXmu a pr^N^NH, X-FF (R)-1 -(1 -(2,2-difluoropropyl)-8- methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 5,6-dihydropyrrolo[2, 1 -a] isoquinoline- 3-carbonyl)-2-methylazetidine-2- carboxamide RT(M13) = 1.min [M+H]+ (ESI+) 500.3 /0X^x/X.T II 1 o OHBr'^־xp'NX( JA^F1/N)Ks-^ V/V (9-bromo- 8-methoxy- 1 -(1,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo[2,l- a]isoquinolin-3-yl)((S)-2-methyl-2-((7?)- 2,2,2-trifluoro-l-hydroxyethyl)pyrrolidin- 1 -yl)methanone RT(M11) = 1.min [M+H]+ (ESI+) 571.2/573.2 WO 2024/184461 PCT/EP2024/056026 .XJU 5 . 0»A'WW ,—/ nh 2fH F (7?)-l-(9-bromo-l-(3,3- difluorocyclobutyl)-8-methoxy-5,6- dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl)-2-methylpyrrolidine-2- carboxamide RT(M13)= 1.min [M-128.1]+ (ESI+) 394.2/396.2 /0x/'^x/A _ 0Br TT'n^Hq LJ nh 2V (/?)-1 -(9-bromo-8-methoxy- 1 -(thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carboxamide 1H NMR (4MHz, DMSO-de) ppm 7.58 (br, d, J = 5.13 Hz,2H), 7.41 (s, 1 H), 7.(brs, 1 H), 7.10- 7.16 (m, 2 H), 7.(brd, J=2.75 Hz, H), 6.69 (br s, H), 4.46 - 4.57 (m, H), 4.28 - 4.(m, 3 H), 3.86 (s, H), 3.01 (brt, J = 6.38 Hz, 2 H), 2.- 2.46 (m, 1 H), 1.97 - 2.09 (m, H), 1.68 (brs, 3 H)/0x^x/x^o .־ BrXjQ F (/?)-1 -(9-bromo- 1 -(5-fluoropyridin-2- yl)-8-methoxy-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carbonyl)-2- methylpyrrolidine-2-carboxamide RT(M13) = 1.min [M+H]+ (ESI+) 528.2/530.2 WO 2024/184461 PCT/EP2024/056026 0 ؛ 1 TNN,__ 0 - nh 2 j0N F (R)-1 -(1 -(5-fluoropyridin-2-yl)-8- methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 5,6-dihydropyrrolo[2, 1 -a] isoquinoline- 3-carbonyl)-2-methylazetidine-2- carboxamide RT(M20) = 1.min [M+H]+ (ESI+) 517.2 /Ox/^/xM 4T or 1H ؟ 1 A N Pja»،,؟ A /-Ca ((5*)-9-bromo-8-methoxy-6-methyl- 1 - (thiophen-2-yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-3 -yl)((R)-2-((R)- 1 - hydroxyethyl)-2-methylpyrrolidin- 1 - yl)methanone RT (MH) = 2.min [M+H]+ (ESI+) 529.2/531.2 110 h 2nTAX JI 1 ־Br L/NCo (Ry 1 -((،S'*)-9-bromo-8-methoxy-6- methyl- 1 -(thiophen-2-yl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl)-2-methylpyrrolidine-2- carboxamide RT (MH) = 3.min [M+H]+ (ESI+) 528.2/530.2 /Ox^x/Xy*J || T 0 ohAAA // = 7 c> F ((R)-9-bromo-8-methoxy-5-methyl- 1 - (thiophen-2-yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-3-yl)((R)-2-methyl-2-((S)- 2,2,2-trifluoro-l-hydroxyethyl)pyrrolidin- 1 -yl)m ethanone RT (MH) = 2.min [M+H]+ (ESI+) 583.3/585.3 A o ho ך ד x , LA/Nx J/ F Br g **P((lS)-9-bromo-8-methoxy-5-methyl- 1 - (thiophen-2-yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-3-yl)((R)-2-methyl-2-((S)- 2,2,2-trifluoro-l-hydroxyethyl)pyrrolidin- 1 -yl)m ethanone RT (MH) = 2.min [M+H]+ (ESI+) 583.2/585.3 WO 2024/184461 PCT/EP2024/056026 T T 0 ז oh((R)-9-bromo-8-methoxy-5-methyl- 1 - (thiophen-2-yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-3 -yl)((R)-2-((R)- 1 - hydroxyethyl)-2-methylpyrrolidin- 1 - yl)methanone RT (MH) = 2.min [M+H]+ (ESI+) 529.1/531.1 /°Z^Z^Z'H ؟ ° n((lS)-9-bromo-8-methoxy-5-methyl- 1 - (thiophen-2-yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-3 -yl)((R)-2-((R)- 1 - hydroxyethyl)-2-methylpyrrolidin- 1 - yl)methanone RT (MH) = 2.min [M+H]+ (ESI+) 529.1/531.2 0 h 2n ן 11= JCxA/N ABr TrN،o(R)-1 -((S)-9-bromo-8-methoxy-5- methyl- 1 -(thiophen-2-yl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl)-2-methylpyrrolidine-2- carboxamide RT (M27) = 2.min [M+H]+ (ESI+) 528.4/530.0 || I o OHF ־، a^VNxJ A~F F F ((R)-9-bromo-8-methoxy-5-methyl- 1 - (2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,l-a]isoquinolin-3- yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro- -hydroxyethyl)pyrrolidin- 1 - yl)methanone RT (M30) = 0.min [M+H]+ (ESI+) 583.2/585.1 /°xZ^Z־־A Z^/FL/ N-(s)Ks OP F F ((1 aR,9bR)-7-bromo-8-methoxy-5- (thiophen-2-yl)-1 a,9b-dihydro- 1H- cyclopropa[c] pyrrolo[2,l-a]isoquinolin- 3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro- 1 -hydroxyethyl) pyrrolidin- 1 - yl)methanone RT (MH) = 0.min [M+H]+ (ESI+) 581.2/583.2 WO 2024/184461 PCT/EP2024/056026 * Denotes unknown stereochemistry, isolated from a diastereomeric mixture using SFCchromatography

[00303] Synthetic Method 3

[00304] Scheme for Method 3

[00305] Step 1, Method 3

[00306](llS)-2,2,2-trifluoro-l-[(27?)-2-methylpynolidin-2-yl]ethanol hydrochloride (447 mg, 2.0 mmol, synthesized by method 16) was added to a stirred solution of di(imidazol-l- yl)methanone (412 mg, 2.5 mmol, CAS 530-62-1) and 9-bromo-8-methoxy-l-(2-thienyl)-5,6- dihydropyrrolo[2,l-،2]isoquinoline-3-carboxylic acid (690 mg, 1.7 mmol) in anhydrous DMF (mL) and left at rt overnight. The reaction was then heated to 50 °C and stirred for 8 h before it was retreated with (llS)-2,2,2-trifluoro-l-[(27?)-2-methylpyrrolidin-2-yl]ethanol hydrochloride (4mg, 2.0 mmol) and stirred at rt for a further 72 h. The reaction mixture was concentrated in vacuo and partitioned between DCM and water. The layers were separated, the organic passed through a phase separator and concentrated in vacuo to give the crude product as a yellow oil which was purified by FCC (silica, eluting 0-100% EtOAc in heptane). Product containing fractions were collected, combined and the solvent removed in vacuo to give [9-bromo-8-methoxy-l -(2-thienyl)- 5,6-dihydropynolo[2,l-a!]isoquinohn-3-yl]-[(27?)-2-methyl-2-[(l lS)-2,2,2-tri fluoro- 1-hydroxy- ethyl]pyrrolidin-l-yl]methanone (80% purity, 1.05 g, 87% yield) as a beige solid. RT (M2) =1.min [M+H]+ (ES1+) 569.1 / 571.1; 1HNMR (400 MHz, DMSO) 6 7.56 (dd, J = 5.2, 1.2 Hz, 1H), 7.43 (s, 1H), 7.16 - 7.09 (m, 2H), 7.06 (dd, J= 3.5, 1.2 Hz, 1H), 6.66 (d, J= 7.2 Hz, 1H), 6.50 (s, 1H), 4.99 (p, J = 8.4 Hz, 1H), 4.31 - 4.10 (m, 2H), 3.88-3.84 (m, 4H), 3.70 - 3.59 (m, 1H), 3.(t, J=6.5 Hz, 2H), 2.43 - 2.28 (m, 1H), 1.85- 1.74 (m, 2H), 1.74- 1.63 (m, 1H), 1.60 (s, 3H).

WO 2024/184461 PCT/EP2024/056026

[00307] Synthetic Method 4

[00308] Scheme for Method 4

[00309] Step 1, Method 4

[00310] (1R- )-1-[(2/?)-2-methylpyrrolidin-2-yl]ethanol hydrochloride (492 mg, 3.0 mmol,synthesized by method 15) was added to a stirred solution of di(imidazol- 1 -yl)methanone (6mg, 3.7 mmol, CAS 530-62-1) and 9-bromo-8-methoxy-l-(2-thienyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxylic acid (1.00 g, 2.5 mmol) in anhydrous DMF (14 mL) and the reaction mixture heated at 90 °C for 2.5 h. DIPEA (1.1 mL, 6.2 mmol, CAS 7087-68-5) was added and the mixture stirred at 90 °C overnight. The reaction mixture was concentrated in vacuo and dissolved in DCM and water. The layers were separated, the organic passed through a phase separator and concentrated in vacuo to give an oil that was purified by FCC (silica, eluting 0-100% EtOAc in heptane). The fractions were concentrated in vacuo to give [9-bromo-8-methoxy-l -(2-thienyl)- 5,6-dihydropynolo[2,l-a!]isoquinohn-3-yl]-[(2R)-2-[(U?)-l-hydroxyethyl]-2-methyl-pynohdin- 1-yl]methanone (72.0% purity) (594 mg, 0.8 mmol, 34% yield) as a pale brown solid. RT (M3) = 0.99 min, (ESI+) (M+H)+ 515.3 / 517.3. 1H NMR (500 MHz, DMSO) 6 7.55 (dd, J= 5.2, 1.1 Hz, 1H), 7.43 (s, 1H), 7.14-7.10 (m, 2H), 7.06 (dd, J= 3.5, 1.2 Hz, 1H), 6.53 (s, 1H), 4.96 (d, J=4.Hz, 1H), 4.44 (p, J = 6.3 Hz, 1H), 4.31 (dt, J = 13.0, 6.5 Hz, 1H), 4.11 - 4.05 (m, 1H), 3.85 (s, 3H),3.81 (ddd, 10.0,6.6,3.5 Hz, 1H), 3.67 - 3.59 (m, 1H), 3.01 (t,J=6.5 Hz, 2H), 2.07 (ddd, J= 12.6, 10.2, 7.7 Hz, 1H), 1.81 - 1.71 (m, 2H), 1.57 - 1.51 (m, 1H), 1.50 (s, 3H), 1.00 (d, J= 6.Hz, 3H).

[00311]The following analogs were made by analogous method: WO 2024/184461 PCT/EP2024/056026 Structure Name LCMS 1T 1 ° [(5R)-9-bromo-8-m ethoxy-5-methyl- 1 -(2- thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-3-yl]-[(2 lS)-2-methyl-2-[(U?)- 2,2,2-trifluoro- 1 -hydroxyethyl]pyrrolidin- 1 - yl]methanone RT (M2) = 1.25 min, (ESI+) (M+H)+ 583.0/585.0 1Br^=^VNsrX '0H s-/^ O ZFO fN [(5R)-9-bromo-8-m ethoxy-5-methyl- 1 - thiazol-5-yl-5,6-dihydropyrrolo[2,l- a]isoquinolin-3-yl]-[(2R)-2-methyl-2-[(l lS)- 2,2,2-trifluoro- 1 -hydroxyethyl]pyrrolidin- 1 - yl]methanone RT (M2) = 1.25 min, (ESI+) (M+H)+ 583.0/585.0 ״ ZZ-M ,pא jf X/N-e-(Fn-n g 0 y FV F Compound 4-1 [8-methoxy-9-(l -methylpyrazol-3-yl)-1 - thiazol-5-yl-5,6-dihydropyrrolo[2,l- a]isoquinolin-3-yl]-[(2 lS)-2-methyl-2-[(U?)- 2,2,2-trifluoro- 1 -hydroxyethyl]pyrrolidin- 1 - yl]methanone RT (M4) = 3.46 min, (ESI+) (M+H)+572.2 h f ,؟ nJUCO .F ؟ 0 ؛ N-N _^O ׳ N F Compound 4-2 (l-(5-fluoropyridin-2-yl)-8-methoxy-9-(2- methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl)((S)- -methyl-2 -((R)-2,2,2 -trifluoro- 1 - hydroxyethyl)pyrrolidin- 1 -yl)m ethanone RT (M36) = 3.min, (ESI+) (M+H)+ 586.3 f£00fT Compound 4-3 (R)-8-methoxy-5-methyl-3-((R)-2-methyl-2- ((،2,2,2-(؟-trifluoro- 1 -hydroxyethyl) pyrrolidine-l-carbonyl)-N-(l-methyl-2-oxo- 1,2-dihydropyridin-3-yl)- 1 -(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide RT (M34) = 2.min, (ESI+) (M+H)+ 655.3 WO 2024/184461 PCT/EP2024/056026

[00312] Synthetic Method 5

[00313] Scheme for Method 5 HCI HO,

[00314] Step 1, Method 5

[00315] 1 M Aqueous lithium hydroxide (1.1 mL, 1.1 mmol) was added to a stirred suspensionof ethyl 9-bromo-8-methoxy-l-propyl-5,6-dihydropyrrolo[2,l-a!]isoquinohne-3-carboxylate (2mg, 0.5 mmol, synthesized by method 1) in ethanol (4.7 mL) and the mixture heated at 80 °C for h, forming a solution. After cooling to rt the mixture was concentrated in vacuo to afford the product lithium 9-bromo- 8-methoxy- 1 -propyl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylate hydroxide (226 mg, quantitative) as an off-white powder. RT (M2) = 1.03 min, (ESI+) (M+H)+ 364.1/366.1; 1HNMR (400 MHz, DMSO-d6) 8 7.54 (s, 1H), 7.06 (s, 1H), 6.30 (s, 1H), 4.62 (t, J= 6.3 Hz, 2H), 3.84 (s, 3H), 2.84 (t, J= 6.3 Hz, 2H), 2.60-2.53 (m, 2H), 1.59 (h, J= Hz, 2H), 0.97 (t, J= 13 Hz, 3H).

[00316] Step 2, Method 5

[00317]DIPEA (1.4 mL, 8.0 mmol, CAS 7087-68-5) was added to a stirred suspension of lithium 9-bromo-8-methoxy- 1 -propyl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylate hydroxide (1.04 g, 2.6 mmol) and (lR)-l-[(2R)-2-methylpyrrolidin-2-yl]ethanol hydrochloride (580 mg, 1.3 mmol, synthesized by method 15) in DMA (25 mL) and the mixture stirred at 20 °C for 5 min, forming a hazy solution. 2-Chloro- 1-methylpyridinium iodide (1.50 g, 5.9 mmol, CAS 14338-32-0) was added and the reaction mixture stirred at 20 °C for 17 h. The reaction mixture was diluted with water (150 mL), sonicated and left to stand for 10 min. The solids were collected by filtration, washing with water (3 x 30 mL). The solids were then dissolved into EtOAc (2 WO 2024/184461 PCT/EP2024/056026 mL) and the organic mixture filtered through a hydrophobic filter paper. The organic filtrate was concentrated in vacuo to afford the crude product (913 mg) as a tan powder. The crude product was purified by FCC (silica, eluting with 10-100% EtOAc in heptane) to give (9-bromo-8- methoxy-l-propyl-5,6-dihydropynolo[2,l-a!]isoquinolin-3-yl)-[(2R)-2-[(lR)-l-hydroxyethyl]-2- methyl-pyrrolidin-l-yl]methanone (507 mg, 38% yield) as a pale tan powder. RT (M2) = 1.min, (ES1+) (M+H)+ 475.2/477.2; 1H NMR (400 MHz, DMSO) 6 7.62 (s, 1H), 7.12 (s, 1H), 6.(s, 1H), 5.01 (d, J= 4.7 Hz, 1H), 4.47 - 4.35 (m, 1H), 4.25 (dt, J= 13.0, 6.5 Hz, 1H), 4.05 (dt, J= 12.6, 6.2 Hz, 1H), 3.86 (s, 3H), 3.77 (dt, J = 10.4,5.2 Hz, 1H), 3.66 - 3.52 (m, 1H), 2.93 (t, J = 6.5 Hz, 2H), 2.66-2.57 (m, 2H), 2.05 (dt,J= 12.8, 8.8 Hz, 1H), 1.86- 1.68 (m, 2H), 1.67-1.(m, 3H), 1.49 (s, 3H), 1.02 - 0.92 (m, 6H).

[00318] Synthetic Method 6

[00319] Scheme for Method 6

[00320] Step 1, Method 6

[00321](Methyl N-(triethylammoniumsulfonyl)carbamate) (2.35 g, 9.9 mmol, CAS 29684-56- 8) (Burgess reagent) was added to a mixture of (2R)-l-[9-bromo-8-methoxy-l-(2-thienyl)-5,6- dihydropyrrolo[2,l-a!]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carboxamide (2.54 g, 4.mmol, synthesized by method 2) in THF (20 mL) and DCM (20 mL) at 0 °C and the reaction mixture warmed to 20 °C and stirred for 1 h. The reaction mixture was poured into water (20 mL) and the aqueous phase extracted with DCM (3 x 20 mL). The combined organic phases were washed with brine (saturated solution of NaQ in deionized water) (50 mL), dried with anhydrous Na2S04, filtered and concentrated in vacuo. The resulting residue was purified by FCC (silica, eluting 0-100% EtOAc in heptane) and the product containing fractions concentrated in vacuo to Burgess reagent WO 2024/184461 PCT/EP2024/056026 give (2R)-l-[9-bromo-8-methoxy-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a!]isoquinoline-3- carbonyl]-2-methyl-pyrrolidine-2-carbonitrile (92%) (2.10 g, 79% yield) as a pale yellow solid. RT (M2) = 1.09 min, (ESI+) (M+H)+ 496.0/497.9; 1H NMR (500 MHz, DMSO) 6 7.58 (dd, J = 5.2, 1.2 Hz, 1H), 7.43 (s, 1H), 7.16 - 7.11 (m, 2H), 7.08 (dd, J = 3.5, 1.2 Hz, 1H), 6.72 (s, 1H), 4.46 - 4.37 (m, 1H), 4.33 - 4.20 (m, 1H), 3.91-3.85 (m, 4H), 3.84 - 3.77 (m, 1H), 3.05 (t, J= 6.Hz, 2H), 2.47 (dd, J = 9.0, 3.7 Hz, 1H), 2.12 (ddd, J = 12.8, 10.1, 6.0 Hz, 1H), 2.02 - 1.99 (m, 1H), 1.95 - 1.85 (m, 1H), 1.74 (s, 3H).

[00322]The following analogs were made by analogous method: Structure Name LCMS 1I Y 1 0 ,n /// , A-Ax/^ JI ״ (2/?)-1 -[9-bromo- 1 -(4-fluorophenyl)-8- methoxy-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl]-2-methyl- pyrrolidine-2-carbonitrile RT (M2) = 1.11 min, (ESI+) (M+H)+508.0/510.0 1Ox/Sx/X,0 , n ן ץAA/NX JI - ״Br u -■J- V !j N (2/?)-1 -(9-bromo-8-methoxy- 1 -propyl- 5,6-dihydropyrrolo[2, 1-،2]isoquinoline- 3-carbonyl)-2-methyl-pyrrolidine-2- carbonitrile RT (M2) = 1.13 min, (ESI+) (M+H)+456.2/458.2 1T 1 ° /,NBr y-A Vyj/ n-kVF (2/?)-1 -[9-bromo-8-methoxy- 1 -(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl]-2-methyl- pyrrolidine-2-carbonitrile RT (M3) = 1.06 min, (ESI+) (M+H)+496.2/498.2 WO 2024/184461 PCT/EP2024/056026 1ZCO^J0 . / (TKnV Compound 6-1 (3lS)-4-[8-methoxy-9-(l-methylpyrazol- 3-yl)-l-(2-thienyl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-3- carbonyl] -3 -methyl-morpholine-3 - carbonitrile RT (M5) = 3.78 min, (ESI+) (M+H)+514.3 T I 1 0^VA.N. 11 ' — mAAOn N Compound 6-2 (27?)-l-[8-methoxy-9-(l-methylpyrazol-3-yl)-l-thiazol-5-yl-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-3- carbonyl] -2-methyl-pyrrolidine-2- carbonitrile RT (M4) = 3.17 min, (ESI+) (M+H)+499.3 j^N yjj ^־ N (27?)-1 -(9-bromo-8-methoxy- 1 -thiazol- 5-yl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methyl- pyrrolidine-2-carbonitrile RT (M2) = 0.93 min, (ESI+) (M+H)+497.1/499.1 1 T 1 ,°XJk,N z Br/—' I cf3 (7?)-1 -(9-bromo-8-methoxy- 1 -(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile RT (MH) = 1.min, (ESI+) (M+H)+ 482.2/484.1 /0-^Xx/Xx^BrXXj^, 0 ..If N־־־y ־=N F-q F (7?)-l-(9-bromo-l-(3,3-difluorocyclobutyl)-8-methoxy-5,6- dihydropyrrolo [2,1 -a]isoquinoline-3 - carbonyl)-2-methylpyrrolidine-2- carbonitrile RT (M27) = 2.min, (ESI+) (M+H)+ 504.0/506.0 WO 2024/184461 PCT/EP2024/056026 11 T 1 °jlax,n x J!BrC> (R)-1 -(9-bromo-8-methoxy- 1 - (thiophen-2-yl)-5,6-dihydropyrrolo [2,1 -a]isoquino line-3 - carbonyl)-2-methylazetidine-2- carbonitrile RT (M25) = 2.min, (ESI+) (M+H)+ 482.0/484.0 /Ox_^/xT £ £ ,°£_y ' N—/~v — FZ (/?)-1 -(9-bromo- 1 -(5-fluoropyridin-2- yl)-8-methoxy-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl)-2- methylpyrrolidine-2-carbonitrile RT (M13) = 1.min, (ESI+) (M+H)+ 509.2/511.1 /0xAZX/ X/ X/ 0r1 ין= ע AAA ״ (/?*)-1 -((S)-9-bromo-8-m ethoxy-6- methyl- 1 -(thiophen-2-yl)-5 ,6- dihydropyrrolo [2,1 -a]isoquinoline-3 - carbonyl)-2-methylpyrrolidine-2- carbonitrile RT (MH) = 2.min, (ESI+) (M+H)+ 510.2/512.2 X53 ״° ץת، Br (7?)-l-((S)-9-bromo-8-methoxy-5- methyl- 1 -(thiophen-2-yl)-5 ,6- dihydropyrrolo [2,1 -a]isoquinoline-3 - carbonyl)-2-methylpyrrolidine-2- carbonitrile RT (M12) = 0.7min, (ESI+) (M+H)+ 510.2/512.2 1ך T 1 pN I Vj N-V^N'N kzOH Compound 6-3 (/?)-1 -(1 -(1 -hydroxy-2-methylpropan- 2-yl)-8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carbonyl)-2- methylpyrrolidine-2-carbonitrile RT (M36) = 3.min, (ESI+) (M- OH)+ 472.1 WO 2024/184461 PCT/EP2024/056026 ASALN9 - y« vt^n^n ^F Compound 64־ (7?)-l -(1 -(2,2-difluoropropyl)-8- methoxy-9-(2-methyl-2H-tetr azol-5- yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl)-2- methylpyrrolidine-2-carbonitrile RT (M36) = 2.min, (ESI+) (M+H)+ 496.3 ץ II 1 0yl ץ F /؟ Compound 6-5 (7?)-l -(1 -(2,2-difluoropropyl)-8- methoxy-9-(2-methyl-2H-tetr azol-5- yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl)-2- methylazetidine-2-carbonitrile RT (M24)= 2.min, (ESI+) (M+H)+ 482.2 r II 1 9yl mot Compound 6-6 (7?)-1 -(8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-1 -propyl-5 ,6- dihydropyrrolo [2,1 -a]isoquinoline-3 - carbonyl)-2-methylazetidine-2- carbonitrile RT (M37) = 2.min, (ESI+) (M+H)+ 446.2 .Oxz^/T if 1 o nAA/V n' n XJn-n ,H Compound 6-7 (7?)-l -(1 -(5-fluoropyridin-2-yl)-8- methoxy-9-(2-methyl-2H-tetr azol-5- yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl)-2- methylazetidine-2-carbonitrile RT (M24) = 2.min, (ESI+) (M+H)+ 499.1 r if 1 oN - ؛ NvVvMn' T jrN-N >-> U™ Compound 6-8 (7?)-l -(1 -(4-fluorophenyl)-8-methoxy- 9-(2-methyl-2H-tetrazol-5-yl)-5 ,6- dihydropyrrolo [2,1 -a]isoquinoline-3 - carbonyl)-2-methylazetidine-2- carbonitrile RT (M24) = 3.min, (ESI+) (M+H)+ 498.2 WO 2024/184461 PCT/EP2024/056026 * Denotes unknown stereochemistry, isolated from a diastereomeric mixture using SFC chromatography

[00323] Synthetic Method 7 v —N N XPhos Rd G2 ,°. Pd(dppf)CI2 KOAc

[00325] Step 1, Method 7

[00326] In a pressure relief vial, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (338 mg, 1.3 mmol, CAS 73183-34-3), (2R)-l-[9-bromo-8-methoxy-l- (2-thienyl)-5,6-dihydropyrrolo[2,l-o ؛]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2- carbonitrile (600 mg, 1.2 mmol, synthesized by method 6) and potassium acetate (300 mg, 3.mmol, CAS 127-08-2) were dissolved in anhydrous 1,4-dioxane (13 mL) and degassed with nitrogen. [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (99 mg, 121 umol, CAS 95464-05-4) was added and the reaction mixture was stirred at 90 °C overnight. The reaction mixture was concentrated and partitioned between DCM and water. The layers were separated, the organics passed through a phase separator cartridge and concentrated in vacuo. The crude material was then purified by FCC (silica, eluting with 0-100% EtOAc in heptane). Product containing fractions were collected, combined and the solvent removed in vacuo to give (2R)-l-[8-methoxy-9-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l- (2-thienyl)-5,6-dihydropyrrolo[2,l-o ؛]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2- carbonitrile (425 mg, 57% yield) as a pale brown solid. RT (M2) =1.1 min [M+H]+ (ESI+) 544.3; 1HNMR (500 MHz, DMSO) 6 7.67 (s, 1H), 7.50 (dd,J=5.1, 1.2 Hz, 1H), 7.09-7.03 (m, 2H), 6.94 (s, 1H), 6.72 (s, 1H), 4.40 (dt, J= 13.3, 6.5 Hz, 1H), 4.26 (dt, J= 13.1, 6.2 Hz, 1H), 3.89 (td, J = 8.8, 7.3, 3.8 Hz, 1H), 3.84 - 3.78 (m, 1H), 3.76 (s, 3H), 3.06 (t, J = 6.5 Hz, 2H), 2.48 - 2.

[00324] Scheme for Method 7 WO 2024/184461 PCT/EP2024/056026 (m, 1H), 2.17 -2.08 (m, 1H), 1.99 (s, 1H), 1.93 (dd, J = 15.5, 6.8 Hz, 1H), 1.74 (s, 3H), 1.17 (s, 12H)

[00327] Step 2, Method 7

[00328]A solution of (27?)-l-[8-methoxy-9-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l- (2-thienyl)-5,6-dihydropyrrolo[2,l-a!]isoquinohne-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile (100 mg, 184 umol), 2-bromo- 1,3-oxazole (34 mg, 221 umol, CAS 125533-82-6) and dicaesium carbonate (240 mg, 736 umol, CAS 534-17-8) in 1,4-dioxane (2.4 mL) and water (0.mL) was degassed with nitrogen for 5 min. XPhos Pd G2 (29 mg, 18 umol, CAS 1310584-14-5) was then added and the mixture degassed with nitrogen for 5 min. The reaction mixture was stirred at 80 °C overnight. The reaction was allowed to cool to rt, treated with water (5 mL) and extracted with EtOAc (3x5 mL). The organic phases were combined, passed through a phase separator and concentrated in vacuo. The compound was purified by acidic prep HPLC (Method P2) and then basic prep HPLC (Method P4) to give a white solid. The white solid was further purified by chiral prep (Chiralpak AD-H, mobile phase ethanol at 9 mL/min) and freeze dried to give (27?)-l-[8- mcthoxy-9-oxazol-2-yl-1 -(2-thicnyl)-5,6-dihydropyrrolo[2, 1-،؛/]isoquinolinc-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile (Compound 7-1) (24 mg, 27% yield) as a white solid. RT (M4) = 3.62 min, (ESI+) (M+H)+ 485.2; 1H NMR (400 MHz, DMSO) 6 8.09 (s, 1H), 7.96 (s, 1H), 7.(dd, J= 3.9, 2.5 Hz, 1H), 7.28 - 7.20 (m, 2H), 7.12 - 7.05 (m, 2H), 6.73 (s, 1H), 4.50 - 4.39 (m, 1H), 4.35 - 4.23 (m, 1H), 3.93 - 3.86 (m, 4H), 3.86 - 3.77 (m, 1H), 3.13 (t, J= 6.4 Hz, 2H), 2.47-2.42(m, 1H), 2.19-2.08 (m, 1H), 2.05 - 1.85 (m, 2H), 1.74 (s, 3H).

[00329]The following analogs were made by analogous method: Structure Name LCMS 1 H ° ؛ YxJUyM ° T Compound 7-2 4-[3-[(2R)-2-[(lR)-l-hydroxyethyl]-2- methyl-pyrrolidine- 1 -carbonyl] -8- methoxy- 1 -(2-thienyl)-5 ,6-dihydropyrrolo[2,l-،2]isoquinolin-9- yl]-6-methyl-l//-pyridin-2-one RT(M4) = 3.min [M+H]+ (ESI+) 544.3 WO 2024/184461 PCT/EP2024/056026 h ? ؛ 0C,n >l7 A—K Compound 7-3 [(2R)-2-[(lR)-l-hydroxyethyl]-2- methyl-pyrrolidin- 1 -yl] - [8 -methoxy-9- oxazol-2-yl-1 -(2-thienyl)-5 ,6- dihydropyrrolo[2,l-a!]isoquinolin-3- yl] methanone RT (M4) = 3.min [M+H]+ (ESI+) 504.3 X/XO - ־؟^ 1 ! J yj n FZ Compound 7-4 3-[3-[(27?)-2-cyano-2-methyl- pyrrolidine- 1 -carbonyl] -1 -(4- fluorophenyl) - 8 -methoxy- 5,6 - dihydropyrrolo[2,l-،2]isoquinolin-9- yl]pyridine-2-carbonitrile RT (M4) = 4.min [M+H]+ (ESI+) 532.3 1 pH ״° N ؟ N،M Compound 7-5 3-[3-[(2R)-2-[(lR)-l-hydroxyethyl]-2- methyl-pyrrolidine- 1 -carbonyl] -8- methoxy- 1 -propyl-5 ,6-dihydropyrrolo[2,l-a!]isoquinolin-9- yl]pyridine-2-carbonitrile RT (M2) = 0.min [M+H]+ (ESI+) 499.7 1HC ؛؛ - ’ N JUU'nx J Compound 7-6 [8-methoxy-9-(2-methyltetrazol-5-yl)- -(2-thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-3-yl]-[(27?)-2-methyl-2- [(l،2,2,2-(؟-trifluoro- 1 -hydroxy- ethyl]pyrrolidin- 1 -yl]methanone RT (M4) = 3.min [M+H]+ (ESI+) 573.2 1h JUU^0 ; f^f Compound 7-7 (27?)-l-[9-(l//-imidazol-2-yl)-8- methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2, 1-،2]isoquinoline-3 - carbonyl] -2-methyl-pyrrolidine-2- carbonitrile RT (M4) = 2.min [M+H]+ (ESI+) 484.3 WO 2024/184461 PCT/EP2024/056026 Compound 7-8 (27?)-l-[8-methoxy-9-(2- methyltetrazol-5-yl)- 1 -(2-thienyl)-5,6- dihydropyrrolo[2,l-a!]isoquinoline-3- carbonyl] -2-methyl-pyrrolidine-2- carbonitrile RT (M4) = 3.min [M+H]+ (ESI+) 500.2 Compound 7-9 (27?)-l-[8-methoxy-9-(2-methyltetrazol-5-yl)- 1 -propyl-5,6- dihydropyrrolo[2,l-،2]isoquinoline-3- carbonyl] -2-methyl-pyrrolidine-2- carbonitrile RT(M4) = 3.min [M+H]+ (ESI+) 460.1 1- 9HN? T I/n-vt M-N c / ל׳ y v Compound 7-10 [(2R)-2-[(lR)-l-hydroxyethyl]-2- methyl-pyrrolidin- 1 -yl] - [8 -methoxy-9- (2-methyltetrazol-5-yl)- 1 -(2-thienyl)- 5,6-dihydropyrrolo[2,l-a ؛]isoquinolin- 3-yl] methanone RT (M4) = 3.min [M+H]+ (ESI+) 519.1 1,N JUO^0 =' Vf^f Compound 7-11 (27?)-l-[8-methoxy-9-(2- methyltetrazol-5-yl)- 1 -(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl]-2-methyl- pyrrolidine-2-carbonitrile RT (M4) = 3.min [M+H]+ (ESI+) 500.1 1N JUUx ״° . OH ל-" ynjV F Compound 7-12 [(57?)-8-methoxy-5-methyl-9-(2- methyltetrazol-5-yl)- 1 -(2-thienyl)-5,6- dihydropyrrolo[2,l-،2]isoquinolin-3- yl]-[(2S)-2-methyl-2-[(17?)-2,2,2- trifluoro- 1 -hydroxy-ethyl]pyrro lidin- 1-yl] methanone RT (M4) = 4.min [M+H]+ (ESI+) 587.4 WO 2024/184461 PCT/EP2024/056026 1؛<״ = ״° n ׳ XJL ״ n ' V °F Compound 7-13 [(57?)-8-methoxy-5-methyl-9-(2- methyltetrazol-5-yl)- 1 -thiazol-5-yl- 5,6-dihydropyrrolo[2, 1-،2]isoquinolin- 3-yl]-[(27?)-2-methyl-2-[(15)-2,2,2- trifluoro- 1 -hydroxy-ethyl]pyrro lidin- 1-yl] methanone RT (M5) = 3.min [M+H]+ (ESI+) 588.3 /ox/x/x - ״° NJUUn .

N Compound 7-14 (27?)-l-[8-methoxy-9-(2-methyltetrazol-5-yl)- 1 -thiazol-5-yl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carbonyl]-2-methyl- pyrrolidine-2-carbonitrile RT (M4) = 2.min [M+H]+ (ESI+) 501.2 N IIIV ־־־ n ؛/-^ nQ cf3 cf3 Compound 7-15 (7?)-3-(3-(2-cyano-2-methylpyrrolidine- 1 -carbonyl)-8- methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2, 1-a]isoquinolin-9- yl)-5-(trifluoromethyl)picolinonitrile RT (M36) = 3.min [M+H]+ (ESI+) 588.3 /)x^v^, f T 1 ,9n 17 v!vn u cf3 Compound 7-16 (/?)-1 -(8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-1 -(2,2,2-trifluoroethyl)- 5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl)-2- methylazetidine-2-carbonitrile RT (M24) = 2.min [M+H]+ (ESI+) 489.1 /Ox^x/XT T 1 O OH » | ! , sA r^F ؟،? n-n /-y/ H F VN Compound 7-17 (8-methoxy-9-(2-methyl-2H-tetrazol- 5-yl)- 1 -(1,3,4-thiadiazol-2-yl)-5,6- dihydropyrrolo[2, 1-a]isoquinolin-3- yl)((5)-2-methyl-2-((7?)-2,2,2- trifluoro- 1 -hydroxyethyl)pyrro lidin- 1 - yl)methanone RT(M36) = 2.min [M+H]+ (ESI+) 575.3 WO 2024/184461 PCT/EP2024/056026 nJUU, ״° - V LApz ו־ך /f״! F Compound 7-18 (R)-l-(l-(3,3-difluorocyclobutyl)-8- methoxy-9-(2-methyl-2H-tetr azol-5- yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl)-2- methylpyrrolidine-2-carbonitrile RT (M36) = 3.min [M+H]+ (ESI+) 508.3 ,° ו ן 11 n-n sV^ U' V Compound 7-19 (R)-1 -(8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-l-(thiophen-2-yl)-5,6- dihydropyrrolo[2, 1-a]isoquinoline-3- carbonyl)-2-methylazetidine-2- carbonitrile RT (M24) = 2.min [M+H]+ (ESI+) 486.1 N § - N N' // Zx F Compound 7-20 (R)-l-(l-(5-fluoropyridin-2-yl)-8- methoxy-9-(2-methyl-2H-tetr azol-5- yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl)-2- methylpyrrolidine-2-carbonitrile RT (M36) = 2.min [M+H]+ (ESI+) 513.2 nJzU.j’ -n;1 LTnP / zP f' Compound 7-21 (/?)-1 -(1 -(4-fluorophenyl)-8-methoxy- 9-(2-methyl-2H-tetrazol-5-yl)-5 ,6- dihydropyrrolo[2, 1-a]isoquinoline-3- carbonyl)-2-methylpyrrolidine-2- carbonitrile RT(M24) = 3.min [M+H]+ (ESI+) 512.1 T T 1 O OH Compound 7-22 ((7?)-8-methoxy-5-methyl-9-(2- methyl-2H-tetrazol-5-yl)- 1 -(thiophen- 2-yl)-5,6-dihydropyrrolo[2,l- a]isoquinolin-3-yl)((R)-2-methyl-2-- 1-2,2,2 - trifluoro ))،؟(-hydroxyethyl )pyrro lidin- 1 - yl)methanone RT (M35) = 3.min [M+H]+ (ESI+) 587.2 WO 2024/184461 PCT/EP2024/056026 N^XK3j -9hJ w /7 N—(S)C/ F Fh 2n^o fVf Compound 7-23 -((/?)-8-methoxy-5-methyl-3-((/?)-2- methyl-2-((،2,2,2-( ؟-trifluoro- 1 - hydroxyethyl )pyrrolidine- 1 -carbonyl)- l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2, 1-a]isoquinolin-9- yl)nicotinamide RT(M35) = 2.= min [M+H]+ (ESI+) 625.0 N 1OH ؛ ITT( J v H 'PM1 ^fVfF F Compound 7-24 3-((7?)-8-methoxy-5-methyl-3-((7?)-2- methyl-2-((S)-2,2,2-trifluoro- 1 - hydroxyethyl )pyrrolidine- 1 -carbonyl)- l-(2,2,2-trifluoroethyl)-5,6-dihy dropyrrolo[2, 1-a]isoquinolin-9- yl)picolinonitrile RT(M35) = 3.min [M+H]+ (ESI+) 607.3 1Nyu3G° yh ys ^Yf Yf F F Compound 7-25 ((7?)-8-methoxy-5-methyl-9-(2- methyl-2H-tetrazol-5-yl)- 1 -(2,2,2- trifluoroethyl)-5,6-dihydrop yrrolo[2, 1 -a]isoquinolin-3 -yl)((7?)-2- methyl-2-((S)-2,2,2-trifluoro- 1 - hydroxyethyl )pyrro lidin- 1 - yl)methanone RT (M25) = 2.min [M+H]+ (ESI+) 587.2 T T (R) ° °HN" TN'N S-V l > F FV Compound 7-26 ((1 a7?,9b/?)-8-methoxy-7-(2-methyl- 2H-tetrazol-5-yl)-5-(thiophen-2-yl)- la,9b-dihydro-lH- cyclopropa[c]pyrrolo[2, 1 - a]isoquinolin-3-yl)((7?)-2-methyl-2- ((،S)-2,2,2-trifluoro- 1 - hydroxyethyl)pyrrolidin- 1 - yl)methanone RT(M13) = 3.min [M+H]+ (ESI+) 585.2 WO 2024/184461 PCT/EP2024/056026 II T 1 o HQ !rw Compound 7-27 [(2R)-2-[(17?)-l-hydroxyethyl]-2-methyl-pyrrolidin- 1 -yl] - [8 -methoxy-9- (2-methyltetrazol-5 -yl)- 1 -thiazol-5 -yl- 5,6-dihydropyrrolo[2,l-a ؛]isoquinolin- 3-yl] methanone RT (M4) = 2.min [M+H]+ (ESI+) 520.2 * OH > CT n^f Compound 7-28 [8-methoxy-9-(2-methyltetrazol-5-yl)- -(2-thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-3-yl]-[(2 lS)-2-methyl-2- [(1 R)-2,2,2-trifluoro- 1 -hydroxy- ethyl]pyrrolidin- 1 -yl]methanone RT (M4) = 3.min [M+H]+ (ESI+) 573.2 T T 1 0 ^JAf NA N11 ״ W // OEt N'N /־׳ OBn ethyl 1 -(1 -(benzyloxy)-2-methylpropan-2-yl)-8-methoxy-9-(2- methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2, 1-a]isoquinoline-3- carboxylate RT (M34) = 0.min [M+H]+ (ESI+) 516.4 p U/ouVf /F ethyl l-(2,2-difluoropropyl)-8- methoxy-9-(2-methyl-2H-tetr azol-5- yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carboxylate RT(M29) = 1.min [M-Et]+ (ESI+) 404.2 WO 2024/184461 PCT/EP2024/056026

[00330] Synthetic Method 8

[00331] Scheme for Method 8 Cmp 8-1

[00332] Step 1, Method 8

[00333]A solution of (27?)-l-[9-bromo-8-methoxy-l-(2-thienyl)-5,6-dihydropynolo[2,l- o ؛]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile (600 mg, 1.2 mmol, synthesized by method 6), l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (334 mg, 1.mmol, CAS 1020174-04-2), dicaesium carbonate (1.58 g, 4.8 mmol, CAS 534-17-8) in 1,4- dioxane (15 mL) and water (6 mL) was degassed with nitrogen. XPhos Pd G2 (190 mg, 121 umol, CAS 1310584-14-5) was added and the reaction mixture was heated to 80 °C for 2 h. The mixture was allowed to cool to rt, poured into water (50 mL) and extracted with DCM (3 x 50 mL). The organic phases were combined, passed through a phase separator and concentrated in vacuo. The compound was purified by FCC (0-100% EtOAC in heptane) to give a brown solid which was further purified by reverse phase FCC (10-100% MeCN in water). Product containing fractions were concentrated in vacuo, freeze dried and dried in vacuum oven over the weekend to give (27?)- 1-[8-methoxy-9-( 1-methylpyrazol-3-yl)-1 -(2-thienyl)-5,6-dihydropyrrolo[2, 1-،2]isoquinoline-3- carbonyl]-2-methyl-pyrrolidine-2-carbonitrile (Compound 8-1) (349 mg, 57% yield) as a white solid. RT (M4) = 3.82 min [M+H]+ (ES1+) 498.3; 1H NMR (400 MHz, DMSO) 6 8.09 (s, 1H), 7.(d, J=2.1 Hz, 1H), 7.50 (dd, J= 3.8, 2.6 Hz, 1H), 7.12 - 7.09 (m, 2H), 7.06 (s, 1H), 6.72 (s, 1H), 6.52 (d, J =22 Hz, 1H), 4.51-4.37 (m, 1H), 4.34-4.20 (m, 1H), 3.94 -3.88 (m, 1H), 3.87 (s, WO 2024/184461 PCT/EP2024/056026 3H), 3.85 - 3.78 (m, 1H), 3.76 (s, 3H), 3.06 (t, J= 6.4 Hz, 2H), 2.48 - 2.42 (m, 1H), 2.20 - 2.(m, 1H), 2.05 - 1.87 (m, 2H), 1.74 (s, 3H).

[00334]The following analogs were made by analogous method: Structure Name LCMS HN'N 0 2^ / )V Compound 8-2 (27?)-l-[8-methoxy-9-(177-pyrazol-3- yl)- 1 -(2-thienyl)-5,6-dihydropyrrolo[2,l-a!]isoquinohne-3- carbonyl]-2-methyl-pyrrolidine-2- carbonitrile RT (M4) = 3.min [M+H]+ (ESI+) 484.2 1<^r^V>X0 1-^ pl At Compound 8-3 (27?)-1 -[ 1 -(4-fluorophenyl)-8- methoxy-9-(l-methylpyrazol-3-yl)- 5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2-methyl- pyrrolidine-2-carbonitrile RT (M4) = 3.min [M+H]+ (ESI+) 510.3 /-PCQU0 l^n ! Compound 8-4 (27?)-1 -[8-methoxy-9-( 1 - methylpyrazol-3-yl)-1 -propyl-5,6- dihydropyrrolo[2, 1-،2]isoquinoline-3- carbonyl]-2-methyl-pyrrolidine-2- carbonitrile RT (M4) = 3.min [M+H]+ (ESI+) 458.3 1» = PHJUr — Compound 8-5 4-[3-[(27?)-2-[(17?)-l-hydroxyethyl]- 2-methyl-pyrrolidine- 1 -carbonyl] -8-methoxy- 1 -propyl-5,6-dihydropyrrolo[2, 1 -«] isoquinolin-9- yl] -1 -methyl -pyridin-2-one RT (M4) = 3.min [M+H]+ (ESI+) 504.4 WO 2024/184461 PCT/EP2024/056026 1ph ؛ I jN 7^ N־^HN'n V Compound 8-6 [(27?)-2-[(17?)-l-hydroxyethyl]-2-methyl-pyrrolidin- 1 -yl]-[8-methoxy- 9-( 1/7-pyr azol-3-yl)-l-(2-thienyl)- 5,6-dihydropyrrolo[2,l-،2]isoquinolin- 3-yl] methanone RT (M4) = 3.min [M+H]+ (ESI+) 503.3 1CK-N^A^Au 5 ; pHT J A v 'n —C> F Compound 8-7 6-[8-methoxy-3-[(2R)-2-methyl-2- [(1 S)-2,2,2-trifluoro- 1 -hydroxy- ethyl]pyrrolidine- 1 -carbonyl] -1 -(2- thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-9-yl]-l//-pyridin-2-one RT (M4) = 3.min [M+H]+ (ESI+) 584.2 1o^^Jl^LA n z PH 3_/-^ Compound 8-8 4-[3-[(27?)-2-[(17?)-l-hydroxyethyl]-2-methyl-pyrrolidine- 1 -carbonyl] -8- methoxy- 1 -(2-thienyl)-5,6-dihydropyrrolo[2, 1 -«] isoquinolin-9- yl] -1 -methyl -pyridin-2-one RT (M4) = 3.min [M+H]+ (ESI+) 544.3 N 1III 3x/X^x .AJCCO = V /^FF Compound 8-9 3 - [3 - [(27?)-2-cyano-2-methyl- pyrrolidine- 1 -carbonyl] -8 -methoxy--(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2, 1 -«] isoquinolin-9-yl]pyridine-2-carbonitrile RT (M4) = 3.71 min [M+Na] + (ESI+)542.2 1 /AAA N = pH Compound 8-10 [(5_Z?)-8-methoxy-5-methyl-9-(l- methylpyrazol-3-yl)-1 -thiazol-5-yl- 5,6-dihydropyrrolo[2, 1-،2]isoquinolin- -yl] - [(27?)-2-methyl-2- [(1 S)-2,2,2- trifluoro- 1 -hydroxy-ethyl]pyrrolidin- -yl] methanone RT (M4) = 3.min [M+H]+ (ESI+) 586.2 WO 2024/184461 PCT/EP2024/056026 Bl* ° N'n e 1 1' V Compound 8-11 (R)-1 -(8-methoxy-9-( 1 -methyl- 1H- pyrazol-3-yl)-l-(thiophen-2-yl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl)-2-methylazetidine-2- carbonitrile RT(M36) = 3.min [M+H]+ (ESI+) 484.2 X y N7^n -־n / ts>' 0 Compound 8-12 (7?)-l-((S*)-8-methoxy-6-methyl-9-(1 -methyl- 1 H-pyrazol-3 -yl)- 1 -(thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl)-2-methylpyrrolidine-2- carbonitrile RT (M36) = 3.min [M+H]+ (ESI+) 512.3 T T I O OH /xAX/NJ =F vXX^^ Compound 8-13 ((R)-8-methoxy-5-methyl-9-(l- methyl- 1 H-pyrazol-3-yl)- 1 - (thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3- yl)((R)-2-methyl-2-((S)-2,2,2- trifluoro- 1 -hydroxyethyl)pyrrolidin- -yl)methanone RT(M35) = 3.min [M+H]+ (ESI+) 585.2 H ؟ ° N ׳ v Compound 8-14 ((R)-2-((R)-1 -hydroxyethyl)-2- methylpyrrolidin- 1 -yl)((S)-8- methoxy- 5 -methyl-9-( 1 -methyl- 1H- pyrazol-3-yl)-l-(thiophen-2-yl)-5,6- dihydropyrrolo[2,l-a]isoquinolin-3- yl)methanone RT (M35) = 2.min [M+H]+ (ESI+) 531.2 WO 2024/184461 PCT/EP2024/056026 * Denotes unknown stereochemistry, isolated from a diastereomeric mixture using SFC Y Y 0 OH N—RE M'N F F V Compound 8-15 ((1 a/?,9b/?)-8-methoxy-7-(l-methyl- H-pyrazol-3 -yl)-5 -(thiophen-2-yl)- la,9b-dihydro-lH- cyclopropa[c]pyrrolo[2,l- a]isoquinolin-3-yl)((/?)-2-mcthyl-2-- 1-2,2,2 - tri fluoro ))،؟(-hydroxyethyl)pyrrolidin- 1 - yl)methanone RT (M25) = 2.min [M+H]+ (ESC) 583.2 1 T 1 0 OH lY. F N-N/-I Na)”) KF / H V F v Compound 8-16 (8 -methoxy-9-( 1 -methyl- 1 H-pyrazol- -yl)- 1 -(1,3,4-thiadiazol-2-yl)-5 ,6- dihydropyrrolo[2,l-a]isoquinolin-3- yl)((S)-2-methyl-2-((R)-2,2,2- trifluoro- 1 -hydroxyethyl)pyrrolidin- -yl)methanone RT (M36) = 2.min [M+H]+ (ESC) 573.3/574.3 chromatography

[00335] Synthetic Method 9

[00336] Scheme for Method 9 Cmp 9-1

[00337] Step 1, Method 9

[00338]4,4,5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (234 mg, 922 umol, CAS 73183-34-3), [9-bromo-8-methoxy-l-(2-thienyl)-5,6-dihydropyrrolo[2, 1-«]isoquinolin-3-yl]-[(2/?)-2-[( 1 /?)-1-hydroxyethyl]-2-methyl-pyrrolidin- 1 - WO 2024/184461 PCT/EP2024/056026 yl]methanone (540 mg, 838 pmol, synthesized by method 4) and potassium acetate (208 mg, 2.mmol, CAS 127-08-2) were dissolved in anhydrous 1,4-dioxane (8 mL) and the mixture degassed with N2. [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (68 mg, 84 umol, CAS 95464-05-4) was added and the reaction mixture was stirred at 90 °C overnight. The reaction mixture was cooled, concentrated in vacuo and partitioned between DCM and water. The organic layer was separated, dried through a phase separator cartridge and concentrated in vacuo to give the crude product. The crude was purified by FCC (silica, eluting with 0-100% EtOAc in heptane). Product containing fractions were combined and concentrated in vacuo to give [(27?)-2-[(17?)-l-hydroxyethyl]-2-methyl-pyrrolidin-l-yl]-[8- methoxy-9-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)- 1 -(2-thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-3-yl]methanone (230 mg, 44% yield) as a brown solid. RT (M5) = 1.02 min [M+H]+ (ESI)+ 563.5; 1H NMR (500 MHz, DMSO) 6 7.67 (s, 1H), 7.49 - 7.46 (m, 1H), 7.07 - 7.01 (m, 2H), 6.91 (s, 1H), 6.52 (s, 1H), 4.98 (d, J= 4.8 Hz, 1H), 4.47 - 4.40 (m, 1H), 4.34 - 4.27 (m, 1H), 4.11 - 4.04 (m, 1H), 3.85 - 3.79 (m, 1H), 3.75 (s, 3H), 3.67 - 3.60 (m, 1H), 3.02 (t, J = 6.5 Hz, 2H), 2.10 - 2.02 (m, 1H), 1.80 - 1.69 (m, 2H), 1.56 - 1.51 (m, 1H), 1.51 (s, 3H), 1.17 (s, 12H), 1.00 (d, J=6A Hz, 3H).

[00339] Step 2, Method 9

[00340] A solution of [(2R)-2-[(lR)-l-hydroxyethyl]-2-methyl-pyrrolidin-l-yl]-[8-methoxy-9-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)- 1 -(2-thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-3-yl]methanone (110 mg, 176 umol), tert-butyl 2-bromoimidazole-l-carboxylate (52 mg, 211 umol, CAS 1207457-15-5), dicaesium carbonate (229 mg, 704 umol, CAS 534-17-8) in 1,4-dioxane (2 mL) and water (680 pL) was degassed with N2. XPhos Pd G2 (28 mg, 18 umol, CAS 1310584-14-5) was added, the reaction heated to 80 °C and stirred overnight. The reaction was cooled to rt and concentrated in vacuo. The resulting residue was diluted with water and extracted with DCM (3x10 mL). The combined organic extracts were concentrated in vacuo and purified by acidic prep HPLC (P3). Product containing fractions were concentrated in vacuo and freeze dried to give [(2R)-2-[(lR) -l-hydroxyethyl]-2-methyl-pynolidin-l-yl]-[9-(l/7-imidazol-2- yl)-8-methoxy- 1 -(2-thienyl)-5,6-dihydropyrrolo[2, 1 -،2]isoquinolin-3-yl]methanone (Compound WO 2024/184461 PCT/EP2024/056026 9-1) (13 mg, 14% yield) as a white solid. RT (M4) = 2.1 min [M+H]+(ESI+) 503.3; 1H NMR (5MHz, DMSO) 6 11.68 (s, 1H), 8.36 (s, 1H), 7.48-7.43 (m, lH),7.13(s, 1H), 7.11 -7.04 (m, 3H), 6.89 (s, 1H), 6.54 (s, 1H), 4.99 (s, 1H), 4.49 - 4.41 (m, 1H), 4.37 - 4.29 (m, 1H), 4.13 - 4.04 (m, 1H), 3.97 (s, 3H), 3.87 - 3.79 (m, 1H), 3.69 - 3.62 (m, 1H), 3.05 (t, J= 6.4 Hz, 2H), 2.12 - 2.(m, 1H), 1.83 - 1.70 (m, 2H), 1.58- 1.53 (m, 1H), 1.52 (s, 3H), 1.02 (d,J=6.3 Hz, 3H).

[00341]The following analog was made by analogous method: Structure Name LCMS N--^ ''Cnh Compound 9-2 (2R)-l-[9-(l//-imidazol-2-yl)-8- methoxy- 1 -(2-thienyl)-5,6- dihydropyrrolo[2, 1-،2]isoquinoline-3- carbonyl]-2-methyl-pyrrolidine-2- carbonitrile RT(M4) = 2.min [M+H]+ (ESI+) 484.3

[00342] Synthetic Method 10

[00343] Scheme for Method 10 Pd(dppf)CI2 PhOCHO NEt3 DMF LION IMF it HATU DIPEA DCM/DMF

[00344] Step 1, Method 10

[00345]In a 20 mL pressure tube, a stirred solution of (2R)-l-[9-bromo-8-methoxy-l-(2- thienyl)-5,6-dihydropyrrolo[2,l-o ؛]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile(300 mg, 604 umol, synthesized by method 6), phenyl formate (340 pL, 3.0 mmol, CAS 1864-94--189- WO 2024/184461 PCT/EP2024/056026 4) and triethylamine (420 pL, 3.0 mmol, CAS 121-44-8) in anhydrous DMF (5 mL) was degassed with nitrogen for 5 min. [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44 mg, 60 umol, CAS 72287-26-4) was added, the solution degassed with nitrogen for 5 min and heated to 100 °C for 4 h. The reaction mixture was cooled to rt, the CO released slowly and then purged with nitrogen. The mixture was concentrated in vacuo, diluted with water (5 mL) and extracted with dichloromethane (3x5 mL). The combined organic extracts were concentrated in vacuo to afford a residue that was purified by FCC (silica, eluting with 0-100% EtOAc in heptane) to give phenyl 3-[(27?)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l-(2-thienyl)-5,6- dihydropyrrolo[2,l-a!]isoquinoline-9-carboxylate (280 mg, 78% yield) as a brown solid. RT (M2) = 1.05 min, (ESI+) (M+H)+ 538.2; 1HNMR (500 MHz, DMSO-d6) 3 7.99 (s, 1H), 7.54 - 7.50 (m, 1H), 7.46 - 7.41 (m, 2H), 7.30 - 7.23 (m, 2H), 7.13 - 7.03 (m, 4H), 6.75 (s, 1H), 4.50 - 4.43 (m, 1H), 4.35 - 4.28 (m, 1H), 3.92 - 3.85 (m, 4H), 3.86 - 3.77 (m, 1H), 3.17 (t, J= 6.7 Hz, 2H), 2.-2.09(m, 1H), 2.03- 1.99 (m, 1H), 1.95 - 1.85 (m, 1H), 1.75 (s, 3H), 1.67- 1.53 (m, 1H).

[00346] Step 2, Method 10

[00347] 2 M lithium hydroxide hydrate aq. (1.4 mL, 2.8 mmol) was added to a stirred solutionof phenyl 3-[(2R)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy- 1-(2-thienyl)-5, 6-dihydropyrrolo[2,l-a!]isoquinoline-9-carboxylate (90% purity, 280 mg, 469 umol) in THE (mL) at rt and the reaction mixture stirred overnight. The reaction mixture was concentrated in vacuo, acidified to pH 1 with 1 M aq HC1 and extracted with EtOAc (3x10 mL). The organics were combined, passed through a phase separator cartridge and concentrated in vacuo to give 3- [(2R)-2-cyano-2-methyl-pyrrolidine- 1 -carbonyl] -8-methoxy- 1 -(2-thienyl)-5,6- dihydropyrrolo[2,l-،2]isoquinoline-9-carboxylic acid (80% purity, 270 mg, 100% yield) as a brown solid. RT (M2) = 0.83 min, (ESI+) (M+H)+ 462.2.

[00348] Step 3, Method 10

[00349]HATU (111 mg, 293 umol, CAS 148893-10-1) and 1-aminocyclobutanecarbonitrile hydrochloride (1:1) (31 mg, 234 umol, CAS 845821-84-3) were added to a stirred solution of 3- [(2R)-2-cyano-2-methyl-pyrrolidine- 1 -carbonyl] -8-methoxy- 1 -(2-thienyl)-5,6-dihydropyrrolo[2,l-a!]isoquinoline-9-carboxylic acid (90 mg, 195 umol) and DIPEA (140 pL, 7 WO 2024/184461 PCT/EP2024/056026 pmol, CAS 7087-68-5) in DCM (4 mL) and anhydrous DMF (400 pL) at rt and the reaction mixture stirred overnight. The reaction mixture was poured into water (3 mL) and extracted with DCM (3x3 mL). The organic phases were combined, passed through a phase separator and concentrated in vacuo. The crude was purified by acidic prep HPLC (Method P2) and the product- containing fractions freeze dried to giveN-(1-cyanocyclobuty1)-3-[(2R)-2-cyano-2-methyl- pyrrolidine-1-carbonyl]-8-mcthoxy-1 -(2-thicnyl)-5,6-dihydropyrrolo[2, 1 -،/]isoquinolinc-9- carboxamide (Compound 10-1) (36 mg, 34% yield) as a white solid. RT (M4) = 3.76 min, (ESI+) (M+H)+ 540.3; 1H NMR (500 MHz, DMSO-d6) 8 8.73 (s, 1H), 7.79 (s, 1H), 7.53 (dd, J= 5.0, 1.Hz, 1H), 7.19 (s, 1H), 7.13 - 7.07 (m, 2H), 6.73 (s, 1H), 4.43 (dt, J = 13.2, 6.6 Hz, 1H), 4.28 (dt, J= 12.9, 6.2 Hz, 1H), 3.92 (s, 3H), 3.91-3.76 (m, 2H), 3.12 (t, J=6.6 Hz, 2H), 2.71 -2.58 (m, 2H), 2.54 - 2.52 (m, 1H), 2.34 (ddd, J= 12.9, 9.4, 7.7 Hz, 2H), 2.14 (ddd, J= 12.7, 10.1, 5.9 Hz, 1H), 2.08 - 1.86 (m, 4H), 1.75 (s, 3H).

[00350]The following analogs were made by analogous method: Structure Name LCMS Vttl=.

FZ Compound 10-2 TV-( 1-cyano- 1-methyl-ethyl)-3-[(2R)- 2-cyano-2-methyl-pyrrolidine- 1 - carbonyl]- 1 -(4-fluorophenyl)-8- methoxy-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide RT (M4) = 3.81 min, (ESI+) (M+H)+540.2 ؛ AKC9 FZ Compound 10-3 3-[(2R)-2-cyano-2-methyl- pyrrolidine- 1 -carbonyl] -1 -(4- fluorophenyl)-8-methoxy-7V-(2-oxo- l//-pyridin-3-yl)-5,6- dihydropyrrolo[2, 1 -«] isoquinoline-9- carboxamide RT (M4) = 3.53 min, (ESI+) (M+H)+566.2 WO 2024/184461 PCT/EP2024/056026 u 8 A* FZ Compound 10-4 3-[(27?)-2-cyano-2-methyl- pyrrolidine- 1 -carbonyl] -1 -(4- fluorophenyl)-8 -methoxy-7V-( 1 - methyl-2-oxo-3-pyridyl)-5,6- dihydropyrrolo[2, 1 -«] isoquinoline-9- carboxamide RT (M4) = 3.79 min, (ESI+) (M+H)+580.2 0 * Compound 10-5 3-[(27?)-2-cyano-2-methyl- pyrrolidine- 1 -carbonyl] -8 -methoxy- ;V-(2-oxo- 1 H-pyridin-3-yl)-1 -propyl- 5,6-dihydropyrrolo[2,l- a]isoquinoline-9-carboxamide RT (M4) = 3.48 min, (ESI+) (M+H)+514.3 v Compound 10-6 3-[(27?)-2-cyano-2-methyl- pyrrolidine- 1 -carbonyl] -8 -methoxy- TV-( 1 -methyl-2-oxo-3 -pyridyl)- 1 - propyl-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide RT (M4) = 3.79 min, (ESI+) (M+H)+528.3 Compound 10-7 TV-( 1-cyano- 1-methyl-ethyl)-3 -[(27?)- 2-[( 17?)-1 -hydroxyethyl] -2-methyl- pyrrolidine- 1 -carbonyl] -8 -methoxy- -propyl-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide RT (M4) = 3.89 min, (ESI+) (M+H)+507.7 /O.^. P H° O o Compound 10-8 7V-(l-cyanocyclobutyl)-3-[(27?)-2- [(17?)-1 -hydroxyethyl] -2-methyl- pyrrolidine- 1 -carbonyl] -8 -methoxy- -propyl-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide RT (M4) = 3.97 min, (ESI+) (M+H)+519.3 WO 2024/184461 PCT/EP2024/056026 Nx H Y^l 1 ° Compound 10-9 TV-( 1-cyano- 1-methyl-ethyl)-3 -[(27?)- 2-cyano-2-methyl-pyrrolidine- 1 - carbonyl]-8-methoxy- 1 -propyl-5,6- dihydropyrrolo[2, 1 -a]isoquino line-9- carboxamide RT (M4) = 3.80 min, (ESI+) (M+H)+488.3 0 ך ךז 0 m x,ujuvvT i 1I V Compound 10-10 7V-[2-(dimethylamino)-2-oxo-ethyl]- 3-[(27?)-2-(hydroxymethyl)-2-methyl- pyrrolidine- 1 -carbonyl] -8 -methoxy- -(2-thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide RT (M4) = 2.97 min, (ESI+) (M+H)+551.3 n-n h 11 1ך o n jLn 1 Y IPn° 0 Compound 10-11 3 -(2,2-dimethylpyrrolidine- 1 - carbonyl )-8-methoxy-.V-( 1 H-tetrazol- -ylmethyl)- 1 -(2-thienyl)-5 ,6- dihydropyrrolo[2, 1 -a]isoquino line-9- carboxamide RT (M4) = 3.46 min, (ESI+) (M+H)+532.3 /O^ySx/X 0h n I 1 0 U ° AO Compound 10-12 3-[(27?)-2-cyano-2-methyl- pyrrolidine- 1 -carbonyl] -8 -methoxy- TV-( l-methyl-2-oxo-3-pyridyl)- 1-(2- thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide RT (M4) = 3.64 min, (ESI+) (M+H)+568.2 /Ox/^x/ O M II T 1 0 ajjvvvJ HU 3/A20 Compound 10-13 3-[(27?)-2-cyano-2-methyl- pyrrolidine- 1 -carbonyl] -8 -methoxy- 7V-(2-oxo- l//-pyridin-3-yl)- 1 -(2- thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide RT (M4) = 3.35 min, (ESI+) (M+H)+554.2 WO 2024/184461 PCT/EP2024/056026 p h°CF3 ؟/~ I if H /L# n-¥ s~Z / V Compound 10-14 TV-( 1 -cyano- 1 -methyl-ethyl)-8- methoxy-3-[(27?)-2-methyl-2-[(l >S)- 2,2,2-trifluoro- 1 -hydroxy- ethyl]pyrrolidine- 1 -carbonyl] -1 -(2- thienyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-9-carboxamide RT (M4) = 3.91 min, (ESI+) (M+H)+601.3 /°x//Xn^S<^x/^xn P h0'<> T ץ yA x/-ch 3X/ O KJ n-T Compound 10-15 TV-(l-cyanocyclobutyl)-3-[(27?)-2- [(17?)-1 -hydroxyethyl] -2-methyl- pyrrolidine- 1 -carbonyl] -8 -methoxy- -(2-thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide RT (M4) = 3.68 min, (ESI+) (M+H)+559.3 h 11 1X Compound 10-16 TV-( 1-cyano- 1-methyl-ethyl)-3 -[(27?)- 2-[( 17?)-1 -hydroxyethyl] -2-methyl- pyrrolidine- 1 -carbonyl] -8 -methoxy- -(2-thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide RT (M4) = 3.61 min, (ESI+) (M+H)+547.3 Nx HT o״ gH/ 0 ~J' n —r" Compound 10-17 TV1 )-־ -cyanocyclobutyl)- 1 -(4- fluorophenyl)-3 - [(27?)-2- [(17?)-1 - hydroxyethyl]-2-methyl-pyrrolidine- -carbonyl]-8-methoxy-5, 6- dihydropyrrolo[2, 1 -a]isoquino line-9- carboxamide RT (M4) = 3.82 min, (ESI+) (M+H)+571.3 /Ox/x/x?״ ؛ EA.AAnO " ' 0 Vj' N—Xv Compound 10-18 TV-( 1 -cyano- 1 -methyl-ethyl)- 1 -(4- fluorophenyl)-3 - [(27?)-2- [(17?)-1 - hydroxyethyl]-2-methyl-pyrrolidine- -carbonyl]-8-methoxy-5, 6- dihydropyrrolo[2, 1 -a]isoquino line-9- carboxamide RT (M4) = 3.74 min, (ESI+) (M+H)+559.3 WO 2024/184461 PCT/EP2024/056026 p h°CF3 ؟/~ Y if h ^L# n-¥ s~Z / V Compound 10-19 TV1 )-־ -cyanocyclopropyl)-8-methoxy- 3-[(27?)-2-methyl-2-[(lS)-2,2,2- trifluoro- 1 -hydroxy- ethyl]pyrrolidine- 1 -carbonyl] -1 -(2- thienyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-9-carboxamide RT (M4) = 3.78 min, (ESI+) (M+H)+599.2 ,A/v _ P h0' Tץ >A ^/-ch 3 O KJ n-T Compound 10-20 7V-(l-cyanocyclopropyl)-3-[(27?)-2- [(17?)-1 -hydroxyethyl] -2-methyl- pyrrolidine- 1 -carbonyl] -8 -methoxy- -(2-thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide RT (M4) = 3.44 min, (ESI+) (M+H)+545.4 0 HQ ؛؛ TXnXJ u Compound 10-21 8-methoxy-7V-(l -methyl-2-oxo-3- pyridyl)-3-[(27?)-2-methyl-2-[(l >S)- 2,2,2-trifluoro- 1 -hydroxy- ethyl]pyrrolidine- 1 -carbonyl] -1 -(2- thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide RT (M4) = 3.91 min, (ESI+) (M+H)+641.3 P H0' 0 c Compound 10-22 7V-(l-cyanocyclobutyl)-8-methoxy-3- [(27?)-2-methyl-2-[(lS)-2,2,2- trifluoro- 1 -hydroxy- ethyl]pyrrolidine- 1 -carbonyl] -1 -(2- thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide RT (M4) = 4.02 min, (ESI+)(M+H)+613.3 /0X^X/X 'Xn^CQ P V 0 A Compound 10-23 7V-(l-cyanocyclobutyl)-3-[(27?)-2- [(17?)-1 -hydroxyethyl] -2-methyl- pyrrolidine- 1 -carbonyl] -8 -methoxy- -(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2, 1 -a]isoquino line-9- carboxamide RT (M5) = 3.61 min, (ESI+) (M+H)+559.4 WO 2024/184461 PCT/EP2024/056026 N Compound 10-24 TV-(l-cyanocyclobutyl)-3-[(27?)-2- cyano-2-methyl-pyrrolidine-1 - carbonyl]- 1 -(4-fluorophenyl)-8- methoxy-5,6-dihydropyrrolo[2,l- a]isoquinoline-9-carboxamide RT (M4) = 3.88 min, (ESI+) (M+H)+552.3 /Ox/XNx H Y 15Y^x n 0 HQ 0! Compound 10-25 TV-(3-cyanooxetan-3-yl)-8-methoxy- 3-[(27?)-2-methyl-2-[(lS)-2,2,2- trifluoro- 1 -hydroxy- ethyl]pyrrolidine- 1 -carbonyl] -1 -(2- thienyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-9-carboxamide RT (M4) = 3.87 min, (ESI+) (M+H)+615.1 /0x/ ?a ° Compound 10-26 TV-(3 -cyanooxetan-3 -yl)-3 - [(2/? )-2- [(17?)-1 -hydroxyethyl] -2-methyl- pyrrolidine- 1 -carbonyl] -8 -methoxy- -(2-thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide RT (M5) = 3.45 min, (ESI+) (M+H)+561.4 /0X^X/xNx H V ן ךזYAU.. /O L/N—or r Compound 10-27 TV-( 1-cyano- 1-methyl-ethyl)-3 -[(27?)- 2-cyano-2-methyl-pyrrolidine- 1 - carbonyl]-8-methoxy- 1 -(2-thienyl)- 5,6-dihydropyrrolo[2 ,1 - a]isoquinoline-9-carboxamide RT (M5) = 3.66 min, (ESI+) (M+H)+528.4 /°x/X /xNx H Y^T 1/ ؛ NYr0NyY 0 ^ Compound 10-28 3-[(27?)-2-cyano-2-methyl- pyrrolidine-1-carbonyl]-TV-[(37?*)-3- cyanotetrahydro furan- 3 -yl] -8 - methoxy- 1 -(2-thienyl)-5,6- dihydropyrrolo[2, 1 -a]isoquino line-9- carboxamide RT (M4) = 3.65 min, (ESI+) (M+H)+556.1 WO 2024/184461 PCT/EP2024/056026 Nx h YY 1 cr Compound 10-29 3-[(27?)-2-cyano-2-methyl-pyrrolidine- 1 -carbonyl]-N-[(3S*)-3- cyanotetrahydro furan- 3 -yl] -8 - methoxy- 1 -(2-thienyl)-5,6- dihydropyrrolo[2, 1 -a]isoquino line-9- carboxamide RT (M4) = 3.64 min, (ESI+) (M+H)+556.1 A/. ,Nx H T ^YnY^x nvY°'' / °0 YA Compound 10-30 3-[(27?)-2-cyano-2-methyl- pyrrolidine- 1 -carbonyl] -Y-(3- cyanooxetan-3-yl)-8-methoxy- 1 - (2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2, 1 -a]isoquino line-9- carboxamide RT (M4) = 3.39 min, (ESI+) (M+H)+542.2 "xX, o yj nYX Compound 10-31 7V-(l-cyanocyclopropyl)-3-[(27?)-2- cyano-2-methyl-pyrrolidine-1 - carbonyl] - 8 -methoxy- 1 - (2,2,2 - trifluoroethyl)-5 ,6- dihydropyrrolo[2, 1 -a]isoquino line-9- carboxamide RT (M5) = 3.48 min, (ESI+) (M+H)+526.4 /Ox/X/ N^< ti T T י °؟ Q 0 JYT n Compound 10-32 7V-(l-cyanocyclobutyl)-3-[(27?)-2- cyano-2-methyl-pyrrolidine-1 - carbonyl]-8-methoxy- 1 -propyl-5,6- dihydropyrrolo[2, 1 -a]isoquino line-9- carboxamide RT (M4) = 4.00 min, (ESI+) (M+H)+500.1 Li T T י oV ° Compound 10-33 3-[(27?)-2-cyano-2-methyl- pyrrolidine- 1 -carbonyl] -7V-(3- cyanooxetan-3-yl)-8-methoxy- 1 - propyl-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide RT (M4) = 3.71 min, (ESI+) (M+H)+502.1 WO 2024/184461 PCT/EP2024/056026 N v ° s J-OV d v Compound 10-34 3-[(2R)-2-cyano-2-methyl- pyrrolidine- 1 -carbonyl] -7V-(3- cyanooxetan-3-yl)-8-methoxy- 1 -(2- thienyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-9-carboxamide RT (M4) = 3.63 min, (ESI+) (M+H)+542.1 li 1! T । °O 0 11sN Compound 10-35 7V-(l-cyanocyclobutyl)-3-[(2R)-2- cyano-2-methyl-pyrrolidine-1 - carbonyl]-8-methoxy- 1 -thiazol-5-yl- 5,6-dihydropyrrolo[2 ,1 - a]isoquinoline-9-carboxamide RT (M4) = 3.21 min, (ESI+) (M+H)+541.2 VfF F ethyl (7?)-8-methoxy-5-methyl-9-((l- methyl-2-oxo-1 ,2-dihydropyridin-3yl)carba moyl)-l -(2,2,2-trifluoroethyl)-5 ,6-dihydropyrrolo[2,l-a]isoquinoline-3- carboxylate RT (M30) = 0.57 min, (ESI+) (M+H)+518.3 u H T T 1 0l jr 5 ' N—cf3 Compound 10-36 (7?)-3-(2-cyano-2-methylazetidine- 1 - carbonyl)-8-methoxy-N-(l-methyl-2- oxo- 1,2-dihydropyridin-3 -yl)- 1 - (2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-9- carboxamide RT (M28) = 2.60 min, (ESI+) (M+H)+554.2 0 /0y^x/WAAN2 . M 1 y^ ״cf3 Compound 10-37 (7?)-3-(2-cyano-2-methylazetidine- 1 - carbonyl)-8-methoxy-N-(2-oxo-l,2- dihydropyridin-3 -yl)- 1 -(2,2,2- trifluoroethyl)-5 ,6- dihydropyrrolo[2, 1 -a]isoquinoline-9- carboxamide RT (M24) = 2.80 min, (ESI+) (M+H)+540.1 WO 2024/184461 PCT/EP2024/056026 H T Y 1 0 OH / 0 XX"' NACK X °׳ Compound 10-38 N- (1 - cyanocyclobutyl) - 8 -methoxy- 3 - ((S)-2-methyl-2-((R)-2, 2,2-tri fluoro- -hydroxy ethyl) pyrrolidine- 1 - carbonyl)- 1 -(1,3,4-thiadiazol-2-yl)- 5,6-dihydropyrrolo[2,l- a]isoquinoline-9-carboxamide RT (M36) = 2.85 min, (ESI+) (M+H)+615.3 JbJCQ,0 -O s U/NPENC> Compound 10-39 (7?)-3-(2-cyano-2-methylazetidine- 1 - carbonyl)-N-( 1 -cyanocyclobutyl)-8- methoxy- 1 -(thiophen-2-yl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-9- carboxamide RT (M24) = 3.09 min, (ESI+) (M+H)+526.0 "KLPA2 y ״ Compound 10-40 (،S'*)-N-(l-cyanocyclobutyl)-3-((R)-2-((7?)-1 -hydroxyethyl)-2-methylpyrrolidine- 1 -carbonyl)-8-methoxy-6-methyl-1 -(thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide RT (M35) = 3.02 min, (ESI+) (M+H)+573.3 ALPA C> Compound 10-41 (S*)-3-((R)-2-cyano-2- methylpyrrolidine- 1 -carbonyl)-N-( 1 - cyanocyclobutyl) - 8 -methoxy-6 - methyl- 1 -(thiophen-2-yl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-9- carboxamide RT (M39) = 2.12 min, (ESI+) (M+H)+554.1 H ؟ ؛ Compound 10-42 (R)-N-( 1 -cyanocyclobutyl)-3-((R)-2- ((R)-1 -hydroxyethyl)-2- methylpyrrolidine- 1 -carbonyl)-8- methoxy- 5 -methyl- 1 -(thiophen-2-yl)- 5,6-dihydropyrrolo[2 ,1 - a]isoquinoline-9-carboxamide RT (M35) = 3.99 min, (ESI+) (M+H)+573.3 WO 2024/184461 PCT/EP2024/056026 h T T । ס oh<3> 0 y־״ p Ap Compound 10-43 (7?)-N-( 1 -cyanocyclobutyl)-8- methoxy-5-methyl-3-((R)-2-methyl- 2-((S)-2,2,2-trifluoro-l- hydroxyethyl)pyrrolidine- 1 - carbonyl)- 1 -(thiophen-2-yl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-9- carboxamide RT (M36) = 3.35 min, (ESI+) (M+H)+627.3 = °H O 0 s Compound 10-44 (،؟)-N-(l-cyanocyclobutyl)-3-((R)-2-((??)-1 -hydroxyethyl)-2-methylpyrrolidine- 1 -carbonyl)-8-methoxy- 5 -methyl- 1 -(thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide RT (M35) = 2.98 min, (ESI+) (M+H)+573.3 /Ox/^VX'^- QH o = Compound 10-45 (4S)-N-(1-cyanocyclobutyl)-?- methoxy-4-methyl-3-((7?)-2-methyl- 2-((5)-2,2,2-trifluoro-l- hydroxyethyl)pyrrolidine- 1 -carbonyl)- 1 -(thiophen-2-yl)-3 a, 5 - dihydro-4H-cyclopenta[a]naphthalene-8- carboxamide RT (M35) = 3.16 min, (ESI+) (M+H)+627.2 JUO $ =<5 s (T Compound 10-46 (.S)-3-((J?)-2-cyano-2-methylpyrrolidine- 1 -carbonyl)-N-( 1 - cyanocyclobutyl)-8-methoxy-5 - methyl- 1 -(thiophen-2-yl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-9- carboxamide RT (M36) = 3.25 min, (ESI+) (M+H)+554.3 WO 2024/184461 PCT/EP2024/056026 * Denotes unknown stereochemistry, isolated N^n^XX/N j? - 5Af Compound 10-47 (7?)-N-( 1 -cyanocyclobutyl)-8- methoxy-5-methyl-3-((R)-2-methyl- 2-((S)-2,2,2-tri fluoro- 1- hydroxyethyl)pyrrolidine- 1 - carbonyl)- 1 -(2,2,2-trifluoroethyl)- 5,6-dihydropyrrolo[2 ,1 - a]isoquinoline-9-carboxamide RT (M39) = 2.93 min, (ESI+) (M+H)+627.2 H ؟ =O oV Compound 10-48 (laR,9bR)-N-(l-cyanocyclobutyl)-8- methoxy-3-((R)-2-methyl-2-((، ؟)- 2,2,2-trifluoro-1- hydroxyethyl)pyrrolidine- 1 - carbonyl)-5 -(thiophen-2-yl)-1 a,9b- dihydro-1H- cyclopropa[c]pyrrolo[2,l- a]isoquinoline-7-carboxamide RT (M36) = 3.29 min, (ESI+) (M+H)+625.3 from a diastereomeric mixture using SFCchromatography

[00351] Synthetic Method 11

[00352] Scheme for Method 11

[00353] Step !,Method 11

[00354]In a 40 mL pressure tube, a solution of (2lS)-l-[9-bromo-8-methoxy-l-(thiophen-2-yl)- 5H,6H-pyrrolo[2,l -،؛/]isoquinolinc-3-carbonyl]-2-cthyl-2-mcthylpyrrolidinc (94% purity, 390 mg, WO 2024/184461 PCT/EP2024/056026 671 pmol, synthesized from method 2) in anhydrous DMF (5 mL) was degassed with nitrogen for min. Phenyl formate (340 pL, 3.1 mmol, CAS 1864-94-4), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (45 mg, 62 umol, CAS 72287-26-4) and triethylamine (430 pL, 3.1 mmol, 121-44-8) were added and the reaction mixture was heated to 100 °C for 3 h 30 min. The reaction mixture was cooled to rt and the CO released under vacuum. The pressure tube was evacuated and refilled with N2 3 times and the reaction mixture concentrated in vacuo. The resulting residue was partitioned between DCM (20 mL) and water (30 mL) and extracted with DCM (2 x 20 mL). The organics were combined and the solvent removed in vacuo to give the crude product as a brown oil, which was purified by FCC (silica, eluting with 0-100% EtOAc in heptane) to give phenyl 3-[(2،S)-2-ethyl-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l- (2-thienyl)-5,6-dihydropyrrolo[2,l-o ؛]isoquinoline-9-carboxylate (86% purity, 206 mg, 62% yield) as a brown oil. RT (M2) =1.21 min, (ESI+) (M+H)+ 541.3; 1HNMR (500 MHz, DMSO-d6) 3 7.(s, 1H), 7.50 (dd,J= 5.1, 1.2 Hz, 1H), 7.46-7.40(m, 2H), 7.29-7.25(m, 1H),7.23 (s, 1H), 7.(dd, J=3.5, 1.2 Hz, 1H), 7.08 - 7.04 (m, 3H), 6.56 (s, 1H), 4.40 - 4.30 (m, 1H), 4.23-4.11 (m, 1H), 3.89 (s, 3H), 3.80 - 3.73 (m, 1H), 3.70 - 3.59 (m, 1H), 3.13 (t, J= 6.5 Hz, 2H), 2.15 - 2.(m, 1H), 1.97 - 1.91 (m, 1H), 1.85 - 1.71 (m, 3H), 1.68 - 1.56 (m, 1H), 1.46 (s, 3H), 0.89 - 0.(m, 3H).

[00355] Step 2, Method 11

[00356]A,A-dimethylglycinamide (25 mg, 246 pmol, CAS 1857-19-8) and dicaesium carbonate (112 mg, 345 pmol, CAS 534-17-8) were added to a stirred solution of phenyl 3-[(2S)- 2-ethyl-2-methyl-cyclopentanecarbonyl]-8-methoxy-l-(2-thienyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-9-carboxylate (86% purity, 103 mg, 164 pmol) in anhydrous DMF (2 mL) at rt. The mixture was warmed to 70 °C and stirred for 5 h 30 min before being cooled to rt and left to stir at rt over the weekend period. The reaction mixture was warmed to 70 °C and stirred for 51 h. The reaction mixture was concentrated in vacuo, DCM (20 mL) and water (20 mL) were added and the layers separated. The aqueous was washed with DCM (2 x 20 mL). The organics were combined, passed through a phase separator and concentrated in vacuo to give the crude product as a brown oil. The crude product was purified by acidic prep HPLC (Method P2) and the product WO 2024/184461 PCT/EP2024/056026 containing fractions freeze dried to give 7V-[2-(dimethylamino)-2-oxo-ethyl]-3-[(2 lS)-2-ethyl-2- methyl-pyrrolidine- 1 -carbonyl] -8-methoxy- 1 -(2-thienyl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline- 9-carboxamide (Compound 11-1) (29 mg, 32% yield) as an off-white solid. RT (M4) = 3.83 min, (ESI+) (M+H)+ 549.3; 1H NMR (500 MHz, DMSO-d6) 5 8.63 (t, J = 4.4 Hz, 1H), 8.19 (s, 1H), 7.47 (dd, J = 5.1, 1.2 Hz, 1H), 7.18 (s, 1H), 7.06 (dd, J = 5.1, 3.5 Hz, 1H), 7.04 (dd, J = 3.5, 1.Hz, 1H), 6.52 (s, 1H), 4.39-4.28 (m, 1H), 4.18-4.07 (m, 3H), 3.97 (s, 3H), 3.81 - 3.73 (m, 1H), 3.71 - 3.60 (m, 1H), 3.08 (t, J= 6.4 Hz, 2H), 2.95 (s, 3H), 2.87 (s, 3H), 2.16 - 2.06 (m, 1H), 2.- 1.90 (m, 1H), 1.78 (dp, J= 13.6,7.1 Hz, 3H), 1.66- 1.59 (m, 1H), 1.46 (s, 3H), 0.82 (t, J=1A Hz, 3H).

[00357] Synthetic Method 12 XPhos Rd G2dioxane °CH2O/EtOH 80°C

[00359] Step 1, Method 12

[00360]l-Methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l//-pyrazole (1.59 g, 7.mmol, CAS 1020174-04-2), caesium carbonate (6.63 g, 20.4 mmol CAS 534-17-8) and XPhos Pd G2 (400 mg, 509 umol, CAS 1310584-14-5) was added to a solution of ethyl 9-bromo-8-methoxy- l-(2-thienyl)-5,6-dihydropyrrolo[2,l-o ؛]isoquinoline-3-carboxylate (2.20 g, 5.1 mmol, synthesized by method 1) in 1,4-dioxane (60 mL) and water (30 mL). The reaction mixture was degassed with nitrogen and heated to 80 °C for 2 hours. The reaction mixture was allowed to cool to rt, poured into water (20 mL) and extracted with DCM (3 x 20 mL). The organic phases were combined, passed through a phase separator and concentrated in vacuo. The resulting residue was purified by FCC (silica, eluting with 0-100% EtOAc in heptane). Product containing fractions were

[00358] Scheme for Method 12 WO 2024/184461 PCT/EP2024/056026 concentrated in vacuo to give ethyl 8-methoxy-9-(l-methylpyrazol-3-yl)-l-(2-thienyl)-5,6- dihydropyrrolo[2,l-a!]isoquinoline-3-carboxylate (2.11 g, 94% yield) as a brown solid. RT (M2) = 1.08 [M+H]+(ESI+) 434.3

[00361] Step 2, Method 12

[00362]To a solution of potassium hydroxide (1.11 g, 19.5 mmol) in water (15 mL) was added ethyl 8-mcthoxy-9-( 1 -mcthylpyrazol-3-yl)- 1-(2-thicnyl)-5,6-dihydropyrrolo[2, 1 -،؛/]isoquinolinc- 3-carboxylate (2.11 g, 4.9 mmol) in ethanol (45 mL). The resultant suspension was heated to °C forming a solution and stirred overnight. The reaction mixture was cooled to rt, concentrated in vacuo and acidified to pH l with 1M aq. HCI. The acidic aqueous was extracted with DCM (x 20 mL). The organics were combined and passed through a phase separator cartridge. Some product precipitated on the cartridge. The filtrate was collected together with the concentrated organics to give 8-methoxy-9-(l-methylpyrazol-3-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxylic acid (1.71 g, 82% yield) as a brown solid. RT (M2) = 0.83 [M+H]+ (ESI+) 406.2; 1H NMR (400 MHz, DMSO) 6 12.43 (s, 1H), 8.09 (s, 1H), 7.60 (d, J= 2.1 Hz, 1H), 7.50 (dd, J= 3.8, 2.6 Hz, 1H), 7.12 - 7.08 (m, 2H), 7.07 (s, 1H), 6.87 (s, 1H), 6.52 (d, J= 2.2 Hz, 1H), 4.55 (t, J= 6.5 Hz, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 3.08 (t, J= 6.5 Hz, 2H).

[00363]The following analogs were made by analogous method: Structure Name LCMS y T/oh/ < 8-methoxy-9-(l -methyl- 177-pyrazol-3-yl)- -propyl-5/7,6/7-pynolo[2, 1 -a]isoquinoline-3-carboxylic acid RT (M2) = 0.min, (ESI+) (M+H)+366.2 003,° f' 1 -(4-fluorophenyl)-8-m ethoxy-9-( 1 - methyl- 177-pyrazol-3-yl )-577,677- pyrrolo[2,l-a!]isoquinoline-3-carboxylic acid RT (M2) = 0.min, (ESI+) (M+H)+418.3 WO 2024/184461 PCT/EP2024/056026 JCO,! N 8-methoxy-9-( 1 -methylpyrazol-3 -yl)- 1 - thiazol-5 -yl-5,6-dihydropyrrolo [2,1- a]isoquinoline-3-carboxylic acid RT (M2) = 0.min, (ESI+)(M+H)+407.2 WO 2024/184461 PCT/EP2024/056026

[00364] Synthetic Method 13 HATU DIPEA Cmp 13-1

[00366] Step 1, Method 13

[00367]DIPEA (1.3 mL, 7.3 mmol, CAS 1205744-09-7), HATU (1.03 g, 2.7 mmol, CAS 148893-10-1) and (U?)-l-[(2R)-2-methylpynolidin-2-yl]ethanol hydrochloride (360 mg, 2.mmol, synthesized by method 15) were added to a stirred solution of 8-methoxy-9-(l- methylpyrazol-3-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a!]isoquinoline-3-carboxyhc acid (7mg, 1.8 mmol, synthesized by method 12) in DCM (20 mL) at rt. After 24 h, the reaction mixture was retreated with (U?)-l-[(2R)-2-methylpyrrolidin-2-yl]ethanol hydrochloride (360 mg, 2.mmol) and DIPEA (1.3 mL, 7.3 mmol) and stirred for a further 2 days. The reaction mixture was diluted with DCM (20 mL) and water (20 mL), the organic phase passed through a phase separator and then concentrated in vacuo to yield the crude product as a brown oil. The crude was then purified by FCC (silica, eluting with 30-100% EtOAc in heptane). Product-containing fractions were collected, combined and the solvent removed in vacuo to yield a brown oil which was further purified by acidic prep HPLC (Method P2). Product containing fractions were collected, combined and the solvent removed in vacuo to give [(2R)-2-[(lR)-l-hydroxyethyl]-2-methyl-pyrrolidin-l- yl]-[8-methoxy-9-( 1-methylpyrazol-3-yl)- 1-(2-thienyl)-5,6-dihydropyrrolo[2, 1 -،؛/]isoquinolin-3- yl]methanone (Compound 13-1) (415 mg, 44% yield) as a white solid. RT (M4) = 3.69 min [M+H]+(ESI+) 517.3; ؛HNMR(500 MHz, DMSO) 6 8.08 (s, 1H), 7.60 (d, J=2.1 Hz, 1H), 7.- 7.44 (m, 1H), 7.12 - 7.06 (m, 2H), 7.03 (s, 1H), 6.53 (s, 1H), 6.52 (d, J= 2.2 Hz, 1H), 4.99 (d, J = 4.8 Hz, 1H),4.51 -4.40(m, 1H), 4.38-4.26 (m, 1H), 4.16-4.03 (m, 1H), 3.93 - 3.79 (m, 4H), 3.76 (s, 3H), 3.69 - 3.59 (m, 1H), 3.03 (t, J = 6.4 Hz, 2H), 2.14 - 1.99 (m, 1H), 1.87 - 1.67 (m, 2H), 1.59 - 1.45 (m, 4H), 1.01 (d, J = 6.3 Hz, 3H).

[00365] Scheme for Method 13 WO 2024/184461 PCT/EP2024/056026

[00368]The following analogs were made by analogous method: Structure Name LCMS 1 || T 1 0 HQ n-n 1 ) Compound 13-2 [8-methoxy-9-(l-methylpyrazol-3-yl)- -(2-thienyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-3-yl]-[(27?)-2-methyl-2- [(lS)-2,2,2-trifluoro- 1 -hydroxy- ethyl]pyrrolidin- 1 -yl]methanone RT (M5) = 3.min [M+H]+ (ESI+) 571.4 co hv ؛ x ^ Compound 13-3 [(2R)-2-[( IS)-1 -hydroxyethyl] -2- methyl-pyrroli din- 1 -yl] - [8 -methoxy-9- (1 -methylpyrazol-3 -yl)- 1 -propyl-5 ,6- dihydropyrrolo[2,l-a!]isoquinolin-3- yl] methanone RT(M4) = 4.min [M+H]+ (ESI+) 477.4 1o ho ו ץ ץ^A^Ax^N A Compound 13-4 [ 1 -(4-fluorophenyl)-8-methoxy-9-( 1 - methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,l-a!]isoquinolin-3-yl]- [(2S)-2-methyl-2-[(17?)-2, 2,2-tri fluoro- -hydroxy-ethyl]pyrro lidin- 1 - yl] methanone RT (M4) = 4.min [M+H]+ (ESI+) 583.3 JCu j ״vא n n-N'n _ / / /=< Vz Compound 13-5 [ 1 -(4-fluorophenyl)-8-methoxy-9-( 1 - methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,l-a!]isoquinolin-3-yl]- [(27?)-2-[( IS)-1 -hydroxyethyl] -2- methyl-pyrroli din-1 -yl]methanone RT (M4) = 3.min [M+H]+ (ESI+) 529.3 WO 2024/184461 PCT/EP2024/056026 10x/Ss/X ג N N- N'N _/ /=< V/M f' Compound 13-6 [ 1 -(4-fluorophenyl)-8-methoxy-9-( 1 -methylpyrazol-3-yl)-5,6-dihydropynolo[2,l-a!]isoquinolin-3-yl]- [(27?)-2- [(17?)-1 -hydroxyethyl] -2-methyl-pyrroli din-1 -yl]methanone RT (M4) = 3.min [M+H]+ (ESI+) 529.3 1 0X^x/ /xJULO .?h N / N'n __ / / /=< ،x/ M V Compound 13-7 [ 1 -(4-fluorophenyl)-8-methoxy-9-( 1 - methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,l-،2]isoquinolin-3-yl]- [(2S)-2-[( 1S)-1 -hydroxyethyl] -2- methyl-pyrroli din-1 -yl]methanone RT (M4) = 3.min [M+H]+ (ESI+) 529.3 1 1 0 ho ן ץ_Cf3 Compound 13-8 [(2S)-2-[( 1S)-1 -hydroxyethyl] -2- methyl-pyrroli din- 1 -yl] - [8 -methoxy-9- (1 -methylpyrazol-3 -yl)- 1 -(2-thienyl)- 5,6-dihydropyrrolo[2, 1-،2]isoquinolin- 3-yl] methanone RT (M4) = 3.min [M+H]+ (ESI+) 571.1 1 ״JUUL? , ?״ E Compound 13-9 [ 1 -(4-fluorophenyl)-8-methoxy-9-(2- methyltetr azol-5-yl)-5, 6-dihydropyrrolo[2, 1-o ؛]isoquinolin-3-yl]- [(2lS)-2-methyl-2-[(17?)-2,2,2-trifluoro- -hydroxy-ethyl]pyrrolidin- 1 - yl] methanone RT (M4) = 3.min [M+H]+ (ESI+) 583.3 WO 2024/184461 PCT/EP2024/056026 H CH ؟ , ° nJXL ״ / /=< x/ Compound 13-10 [ 1 -(4-fluorophenyl)-8-methoxy-9-(2-methyltetr azol-5-yl)-5, 6-dihydropynolo[2,l-a!]isoquinolin-3-yl]- [(2S)-2- [(15*)-1 -hydroxypropyl] -2- methyl-pyrroli din-1 -yl]methanone RT (M4) = 4.min [M+H]+ (ESI+) 545.5 1III ,° oh n -vx Xtu . Y N" T / /־־׳ __ N'n/ /5X W F Compound 13-11 [ 1 -(4-fluorophenyl)-8-methoxy-9-(2-methyltetr azol-5-yl)-5, 6-dihydropyrrolo[2, 1-o ؛]isoquinolin-3-yl]- [(2S)-2-[( 1S)-1 -hydroxyethyl] -2- methyl-pyrroli din-1 -yl]methanone RT (M4) = 3.min [M+H]+ (ESI+) 531.3 ؟ 9 , 1 Ll/-/A^ VNH2< s v ؛؛ vN (27?)-1 -[8-methoxy-9-( 1 - methylpyrazol-3-yl)-1 -thiazol-5-yl-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-3 - carbonyl] -2-methyl-pyrrolidine-2- carboxamide RT (M2) = 0.min [M+H]+ (ESI+) 517.2 Vn IL/n °z * methyl 2-ethyl- 1 -[8-methoxy-9-(l - methylpyrazol-3 -yl)- 1 -(2-thienyl)-5,6- dihydropyrrolo[2, 1-a]isoquinoline-3- carbonyl]pyrrolidine-2-carboxylate RT(M2) = 1.min [M+H]+ (ESI+) 545.2 , JOQx n 11 y J N—7™)'ML,N-N /—7 |__P nh 2/ ( (/?)-1 -(8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-l-propyl-5,6- dihydropyrrolo[2, 1-a]isoquinoline-3- carbonyl)-2-methylazetidine-2- carboxamide RT(M16) = 0.86 min [M+H]+(ESI+)464.3 WO 2024/184461 PCT/EP2024/056026 1 o ho ץ ץn "N M-M v Compound 13-12 (R*>2-(R*>cyclopropyl(hydroxy)methyl)-2-methylpyrrolidin- 1 -yl) (1 - (4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5 ,6-dihydropyrrolo[2, 1-a]isoquinolin-3- yl)methanone RT (M2 8) = 3.17 min [M+H]+(ESL)557.3 n 17 //n-n l—nh 2/ /aW (R)-1 -(1 -(4-fluorophenyl)-8-methoxy- 9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2, 1-a]isoquinoline-3- carbonyl)-2-methylazetidine-2- carboxamide RT(M13) = 1.53 min [M+H]+(ESL) 516.3

[00369] Synthetic Method 14

[00370] Scheme for Method 14 - OH CbzCI Na2COHCI HN/ ---------------L^y dcm rt Swern oxidation KO*BuEt 2OP Br Ph

[00371] Step 1, Method 14

[00372]Cbz-Cl (3.1 mL, 21.8 mmol, CAS 501-53-1) was added drop wise to a stirring mixture of [(2lS)-2-methylpyrrolidin-2-yl]methanol hydrochloride (3.00 g, 19.8 mmol, CAS 1408057-43- 1), 2 M sodium carbonate (35.0 mL, 69.2 mmol) and DCM (45 mL) at 0 °C. The reaction was -210- WO 2024/184461 PCT/EP2024/056026 stirred and allowed to warm to rt overnight. The reaction mixture was diluted with DCM and water, then the layers separated. The aqueous was extracted with further DCM, the combined organic passed through a phase separator and then concentrated. The material was purified by FCC (Silica, eluting 0-100% EtOAc in heptane) to give benzyl (2lS)-2-(hydroxymethyl)-2-methyl-pyrrolidine- 1-carboxylate (3.82 g, 76% yield) as a colorless oil. RT (M2) = 0.80 min [M+H]+ (ES1+) 250.2

[00373] Step 2, Method 14

[00374]Oxalyl chloride (3.8 mL, 44.0 mmol, CAS 79-37-8) was dissolved in DCM (92 mL) and cooled to -78 °C. DMSO (6.3 mL, 88.5 mmol) was added dropwise and the reaction stirred at -78 °C for 10 min. Benzyl (2lS)-2-(hydroxymethyl)-2-methyl-pyrrolidine-l-carboxylate (3.00 g, 12.0 mmol) (as a solution in 5 mL DCM) was added, and stirred at -78 °C for min. Triethylamine (21.0 mL, 0.150 mol) was added dropwise and the reaction stirred at - °C for 3 h. The reaction was quenched by addition of water (20 mL), warmed to rt, diluted with DCM (20 mL) and saturated aq. NaHCO3 solution (50 mL) added. The aqueous was extracted into DCM (3 x 50 mL), dried over MgSO4 and concentrated under reduced pressure. The resulting oil was purified by FCC (silica, eluting 0-60% EtOAc in heptane) to give benzyl (2lS)-2-formyl-2- methyl-pyrrolidine- 1-carboxylate (2.13 g, 65% yield, 91% purity) as a colorless oil. RT (M2) = 0.87 min [M+H]+ (ES1+) 248.1.

[00375] Step 3, Method 14

[00376]Potassium t-butoxide (1.82 g, 16.2 mmol) was added to a suspension of methyl(triphenyl)phosphonium bromide (5.78 g, 16.2 mmol, CAS 1779-49-3) in diethyl ether (130 mL) and the reaction was stirred at rt for 2 h under N2. A solution of benzyl (2S)-2-formyl- 2-methyl-pyrrolidine-l-carboxylate (2.00 g, 8.1 mmol) in diethyl ether (20 mL) was then added dropwise. The reaction was then stirred for 2 h before it was diluted with heptane (50 mL) and filtered. The filtrand was washed with diethyl ether/heptane (1:2 mixture, 150 mL) and the combined filtrate was concentrated under reduced pressure. The resulting solid was purified by FCC (silica, eluting with 0-100% EtOAc in heptane) to give benzyl (2،2-(؟-methyl-2-vinyl- pyrrolidine- 1-carboxylate (1.64 g, 79% yield) as a colorless oil. RT (M2) = 1.01 min [M+H]+ (ES1+) 246.2.

WO 2024/184461 PCT/EP2024/056026

[00377] Step 4, Method 14

[00378]To a solution of benzyl (2lS)-2-methyl-2-vinyl-pyrrolidine-l-carboxylate (1.64 g, 6.mmol) in ethanol (65 mL) was added palladium on carbon (10%, 683 mg, 640 umol) under N2(g). The mixture was stirred under an atmosphere of H2(g) at rt for 4 h. The reaction mixture was filtered through Celite, washing with MeOH. To the filtrate was added 4 M HC1 in dioxane (3.mL, 13.4 mmol), stirred at rt for 10 min and then concentrated to give a yellow semi-solid. The residue was dissolved in DCM and concentrated (x3) to give (2،S)-2-ethyl-2-methyl-pyrrolidine hydrochloride (958 mg, 94% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 3 9.11 (br s, 1H), 8.94 (br s, 1H), 3.19 (s, 2H), 2.03 - 1.86 (m, 2H), 1.76 - 1.65 (m, 4H), 1.25 (br s, 3H), 0.(t, J=7.5 Hz, 3H).

WO 2024/184461 PCT/EP2024/056026

[00379] Synthetic Method 15

[00380] Scheme for Method 15 Swern oxidation MeMgBr THF -78°C - rt H2, Pd/C EtOH rt MCI H

[00381] Step 1, Method 15

[00382]Sodium triacetoxyborohydride (2.80 g, 13.2 mmol, CAS 56553-60-7) was added to a stirred solution of [(2R)-2-methylpyrrolidin-2-yl]methanol hydrochloride (1.25 g, 8.2 mmol, CAS 1408057-43-1) and benzaldehyde (1.0 mL, 9.9 mmol, CAS 100-52-7) in anhydrous THF (41 mL) at rt. The solution was stirred for 24 h. Sat. aq. NH4C1 was added (50 mL) and the resulting mixture was extracted with EtOAc (3 x 30 mL). The organic layers were combined, washed with sat. aq. NH4C1 (2 x 30 mL). The aqueous layers were combined, basified to pH 10 using sat. aq. Na2COsolution and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (30 mL), dried over Na2S04, filtered and the solvent removed in vacuo to give [(2/?)-1 -benzyl-2- methyl-pyrrolidin-2-yl]methanol (1.37 g, 6.0 mmol, 73% yield) as a pale yellow oil which was used without further purification. RT (M10) = 0.77 min [M+H]+ (ESI+) 206.2; 1HNMR (500 MHz, DMSO) 6 7.31 - 7.24 (m, 4H), 7.23 - 7.16 (m, 1H), 4.37 - 4.24 (m, 1H), 3.77 (d, J = 13.4 Hz, 1H),3.43 (d, J= 13.4 Hz, 1H), 3.32 - 3.29 (m, 2H), 2.70-2.61 (m, 1H), 2.43 (q, J=8.1 Hz, 1H), 1.91 - 1.82 (m, 1H), 1.69 - 1.54 (m, 2H), 1.51 - 1.41 (m, 1H), 1.00 (s, 3H).

[00383] Step 2, Method 15

[00384]Oxalyl chloride (5.0 mL, 58.3 mmol, CAS 79-37-8) was dissolved in DCM (70 mL) and cooled to -78 °C. DMSO (8.5 mL, 0.120 mol) was added dropwise and the reaction mixture WO 2024/184461 PCT/EP2024/056026 stirred at -78 °C for 30 min. [(27?)-l-benzyl-2-methyl-pynolidin-2-yl]methanol (3.38 g, 17.mmol) (as a solution in 10 mL DCM) was added, and the reaction mixture stirred at -78 °C for min. Triethylamine (27.0 mL, 0.194 mol, CAS 121-44-8) was added dropwise and the reaction stirred at -78 °C for 15 min before warming to rt and stirring overnight. The reaction mixture was quenched by addition of water (5 mL) and warmed to rt. DCM (10 mL) and sat. aq. NaHCO3 (mL) were added, the layers separated and the aqueous extracted with DCM (3 x 20 mL). The organics were combined, dried over MgSO4 and concentrated in vacuo. The resulting oil was purified by FCC (silica, eluting with 0-20% EtOAc in heptane) to give (27?)-l-benzyl-2-methyl- pyrrolidine-2-carbaldehyde (3.29 g, 81% Yield) as an orange oil. RT (M10) = 0.83 min [M+H]+ (ESI+) 204.4; 1H NMR (400 MHz, DMSO) 6 9.34 (s, 1H), 7.36 - 7.27 (m, 4H), 7.23 (ddt, J= 7.7, 5.7, 2.4 Hz, 1H), 3.63 - 3.51 (m, 2H), 2.86 (td, J = 8.6, 4.4 Hz, 1H), 2.62 - 2.54 (m, 1H), 2.(ddd, 12.5, 10.1,6.5 Hz, 1H), 1.90- 1.70 (m, 2H), 1.59- 1.49 (m, 1H), 1.09 (s, 3H).

[00385] Step 3, Method 15

[00386](2R)-l-benzyl-2-m ethyl -pyrrolidine-2-carbaldehyde (10.0 g, 49.2 mmol) was dissolved in anhydrous THF (106 mL) and cooled to 0 °C under N2. 3 M bromo(methyl)magnesium in ether (25 mL, 73.8 mmol, CAS 75-16-1) was added over 10 min and the reaction mixture was stirred for 30 min before warming to rt. The reaction mixture was quenched with sat. aq. NH4C1 and extracted with EtOAc (3 x 20 mL). The combined organics were dried (MgSO4) and concentrated in vacuo. The crude was purified by FCC (Cl8 silica, eluting with 0-100% EtOAc in heptane) to give (lR)-l-[(2R)-l-benzyl-2-methyl-pyrrolidin-2-yl]ethanol (6.9 g, 64% yield) as a colorless oil. 1H NMR (500 MHz, DMSO) 6 7.29 (d, J= 4.5 Hz, 4H), 7.(h, J=4.1 Hz, 1H), 4.38 (d, J =5.3 Hz, 1H), 3.99 (d, J = 13.5 Hz, 1H), 3.63 (p, J= 6.2 Hz, 1H), 3.23 (d, J = 13.5 Hz, 1H), 2.70 (td, J= 8.4, 2.6 Hz, 1H), 2.35 - 2.22 (m, 1H), 1.86 (ddd,J= 12.8, 9.9, 5.0 Hz, 1H), 1.67- 1.56 (m, 1H), 1.57 - 1.43 (m, 1H), 1.32 (ddd,J= 12.8,9.0, 7.0 Hz, 1H), 1.12 (d, J= 6.4 Hz, 3H), 1.04 (s, 3H). The minor diastereoisomer (l،؟)-l-[(2R)-l-benzyl-2-methyl- pyrrolidin-2-yl] ethanol (430 mg, 4% yield) was also isolated as a colorless oil. RT (M2) = 0.min [M+H]+ (ESI+) 220.2 WO 2024/184461 PCT/EP2024/056026

[00387] Step 4, Method 15

[00388]A solution of (17?)-1-[(27?)-l-benzyl-2-methyl-pyrrolidin-2-yl] ethanol (6.90 g, 31.mmol) and palladium on carbon (10%, 0.70 g, 658 umol, CAS 7440-05-3) in ethanol (200 mL) was stirred under an atmosphere of H2 at rt. After 18 h the reaction was stopped, filtered through a pad of Celite, cooled to 0 °C and 2 M HC1 in ether (15 mL, 62.9 mmol, CAS 7647-01-0) was added. The resulting solution was stirred for 10 min at 0 °C and allowed to warm to rt over 30 min. The solvent was removed in vacuo. The residual oil was dissolved in ethanol (200 mL), palladium on carbon (10%, 0.70 g, 658 umol, CAS 7440-05-3) added and the reaction stirred under a hydrogen atmosphere for a further 24 h. The mixture was filtered through a pad of celite, washed through with methanol (50 mL) and 2 M HC1 in ether (15 mL, 62.9 mmol, CAS 7647-01-0) was added. The solvent was removed in vacuo, and DCM added to the resultant oil and the mixture was concentrated in vacuo to give (17?)-l-[(27?)-2-methylpynolidin-2-yl]ethanol hydrochloride (3.50 g, 67% yield) as a light pink solid. 1H NMR (400 MHz, DMSO) 6 8.86 (s, 1H), 8.58 (s, 1H), 3.78 (q,J=6.4 Hz, 1H), 3.48 - 3.41 (m, 1H), 3.22 - 3.08 (m, 2H), 2.05 - 1.84 (m, 2H), 1.82- 1.72 (m, 1H), 1.69- 1.57 (m, 1H), 1.19 (s,3H), 1.09 (d, J= 6.4 Hz, 3H).

[00389]The following analogs were made by analogous method: Structure Name NMR HCIH ,NOH /؟،، (15)-l-[(27?)-2-methylpyrrolidin-2- yl]ethan-l-olhydrochloride 1HNMR (500 MHz, DMSO) 6 9.02 (s, 1H), 8.(s, 1H), 5.52 (d, J= 5.0 Hz, 1H), 3.84 - 3.73 (m, 1H), 3.25 - 3.09 (m, 2H), 2.08 - 1.80 (m, 3H), 1.63 - 1.53 (m, 1H), 1.21 (s, 3H), 1.10 (d, J = 6.4 Hz, 3H).

HCIHN >OH /؟،، (lS)-l-[(2S)-2- methylpyrrolidin-2- yl]ethan-l-ol hydrochloride 1HNMR(500 MHz, DMSO) 6 8.86 (s, 1H), 8.(s, 1H), 5.49 (s, 1H), 3.77 (q, J = 6.4 Hz, 1H), 3.24-3.11 (m, 2H), 2.06- 1.85 (m, 2H), 1.83- 1.73 (m, 1H), 1.70 - 1.60 (m, 1H), 1.19 (s, 3H), 1.09 (d, J =6.4 Hz, 3H).

WO 2024/184461 PCT/EP2024/056026 * Denotes unknown stereochemistry, isolated from a diastereomeric mixture using SFC HCI (15*)-l-[(2S)-2- methylpyrrolidin-2- yl]propan-l-ol hydrochloride 1H NMR (400 MHz, DMSO) 6 11.71 (s, 1H), 8.88 (s, 1H), 5.16 (t, J = 5.9 Hz, 1H), 4.41 (s, 1H), 3.74 - 3.70 (m, 1H), 3.22 - 3.09 (m, 1H), 2.25-2.12 (m, 1H), 2.08- 1.85 (m, 2H), 1.84- 1.72 (m, 1H), 1.47 - 1.37 (m, 1H), 1.33 - 1.(m, 1H), 1.19 (s, 3H), 0.99 (t, J =7.4 Hz, 3H).

OH HN-vr1_ AsA / (^*)-cyclopropyl- [(2S)-2- methylpyrrolidin-2- yl]methanol 1H NMR (400 MHz, CDCI3) 6 = 4.90 (q, J= 5.9 Hz, 1H), 3.08 (td, J= 6.7, 10.9 Hz, 1H), 2.98 - 2.81 (m, 3H), 1.37 - 1.31 (m, 3H), 1.30 - 1.23 (m, 4H), 0.95 - 0.78 (m, 3H), 0.67 - 0.(m, 1H), 0.58 - 0.46 (m, 3H), 0.43 - 0.26 (m, 3H), 0.17 (qd, J =4.8, 9.7 Hz, 1H) chromatography

[00390] Synthetic Method 16

[00391] Scheme for Method 16

[00392] Step 1, Method 16

[00393]Trimethyl(trifluoromethyl)silane (2.4 mL, 16.3 mmol, CAS 81290-20-2) in anhydrous THF (50 mL) was added to a flask containing (2/?)-l -benzyl-2-methyl-pyrrolidine-2-carbaldehyde (2.21 g, 10.9 mmol, synthesized by method 15, step 2) under N2. The reaction was cooled to 0 °C and tetrabutylammonium difluorotriphenylsilicate (60 mg, 0.11 mmol, CAS 163931-61-1) was added. The reaction was stirred at 0 °C for 1 h and then allowed to warm to rt. After stirring at rt WO 2024/184461 PCT/EP2024/056026 for l h, the reaction mixture was concentrated in vacuo, dissolved in DCM (3 mL) and 1M aq. HCI (8 mL), and stirred vigorously for 5 h. Sat. aq. NaHCO3 was added until pH 10 was reached, the layers separated and the aqueous extracted with DCM (10 x 25 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give a brown oil which was purified by FCC (silica, eluting with 0-100% EtOAc in heptane then 0-100% MeOH in EtOAc). Product containing fractions were concentrated in vacuo to give (lS)-l-[(27?)-l-benzyl-2-methyl- pyrrolidin-2-yl]-2,2,2-trifluoro-ethanol (960 mg, 32% yield) as a yellow oil. RT (M2) = 0.44 min [M+H]+ (ES1+) 274.1; 1H NMR (500 MHz, DMSO) 6 7.34 - 7.26 (m, 4H), 7.25 -7.16 (m, 1H), 6.31 (s, 1H), 4.15 (d, J= 13.4 Hz, 1H), 3.99 (q, J= 8.5 Hz, 1H), 3.31 (d, J= 13.4 Hz, 1H), 2.76- 2.68 (m, 1H), 2.30 (q, J= 8.5 Hz, 1H), 2.19-2.07 (m, 1H), 1.70- 1.60 (m, 1H), 1.60 - 1.53 (m, 1H), 1.53 - 1.45 (m, 1H), 1.15 (s, 3H).

[00394]Mixed fractions (containing minor diastereoisomer) were concentrated to give a colorless oil (625 mg), that was purified by FCC (silica, 0-100% DCM in heptane) to give (1R)- l-[(2R)-l-benzyl-2-methyl-pyrrolidin-2-yl]-2,2,2-trifluoro-ethanol (287 mg, 10% yield) as a colorless oil. 1H NMR (500 MHz, DMSO) 6 7.35 - 7.27 (m, 4H), 7.25 - 7.19 (m, 1H), 5.64 (s, 1H), 4.05 (q, J= 8.5 Hz, 1H), 3.92 (d, J= 13.3 Hz, 1H), 3.33 - 3.28 (m, 1H), 2.72 (td, J= 8.2, 3.Hz, 1H), 2.35 (q, J=8.1 Hz, 1H), 2.25-2.13 (m, 1H), 1.73 - 1.56 (m, 2H), 1.49- 1.38 (m, 1H), 1.12-1.10 (m, 3H).

[00395] Step 2, Method 16

[00396]A solution ofpalladium on carbon (10%, 234 mg, 220 umol, CAS 7440-05-3) and (IS)- l-[(2R)-l-benzyl-2-methyl-pyrrolidin-2-yl]-2,2,2-trifluoro-ethanol (300 mg, 1.1 mmol) in ethanol (7 mL) was stirred under an atmosphere of H2 at rt overnight. The reaction mixture was filtered through Celite washing with DCM (100 mL) and methanol (25 mL). 2 M HCI in diethyl ether (1.mL, 2.0 mmol, CAS 7647-01-0) was added to the filtrate and the mixture was allowed to stand for min before it was concentrated in vacuo to give (lS)-2,2,2-trifluoro-l-[(2R)-2-methylpyrrolidin- 2-yl]ethanol hydrochloride (240 mg, 95% yield) as a pink solid. 1H NMR (400 MHz, DMSO) 9.11 (s, 2H), 7.55 (d, J = 6.3 Hz, 1H), 4.57-4.34 (m, 1H), 3.28-3.16 (m, 2H), 2.16-1.93 (m, 3H), 1.93 - 1.74 (m, 1H), 1.29 (s, 3H).

WO 2024/184461 PCT/EP2024/056026

[00397]The following analogs were made by analogous method: Structure Name NMR HCI H N OH /؟< f3c (lR)-2,2,2-trifluoro-l-[(2R)- 2-methylpyrrolidin-2- yl]ethan-l-ol hydrochloride 1H NMR (400 MHz, DMSO) 6 9.19 (s, 2H), 7.35 (d, J = 6.7 Hz, 1H), 4.45 (s, 1H), 3.30 - 3.21 (m, 2H), 2.14 - 1.(m, 3H), 1.86 - 1.71 (m, 1H), 1.32 (s, 3H) HCI H N > /X^OH f3c (17?)-2,2,2-trifluoro-l-[(25)- 2-methylpyrrolidin-2- yl]ethan-l-ol hydrochloride 1H NMR (400 MHz, DMSO) 6 9.17 (s, 2H), 7.55 (d, J = 6.3 Hz, 1H), 4.57 - 4.42 (m, 1H), 3.27 - 3.14 (m, 2H), 2.- 1.91 (m, 3H), 1.89 - 1.75 (m, 1H), 1.29 (d, J = 1.6 Hz, 3H).

[00398] Synthetic Method 17

[00399] Scheme for Method 17

[00400] Step 1, Method 17

[00401]To a solution of ethyl 9-bromo-8-methoxy-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carboxylate (118 g, 336.94 mmol) in TFA (600 mL) was added with TFAA (353.84 g, 1.68 mol). The mixture was stirred at 80°C for 12 hr under N2 atmosphere. The mixture was concentrated, added with H20 (500 mL), solid Na2CO3 to adjust pH=8. The mixture was extracted with EtOAc WO 2024/184461 PCT/EP2024/056026 (300 mLx4). The organic layers were concentrated under reduced pressure to give a crude product, which was triturated with Petroleum ether (400 mL) at 20°C for 15 min and filtered. The solid was collected and dried under vacuum to afford ethyl 9-bromo-8-methoxy-l -(2,2,2- trifluoroacetyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate_(l 18 g, 78%) as a brown solid. RT (MH) = 2.20 min [M+H]+ (ESI+) 446.1/448.2.

[00402] Step 2, Method 17

[00403]To a solution of ethyl 9-bromo-8-methoxy-l-(2,2,2-trifluoroacetyl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate (90 g, 201.70 mmol) in THF (900 mL) was added with BH3.THF (1 M, 221.87 mL) at 0°C. The mixture was stirred at 25°C for 2 h under Natmosphere. 240 mL sat. NaHCO3 was added with and extracted with EtOAc (150 mLx3). The combined organic phase was washed with brine (100 mL), dried by Na2S04, filtered and concentrated in vacuum. The crude product was triturated with petroleum ether (100 mL) at 25°C for 10 min and filtered to afford ethyl 9-bromo-8-methoxy-l-(2,2,2-trifluoro-l-hydroxyethyl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate_(80 g, 88%) as a brown solid. RT (M14) = 0.min [M+H]+ (ES1+) 448.0/450.0.

[00404] Step 3, Method 17

[00405]To a solution of ethyl 9-bromo-8-methoxy-l-(2,2,2-trifluoro-l-hydroxyethyl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate (105 g, 234.25 mmol) in DCM (1200 mL) was added with BF3.Et20 (166.24 g, 1.17 mol, 144.55 mL) and Et3SiH (136.19 g, 1.17 mol, 187.mL). The mixture was stirred at 20°C for 1 h under N2 atmosphere. The mixture was added with H20 (100 mL). The aqueous layer was separated and extracted with DCM (200 mLx3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/ EtOAc =20/1 to 1/1) to afford ethyl 9-bromo-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carboxylate,( 80 g, 79.01%) as a white solid. RT (M25) = 2.89 min [M+H]+ (ES1+) 432.0/434.1.

[00406]The following analog was made by analogous method: WO 2024/184461 PCT/EP2024/056026

[00407] Synthetic Method 18 Structure Name LCMS BXXx״°ethyl (/?)-9-bromo-8- methoxy- 5-methyl -1 -(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo [2,1-a] isoquinoline-3-carboxylate RT (MH) = 2.18 min [M+H]+(ESL) 446.2/448.2

[00408] Scheme for Method 18

[00409] Step 1, Method 18

[00410]In a 20 mL pressure tube, a stirred solution of (2R)-l-[9-bromo-8-methoxy-l-(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo[2,l-a!]isoquinoline-3-carbonyl]-2-methyl-pyrrohdine-2- carbonitrile (400 mg, 0.8 mmol, synthesized by method 6), phenyl formate (450 pL, 4.0 mmol, CAS 1864-94-4) and tri ethylamine (560 pL, 4.0 mmol, CAS 121-44-8) in anhydrous DMF (5 mL) was degassed with nitrogen for 5 min. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (59 mg, 81 pmol, CAS 72287-26-4) was added, the solution degassed with nitrogen for 5 min and heated to 100 °C for 4 h. The reaction mixture was cooled to rt, the pressure released and the vessel purged with nitrogen. The mixture was concentrated in vacuo, diluted with water (20 mL) and extracted with di chloromethane (3 x WO 2024/184461 PCT/EP2024/056026 mL). The combined organic extracts were concentrated in vacuo to afford a residue that was purified by FCC (silica, eluting with 0-100% EtOAc in heptane) to give phenyl 3-[(27?)-2-cyano- 2-methyl-pyrrolidine- 1 -carbonyl]-8-methoxy- 1 -(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxylate (290 mg, 65% yield) as a light yellow solid. RT (M2) = 1.07 min, (ESI+) (M+H)+ 538.4.

[00411] Step 2, Method 18

[00412] To a solution ofphenyl 3-[(2R)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-o ؛]isoquinoline-9-carboxylate (290 mg, 0.5 mmol) in THF (7 mL) was added potassium trimethylsilanolate (350 mg, 2.6 mmol, CAS 10519-96-7) and the reaction stirred at rt for 18 h. The reaction mixture was concentrated and treated with water (10 mL). The mixture was acidified to pH 1 with 1 M aq HC1 and the formation of a precipitate was observed. The mixture was extracted with ethyl acetate (3 x 30 mL). The organics were combined, dried (MgSO4), filtered and the solvent removed in vacuo to give 3-[(2R)-2-cyano-2- methyl-pyrrolidine- 1 -carbonyl]-8-methoxy- 1 -(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxylic acid (86% purity, 280 mg, 100% Yield) as a yellow solid. RT (M2) = 0.84 min, (ES1+) (M+H)+ 462.4.

[00413] Step 3, Method 18

[00414]HATU (145 mg, 0.4 mmol, CAS 148893-10-1) and 2-amino-2-methylpropanenitrile hydrochloride (1:1) (31 mg, 0.2 mmol, CAS 50846-36-1) were added to a stirred solution of 3- [(2R)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy- 1-(2,2,2-trifluoroethyl)-5, 6- dihydropyrrolo[2,l-،2]isoquinoline-9-carboxylic acid (88% purity, 100 mg, 0.2 mmol) and DIPEA (130 pL, 0.8 mmol, CAS 7087-68-5) in DCM (1.5 mL) in anhydrous DMF (0.5 mL) at RT and the reaction mixture stirred overnight. The reaction mixture was poured into water (3 mL) and extracted with DCM (3x3 mL). The organic phases were combined, passed through a phase separator and concentrated in vacuo. The crude was purified by acidic prep HPLC (Method P2) and the product containing fractions freeze dried to give (R)-3-(2-cyano-2-methylpyrrolidine-l- carbonyl)-N-(2-cyanopropan-2-yl)-8-methoxy- 1 -(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-9-carboxamide (Compound 18-1) (34 mg, 33% yield) as a white solid.; 1H NMR WO 2024/184461 PCT/EP2024/056026 (400 MHz, DMSO) 6 8.44 (s, 1H), 8.00 (s, 1H), 7.24 (s, 1H), 6.70 (s, 1H), 4.43 - 4.20 (m, 2H), 3.95 (s, 3H), 3.89 - 3.81 (m, 1H), 3.81 - 3.66 (m, 3H), 3.05 (t, J = 6.5 Hz, 2H), 2.46 (d, J = 6.Hz, 1H), 2.21 -2.09 (m, 1H), 2.07 - 1.96 (m, 1H), 1.95 - 1.84 (m, 1H), 1.74 (s, 3H), 1.70 (s, 6H); RT (M4) = 3.67 min, (ESI+) (M+H)+ 528.1.

[00415]The following analogs were made by analogous method: Structure Name* LCMS 11 h Y|1 0 Compound 18-2 7V-(l-cyanocyclobutyl)-3-[(2R)-2-cyano-2- methyl-pyrrolidine-1 -carbonyl] -8-methoxy- l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,l-a!]isoquinoline-9- carboxamide RT (M4) = 3.66 min, (ESI+) (M+H)+ 540.3 U6AB Compound 18-3 3-[(2R)-2-[(lR)-l-hydroxyethyl]-2-methyl- pyrrolidine- 1 -carbonyl]-8-methoxy-N-(1- methyl-2-oxo-3-pyridyl)-l-(2-thienyl)-5,6- dihydropyrrolo[2,l-،2]isoquinoline-9- carboxamide RT (M5) = 0.83 min, (ESI+) (M+H)+ 587.4 r, h h T T 1 0 F F Compound 18-4 3-[(2R)-2-cyano-2-methyl-pyrrolidine- 1 - carbonyl] -8-methoxy-TV-( 1 -methyl-2-oxo-3 - pyridyl)- 1-(2,2,2-trifluoroethyl)-5 ,6- dihydropyrrolo[2,l-،2]isoquinoline-9- carboxamide RT (M4) = 3.64 min, (ESI+) (M+H)+ 568.1 Mps Compound 18-5 3-[(2R)-2-cyano-2-methyl-pyrrolidine- 1 - carbonyl]-8-methoxy-/V-(2-oxo-1/7-pyri din- 3-yl)-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,l-،2]isoquinoline-9- carboxamide RT (M4) = 3.26 min, (ESI+) (M+H)+ 554.2 WO 2024/184461 PCT/EP2024/056026 *denotes unknown stereochemistry, f) 00—' V V Compound 18-6 3-[(2R)-2-cyano-2-methyl-pyrrolidine- 1 - carbonyl]-A-[(3R*)-3-cyanotetrahydrofuran-3-yl]-8-methoxy- 1 - (2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-،2]isoquinoline-9- carboxamide RT (M4) = 3.59 min, (ESI+) (M+H)+ 556.2 1 OxA/fS O J-/'N A-SN0—' I k/FT Compound 18-7 3-[(2R)-2-cyano-2-methyl-pyrrolidine- 1 - carbonyl]-A-[(35'*)-3-cyanotetrahydro furan- 3-yl] -8-methoxy- 1 -(2,2,2-trifluoroethyl)- 5,6-dihydropyrrolo[2,l-،2]isoquinoline-9- carboxamide RT (M4) = 3.58 min, (ESI+) (M+H)+ 556.2 isolated from a diastereomeric mixture using SCFchromatography

[00416] Synthetic Method 19

[00417] Scheme for Method 19

[00418] Step 1, Method 19

[00419]4,4,5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (19.0 g, 74.7 umol, CAS 73183-34-3), ethyl 9-bromo-l-(4-fluorophenyl)-8- WO 2024/184461 PCT/EP2024/056026 methoxy-5,6-dihydropyrrolo[2,l-a!]isoquinohne-3-carboxylate (30.2 g, 67.9 mmol) and potassium acetate (20.0 g, 203.4 mmol) were dissolved in anhydrous 1,4-dioxane (530 mL). The suspension was sparged with nitrogen for 5 minutes before the addition of [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (2.8 g, 3.4 mmol, CAS 95464-05-4) and the suspension was sparged with nitrogen for 5 minutes. The mixture was stirred under nitrogen and heated at 90 °C for 16 hours. The reaction was cooled to rt and filtered, washing with DCM (2 x 100 mL). The filtrate was concentrated and purified by trituration with DCM to give ethyl l-(4-fluorophenyl)-8-methoxy-9-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-5,6-dihydropyrrolo[2,l-o ؛]isoquinoline-3-carboxylate (14.8 g, 26.4mmol, 39% Yield) as an off white solid.

[00420]A second crop precipitated from the filtrate and was filtered to give ethyl l-(4- fluorophenyl)-8-methoxy-9-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate (7.9 g, 14.5 mmol, 21% yield) as an off white solid. 1H NMR (400 MHz, DMSO) 5 7.43 - 7.32 (m, 3H), 7.27 -7.15 (m, 2H), 6.93 (d, J = 17.Hz, 2H), 4.57 - 4.49 (m, 2H), 4.25 (q, J = 1A Hz, 2H), 3.75 (d, J = 4.1 Hz, 3H), 3.10 (t, J = 6.Hz, 2H), 1.30 (t, J= 7.1 Hz, 3H), 1.16 (d, J= 8.0 Hz, 12H); RT (M2) = 1.24 min, (ES1+) (M+H)+ 492.3.

[00421] Step 2, Method 19

[00422]A solution of ethyl l-(4-fluorophenyl)-8-methoxy-9-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-5,6-dihydropyrrolo[2,l-o ؛]isoquinoline-3-carboxylate (14.8 g, 30.0 mmol) in 1,4-dioxane (380 mL) and water (150 mL), 5-bromo-2-methyl-tetrazole (6.4 g, 39.1 mmol, CAS 16681-80-4), dicesium carbonate (39.2 g, 120.2 mmol, CAS 534-17-8) was degassed with nitrogen and XPhos Pd G2 (4.7 g, 3.0 mmol, CAS 1310584-14-5) was added. The reaction was heated to °C for 2 h. The reaction was allowed to cool to RT and the organics concentrated in vacuo. The residual aqueous was diluted with water (100 mL) and extracted with DCM (2 x 200 mL). The organics were dried (MgSO4) and concentrated. The residue was triturated with DCM to give ethyl l-(4-fluorophenyl)-8-methoxy-9-(2-methyltetr azol-5-yl)-5,6-dihydropyrrolo[2,l-،2]isoquinoline- 3-carboxylate (12.8 g, 27.1 mmol, 90% Yield) as an off white solid. 1H NMR (400 MHz, DMSO) WO 2024/184461 PCT/EP2024/056026 SI.דס (s, 1H), 7.48-7.38 (m, 2H), 7.26 (s, 1H), 7.24 - 7.15 (m, 2H), 6.93 (s, 1H), 4.62-4.54 (m, 2H), 4.33 (s, 3H), 4.27 (q, J =7.1 Hz, 2H), 3.88 (s, 3H), 3.18 (t, J= 6.5 Hz, 2H), 1.30 (t, J= 1A Hz, 3H); RT (M2) = 1.07 min, (ESI+) (M+H)+ 448.2.

[00423] Step 3, Method 19

[00424]To a solution of ethyl l-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6- dihydropyrrolo[2,l-a!]isoquinoline-3-carboxylate (12.8 g, 28.5 mmol) in ethanol (177 mL) and water (44 mL) was added potassium hydroxide (6.5 g, 114.0 mmol). The resultant suspension was heated to 80 °C and stirred for 2 h. The reaction was cooled to RT, partially concentrated (to remove any ethanol) and diluted with water (50 mL) then acidified to pH 1 with 1 M aq. HCI. The formation of a precipitate was observed. The mixture was filtered, and the grey precipitate dried under vacuum to give l-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6- dihydropyrrolo[2,l-،2]isoquinoline-3-carboxylic acid (10.8 g, 25.7 mmol, 90% Yield) as an off white solid. 1H NMR (400 MHz, DMSO) 6 12.46 (s, 1H), 7.69 (s, 1H), 7.47 - 7.37 (m, 2H), 7.(s, 1H), 7.24 - 7.14 (m, 2H), 6.89 (s, 1H), 4.62 - 4.54 (m, 2H), 4.33 (s, 3H), 3.88 (s, 3H), 3.17 (t, J= 6.5 Hz, 2H); RT (M2) = 0.82 min, (ESI+) (M+H)+ 420.2.

[00425]The following analogs were made by analogous method: Structure Name LCMS nJML^0Vn T-^oh8-methoxy-9-(2-methyltetrazol-5 -yl)- 1 - propyl-5,6-dihydropyrrolo[2, 1 -a]isoquino line-3-carboxylic acid RT (M24) = 2.04 min, (ESI+) (M+H)+ 368.1 nJULO n-n )—U oh/ l-(5-fluoropyridin-2-yl)-8-methoxy-9-(2-met hyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxylic acid RT(M13)= 1.29 min, (ESI+) (M+H)+421.2 WO 2024/184461 PCT/EP2024/056026

[00426] Synthetic Method 20

[00427] Scheme for Method 20

[00428] Step 1, Method 20

[00429] 2.4 M LiAlH4 (1.2 mL, 2.80 mmol) was added to a stirred solution of methyl 4,4-difluoro-2-methyl-pyrrolidine-2-carboxylate hydrochloride (301 mg, 1.4 mmol, CAS 16853-85-3) in anhydrous THF (5 mL) at 0 °C, under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 60 min. The reaction mixture was quenched with water and extracted with DCM. 4 M HCI in dioxane (2 mL) was added to the combined organics and they were dried and concentrated to give (4,4-difluoro-2-methyl-pyrrolidin-2-yl)methanol hydrochloride (260 mg , 89% Yield) as a white solid. 1H NMR (400 MHz, DMSO) 6 9.84 (s, 2H), 5.79 (s, 1H), 3.98 - 3.62 (m, 3H), 3.57 - 3.46 (m, 1H), 2.65 - 2.52 (m, 1H), 2.47 - 2.28 (m, 1H), 1.40 (s, 3H).

[00430] Step 2, Method 20

[00431]2-Chloro-l-methylpyridinium iodide (1.6 g, 6.2 mmol) was added to a stirredsuspension of 8-methoxy-9-(l-methylpyrazol-3-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-،2]isoquinoline-3-carboxylic acid (1.0 g, 2.5 mmol, synthesized by method 19), DIPEA (1.3 mL, 7.4 mmol, CAS 7087-68-5) and (4,4-difluoro-2-methyl-pyrrolidin-2-yl)methanol hydrochloride (694 mg, 3.7 mmol) in DMF (13 mL). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water and DCM the resultant precipitate isolated by filtration. The filtrate was purified by FCC (silica, eluting with 0-100% EtOAc in heptane). The WO 2024/184461 PCT/EP2024/056026 product containing fractions were concentrated in vacuo to give [4,4-difluoro-2-(hydroxymethyl)- 2-methyl-pyrrolidin-l-yl]-[l-(4-fluorophenyl)-8-methoxy-9-(2-methyltetr azol-5-yl)-5, 6- dihydropyrrolo[2,l-a!]isoquinolin-3-yl]methanone (426 mg, 28% Yield) a white solid. RT (M2) = 1.01 min, [M+H]+ (ESI+) 553.3.

[00432] Step 3, Method 20

[00433]Dess-Martin periodinane (491 mg, 1.2 mmol) was added to a stirred a solution of [4,4- difluoro-2-(hydroxymethyl)-2-methyl-pyrrolidin- 1 -yl]-[ 1 -(4-fluorophenyl)-8-methoxy-9-(2- methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a!]isoquinolin-3-yl]methanone (426 mg, 0.8 mmol) in DCM (50 mL). The reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with DCM and washed with water. The precipitate was filtered, and the organics were separated, dried and concentrated. The crude was purified by FCC (silica, eluting with 0-100% EtOAc in heptane) to give 4,4-difluoro-l-[l-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6- dihydropyrrolo[2,l-a!]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbaldehyde (321 mg, 67% Yield) as a white solid. RT (M2) = 0.98 min, [M+H]+ (ES1+) 551.0.

[00434] Step 4, Method 20

[00435]4,4-Difluoro-l-[l-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6- dihydropyrrolo[2,l-a!]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbaldehyde (321 mg, 0.6 mmol) was dissolved in anhydrous THF (5 mL)and cooled to 0 °C under nitrogen. 3 M Bromo(methyl)magnesium (290 pL, 0.9 mmol) was added over 10 min, and the reaction mixture was stirred for 30 min then allowed to warm to RT. The reaction mixture was quenched with sat. aq. NH4C1 and extracted with EtOAc (3 x 20 mL). The combined organics were dried (MgSO4) and concentrated. The compound was purified by acidic prep HPLC (Method P2) to give the crude product as a white solid.

[00436]The method was repeated on a larger scale and both batches were combined for chiral separation. Yields based on combined theoretical yield.

[00437]Chiral separation on Waters Thar SFC [Column: Chiralpak AD-H (4.6 x 250mm, 5pm) at 40°C; Isocratic eluent: 8 70:30 Heptane: Ethanol; Flow rate: 18mL/min; Dilution solvent: WO 2024/184461 PCT/EP2024/056026 MeOH, i-PrOH, acetonitrile; injection volume: 250j1L] to give [l-(4-fluorophenyl)-8-methoxy-9-- 2-4,4 - difluoro ،؟(- isoquinolin-3-yl]-[(2R or ؛[ 2 - methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,l-o )methyl-2-[(17? or S)-1-hydroxyethyljpyrrolidin- 1-yljmethanone (Compound 20-1) (26 mg 7% Yield), as a white powder. RT (M4) = 3.64 min, (ESI+) (M+H)+ 567.2; 1H NMR (400 MHz, DMSO) 6 7.72 (s, 1H), 7.50 - 7.41 (m, 2H), 7.23 (s, 1H), 7.22 - 7.13 (m, 2H), 6.71 (s, 1H), 5.(d, J = 5.1 Hz, 1H), 4.55 - 4.48 (m, 1H), 4.48 - 4.35 (m, 2H), 4.33 (s, 3H), 4.32 - 4.21 (m, 1H), 4.17 - 4.06 (m, 1H), 3.87 (s, 3H), 3.13 (t, J = 6.5 Hz, 2H), 2.74 - 2.58 (m, 1H), 2.07 (t, J= 15.Hz, 1H), 1.68 (s, 3H), 1.08 (d, J= 6.3 Hz, 3H).

[00438][l-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinolin-3-yl]-[(2 lS' or R)-4,4-difluoro-2-methyl-2-[(l،S' or R)-l-hydroxyethyl]pyrrolidin-l- yl]methanone (Compound 20-1, isomer 2) (28 mg, 6% Yield), as a white powder. RT (M4) = 3.min, (ESI+) (M+H)+ 567.2; 1H NMR (400 MHz, DMSO) 6 7.72 (s, 1H), 7.50 - 7.39 (m, 2H), 7.(s, 1H), 7.22-7.13 (m, 2H), 6.71 (s, 1H), 5.03 (d, J = 5.3 Hz, 1H), 4.55 -4.48 (m, 1H), 4.48 - 4.35 (m, 2H),4.33 (s, 3H), 4.32-4.21 (m, 1H), 4.17-4.06 (m, 1H), 3.87 (s, 3H), 3.13 (t, J=6.Hz, 2H), 2.73 -2.58 (m, 1H), 2.07 (t, J= 15.6 Hz, 1H), 1.68 (s, 3H), 1.08 (d, J=6.3 Hz, 3H).

[00439] Synthetic Method 21

[00440] Scheme for Method 21

[00441] Step 1, Method 21

[00442]Di-tert-butyl dicarbonate (2.2 g, 10.2 mmol, CAS 24424-99-5) was added portionwise over 5 min to a solution of methyl (3R)-3-methylmorpholine-3-carboxylate;hydrochloride (1.0 g, 5.1 mmol, CAS 1434126-90-5) and triethylamine (780 pL, 5.6 mmol) in anhydrous methanol (mL). The reaction was stirred at RT. After 90 hours, 4-dimethylaminopyridine (31 mg, 0.3 mmol, CAS 1122-58-3) was added. After a further 24 hours, the solvent was removed in vacuo. The crude material was dissolved in EtOAc (10 mL) and washed with aq. NaHCO3 (3x10 mL). The organic WO 2024/184461 PCT/EP2024/056026 layer was passed through a phase separator and the solvent removed in vacuo to give 04-tert-butyl 03-methyl (3R)-3-methylmorpho line-3,4-dicarboxylate (680 mg, 49% yield) as a white solid. RT (M3) = 0.67 min [M+H]+ (ESI+) 260.2; 1H NMR (500 MHz, DMSO) 6 3.86 - 3.73 (m, 1H), 3.- 3.61 (m, 3H), 3.61 - 3.55 (m, 2H), 3.55 - 3.50 (m, 1H), 3.50 - 3.43 (m, 1H), 3.20 - 3.08 (m, 1H), 1.40 (s, 3H), 1.36 (s, 9H).

[00443] Step 2, Method 21

[00444]To a flask containing 04-tert-butyl 03-methyl (3R)-3-methylmorpholine-3,4- dicarboxylate (680 mg, 2.6 mmol) in ethanol (10 mL) and water (7 mL) was added potassium hydroxide (589 mg, 10.5 mmol, CAS 1310-58-3). The reaction mixture was stirred at rt for 6 days then heated to 80 °C. After a further 24 h the reaction mixture was concentrated in vacuo. The resulting brown oil treated with water (10 mL) and acidified to pH 1 with 1 M aq. HC1 and extracted with DCM (3x10 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo to give (3R)-4-tert-butoxycarbonyl-3-methyl-morpholine-3- carboxylic acid (660 mg, 82% yield) as a brown oil. RT (M3) = 0.32 min [M+H]+ (ESI+) 246.2; 1H NMR (500 MHz, DMSO) 6 12.58 (s, 1H), 5.75 (s, 2H), 3.73 (s, 1H), 3.67 - 3.56 (m, 2H), 3.- 3.39 (m, 2H), 3.20 - 3.09 (m, 1H), 1.38 (d, J= 3.0 Hz, 12H).

[00445] Step 3, Method 21

[00446]DIPEA (1.9 mL, 10.8 mmol, CAS 7087-68-5), HATH (1.5 g, 4.0 mmol, CAS 148893- 10-1) and ammonia (35% in water, 180 pL, 3.2 mmol, CAS 7664-41-7) were added to a stirred solution of (3R)-4-tert-butoxycarbonyl-3-methyl-morpholine-3-carboxylic acid (660 mg, 2.mmol) in DCM (10 mL) at RT. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with water (10 ml), extracted with DCM (3x10 ml) and the combined organic extracts passed through a phase separator and concentrated under vacuum to yield the crude product as a yellow oil. The crude oil was purified by FCC (silica, eluting with 0-100% EtOAc in heptane) to give tert-butyl (3R)-3-carbamoyl-3-methyl-morpholine-4-carboxylate (440 mg, 43% yield) as a pale yellow solid. RT (M3) = 0.45 min [M+H]+ (ESI+) 245.2; 1H NMR (500 MHz, DMSO) 6 7.13 (s, 1H), 6.91 (s, 1H), 3.82 - 3.73 (m, 1H), 3.65 - 3.57 (m, 2H), 3.51 - 3.44 (m, 1H), 3.44 - 3.38 (m, 1H), 3.16 - 3.05 (m, 1H), 1.37 (s, 9H), 1.34 (s, 3H).

WO 2024/184461 PCT/EP2024/056026

[00447] Step 4, Method 21

[00448]HC1 (4 M in dioxane, 2.9 mL, 11.5 mmol, CAS 7647-01-0) was added to a stirred solution of tert-butyl (3R)-3-carbamoyl-3 -methyl-morpholine-4-carboxylate (440 mg, 1.2 mmol) in dioxane (6 mL) and the mixture stirred at rt over the weekend. The reaction mixture was concentrated in vacuo to give (3R)-3-methylmorpholine-3-carboxamide;hydrochloride (219 mg, 100% Yield) as a white solid. 1H NMR (500 MHz, DMSO) 6 10.28 - 8.99 (m, 2H), 8.00 (s, 1H), 7.79 (s, 1H), 4.14 (d, J = 12.7 Hz, 1H), 3.80 - 3.71 (m, 3H), 3.20 - 3.06 (m, 2H), 1.45 (s, 3H).

[00449]The following analog was made by analogous method: Structure Name LCMS _ nh 0 tert-butyl (R)-2-carbamoyl-2-methylazetidine- 1 -carboxylateRT (M13) =0.98 min, (ESI+) (M+Na) +237.3

[00450] Synthetic Method 22

[00451] Scheme for Method 22

[00452] Step 1, Method 22

[00453] 2-Chloro-l-methylpyridinium iodide (236 mg, 0.9 mmol, CAS 14338-32-0) was added to a stirred suspension of 8-methoxy-9-(l-methylpyrazol-3-yl)-l-(2-thienyl)-5,6- dihydropyrrolo[2,l-،2]isoquinoline-3-carboxylic acid (150 mg, 0.4 mmol, prepared by method 22), DIPEA (190 pL, 1.1 mmol, CAS 7087-68-5) and (3R)-3-methylmorpholine-3- carboxamide;hydrochloride (100 mg, 0.6 mmol, prepared by method 22) in DMA (2 mL). The reaction mixture was stirred at RT. After 21 h the mixture was diluted with water (5 mL) and extracted with EtOAc (3x5 mL). The combined organic extracts were passed through a phase WO 2024/184461 PCT/EP2024/056026 separator and concentrated in vacuo. The crude product was purified by FCC (silica, eluting with 0-100% EtOAc in heptane then 0-15% MeOH in EtOAc) to give (3R)-4-[8-methoxy-9-(l- methylpyrazol-3-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a!]isoquinoline-3-carbonyl]-3-methyl- morpholine-3-carboxamide (100 mg, 0.1 mmol, 34% Yield) as an orange solid. RT (M2) = 0.min [M+H]+ (ESI+) 532.2; 1H NMR (500 MHz, DMSO) 6 8.08 (s, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.48 (dd, J = 3.7, 2.7 Hz, 1H), 7.18 (s, 1H), 7.10 (s, 1H), 7.10 - 7.08 (m, 1H), 7.05 (s, 1H), 6.(s, 1H), 6.64 (s, 1H), 6.52 (d, J = 2.2 Hz, 1H), 4.30 - 4.21 (m, 1H), 4.14 - 4.04 (m, 1H), 3.95 - 3.89 (m, 1H), 3.86 (s, 3H), 3.83 - 3.78 (m, 3H), 3.76 (s, 3H), 3.64 -3.55 (m, 1H), 3.50 (d, J= 11.Hz, 1H), 3.03 (t, J= 6.5 Hz, 2H), 1.48 (s, 3H).

[00454] Synthetic Method 23

[00455] Scheme for Method 23

[00456] Step 1, Method 23

[00457]Chloro(propan-2-yl)magnesium (2 M in Et20, 18 mL, 36.0 mmol, CAS 1068-55-9) was added dropwise to a solution of 1 -bromo-4-iodo-2-methoxy-benzene (11.3 g, 36.1 mmol, CAS 755027-18-0) in diethyl ether (10 mL) at -15 °C. The solution was stirred for Ih 45min at -15 °C. Copper(l+) iodide (45 mg, 0.2 mmol, CAS 7681-65-4) was then added and the suspension stirred for a further 15 min at -15 °C to give a cloudy green-brown suspension.

[00458]This suspension was then added in 5 mL portions to a suspension of tert-butyl (4R)-4- methyl- 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (4.5 g, 18.0 mmol, CAS 454248-53-4) in WO 2024/184461 PCT/EP2024/056026 diethyl ether (50 mL) at -15 °C, over 10 min. After 2 h stirring at -15 °C the reaction was sonicated and hand-swirled for 15 min. Citric acid (10% w/v in water, 50 mL) was added slowly at -15 °C and the reaction was then allowed to warm to rt while stirring. After stirring for 90 min the organic was collected and the aqueous extracted with ethyl acetate (50 mL). The combined organics were washed with brine (10 mL) and concentrated in vacuo. The residue was purified by FCC (silica, eluting with 0-100% EtOAc in heptane) to give tert-butyl A-[(lR)-2-(4-bromo-3-methoxy- phenyl)-l-methyl-ethyl]carbamate (91% purity, 5.7 g, 15.2 mmol, 84% Yield) as a brown solid. RT (M2) = 0.98 min [M+H]+ (ES1+) 288.2/290.2; 1H NMR (400 MHz, DMSO) 6 7.43 (d, J = 8.Hz, 1H), 6.92 (d,J = 1.9 Hz, 1H), 6.77 (d, J=8.4Hz, 1H),6.71 (dd,J=8.0, 1.9 Hz, 1H),3.83 (s, 3H), 3.72 - 3.64 (m, 1H), 2.72 - 2.54 (m, 2H), 1.33 (s, 9H), 1.02 (d, J= 6.6 Hz, 3H).

[00459] Step 2, Method 23

[00460]tert-Butyl A-[(lR)-2-(4-bromo-3-methoxy-phenyl)-l-methyl-ethyl]carbamate (5.7 g, 16.7 mmol) was dissolved in DCM (50 mL) and treated with trifluoroacetic acid (5.0 mL, 65.mmol, CAS 76-05-1). After stirring for l h the reaction was retreated with trifluoroacetic acid (mL, 65.3 mmol, CAS 76-05-1). After stirring for a further l h the volatiles were removed under reduced pressure. The residue was dissolved in DCM (50 mL) and treated with DIPEA (5.8 mL, 33.3 mmol, CAS 7087-68-5) and 9/7-fluoren-9-ylmethyl carbonochloridate (4.8 g, 18.3 mmol, CAS 28920-43-6) (exothermic). After stirring overnight the reaction was washed with ammonium chloride (sat. in H2O, 2 x 50 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was triturated with heptane (200 mL) and filtered to give 9/7-fluoren-9-ylmethyl N- [(U?)-2-(4-bromo-3-methoxy-phenyl)-1-methyl-ethyl]carbamate (9.6 g, 86% Yield) as a tan solid. RT (M2) = 1.11 min [M+H]+ (ES1+) 466.2/468.2

[00461] Step 3, Method 23

[00462]A suspension of 9/7-fluoren-9-ylmethyl A-[(lR)-2-(4-bromo-3-methoxy-phenyl)-l- methyl-ethyl]carbamate (9.6 g, 20.6 mmol) and oxoacetic acid hydrate (1:1) (2.8 g, 30.9 mmol, CAS 563-96-2) in acetic acid (100 mL) was treated with sulphuric acid (10 mL) and stirred for h. Acetic acid (50 mL) and sulphuric acid (5 mL) were added to the suspension. After stirring for min the mixture was sonicated for 2 h to give a red solution. The solution was poured into water WO 2024/184461 PCT/EP2024/056026 (IL) and the precipitate was collected by filtration. The pink solid was dissolved in EtOAc (2mL) and dried over Na2S04, filtered and concentrated to give (3R)-7-bromo-2-(9//-fluoren-9- ylmethoxycarbonyl)-6-methoxy-3-methyl-3,4-dihydro-l//-isoquinoline-l-carboxylic acid (8.5 g, 69% Yield) as a pink solid. RT (M2) = 1.30-1.32 min [M+H]+ (ES1+) 522.0/524.0

[00463] Step 4, Method 23

[00464]To a solution of (3R)-7-bromo-2-(9//-fluoren-9-ylmethoxycarbonyl)-6-methoxy-3- methyl-3,4-dihydro-l//-isoquinoline- 1-carboxylic acid (87% purity, 8.5 g, 14.1 mmol) in DMF (80 mL) was added piperidine (8.2 mL, 83.2 mmol, CAS 110-89-4) and the reaction was stirred at room temperature for 24 h. The reaction was concentrated under reduced pressure and the residue was dissolved in THE (100 mL) before the addition of Et20 (100 mL). The precipitate was collected by filtration to give (3R)-7-bromo-6-methoxy-3-methyl- 1,2,3,4-tetrahydroisoquinoline- 1-carboxylic acid (79% purity, 2.8 g, 52% Yield) as a pink solid. RT (M2) = 0.46-0.47 min [M+H]+ (ES1+) 299.9/301.9

[00465]The following analogs were made by analogous method: JL NH Br O^OH 7 -bromo-6-methoxy-4- methyl- 1,2,3,4-tetrahydroisoquinoline- 1 - carboxylic acid RT (Ml 2) = 0.35 min, [M+H]+(ES1+) 300.1 /302.1 ״ NH Br O^OH (laR,7bR)-5-bromo-6- methoxy- 1 a, 2,3,7b- tetrahydro-1H-cyclopropa[c]isoquinoline-3- carboxylic acid RT (M14) = 0.303 min, [M+H]+ (ESL) 297.9/300.0 WO 2024/184461 PCT/EP2024/056026

[00466] Synthetic Method 24

[00467] Scheme for Method 24

[00468] Step 1, Method 24

[00469]In a 20 mL pressure tube, a mixture of (9-bromo-8-methoxy-l-thiazol-5-yl-5,6- dihydropyrrolo [2,1 -a] isoquinolin-3 -yl)- [(2R)-2- [(1R)-1 -hydroxy ethyl] -2-methyl-pyrrolidin- 1 - yl]methanone (250 mg, 0.5 mmol, synthesized by method 2), phenyl formate (0.3 mL, 2.7 mmol, CAS 1864-94-4) and triethylamine (0.4 mL, 2.7 mmol, CAS 121-44-8) in anhydrous DMF (4 mL) was degassed with nitrogen for 5 min. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.05 mmol, CAS 72287-26-4) was added, the solution degassed with nitrogen for 5 mins and heated to 100 °C for 6 h.

[00470]The mixture was cooled to rt and the pressure released slowly and the vessel purged with nitrogen. The mixture was concentrated, diluted with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were concentrated in vacuo to afford a residue that was purified by FCC (silica, eluting with 0-100% EtOAc in heptane) to give phenyl 3-[(2R)-2-[( 1R)-1 -hydroxyethyl]-2-methyl-pyrrolidine- 1 -carbonyl] -8-methoxy- 1 - thiazol-5-yl-5,6-dihydropyrrolo[2,l-،2]isoquinoline-9-carboxylate (150 mg, 50% Yield) as a white solid. RT (M2) = 0.91 min, (ESI+) (M+H)+ 558.2; 1H NMR (400 MHz, DMSO-d6) 3 9.(d, J= 0.6 Hz, 1H), 7.92 - 7.86 (m, 2H), 7.48 - 7.39 (m, 2H), 7.31 - 7.23 (m, 2H), 7.07 (dd, J = 8.5, 1.0 Hz, 2H), 6.64 (s, 1H), 4.96 (d, J= 4.9 Hz, 1H), 4.50 - 4.41 (m, 1H), 4.41 - 4.30 (m, 1H), 4.21-4.10 (m, 1H), 3.90 (s, 3H), 3.86 - 3.78 (m, 1H), 3.71 -3.60 (m, 1H), 3.14 (t, J = 6.4 Hz, 2H), 2.14-2.02 (m, 1H), 1.87 - 1.69 (m, 2H), 1.60 - 1.45 (m, 4H), 1.01 (d, J = 6.3 Hz, 3H).

WO 2024/184461 PCT/EP2024/056026

[00471] Step 2, Method 24

[00472]To a solution of phenyl 3-[(2R)-2-[(lR)-l-hydroxyethyl]-2-methyl-pyrrolidine-l- carbonyl]-8-methoxy-l-thiazol-5-yl-5,6-dihydropyrrolo[2,l-a!]isoquinoline-9-carboxylate (150mg, 0.3 mmol) in THF (10 mL) was added potassium trimethylsilanolate (182 mg, 1.3 mmol, CAS 10519-96-7). The reaction was stirred at rt for 2 h. The reaction mixture was partially concentrated and the mixture treated with water (10 mL). The mixture was acidified to pH l with aq. 1 M HCI and the formation of a precipitate was observed. The mixture was extracted with DCM (3x10 mL) and the combined oraganic passed through a phase separator and concentrated in vacuo to give 3- [(2R)-2-[(lR)-l-hydroxyethyl]-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l-thiazol-5-yl-5, 6- dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxylic acid (77% purity, 160 mg, 95% Yield) as a yellow solid. RT (M2) = 0.68 min, (ESI+) (M+H)+ 482.2.

[00473] Step 3, Method 24

[00474]HATU (243 mg, 0.6 mmol, CAS 148893-10-1) was added to a stirred suspension of 3-[(2R)-2-[( 1R)-1 -hydroxyethyl]-2-methyl-pyrrolidine- 1 -carbonyl]-8-methoxy- 1 -thiazol-5-yl- 5,6-dihydropyrrolo[2,l-،2]isoquinoline-9-carboxylic acid (77%, 160 mg, 0.3 mmol), DIPEA (1uL, 0.8 mmol, CAS 7087-68-5) and 1-aminocyclobutanecarbonitrile hydrochloride (1:1) (51 mg, 0.5 mmol, CAS 845821-84-3) in DCM (2 mL) and 1,4-dioxane (5 mL). The reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo. The mixture was diluted with water (10 mL) and extracted with DCM (3x10 mL). The combined organic extracts were passed through a phase separator and concentrated to give a brown oil. The brown oil was purified by acidic prep HPLC (Pl) and freeze dried to give A-(l-cyanocyclobutyl)-3-[(2R)-2-[(U?)-l- hydroxyethyl] -2-methyl-pyrrolidine- 1 -carbonyl] -8-methoxy- 1 -thiazol-5-yl-5 ,6- dihydropyrrolo[2,l-a!]isoquinoline-9-carboxamide (compound 24-1) (56 mg, 38% Yield) as a white solid. RT (M4) = 3.09 min, (ESI+) (M+H)+ 560.2. 1H NMR (500 MHz, DMSO-d6) 3 9.(s, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.72 (s, 1H), 7.18 (s, 1H), 6.62 (s, 1H), 4.96 (d, J=4.8Hz, 1H), 4.49 _ 4.40 (m, 1H), 4.38 - 4.28 (m, 1H), 4.16 - 4.06 (m, 1H), 3.92 (s, 3H), 3.85 - 3.77 (m, 1H), 3.69 - 3.59 (m, 1H), 3.09 (t, J= 6.4 Hz, 2H), 2.67 - 2.58 (m, 2H), 2.39 - 2.30 (m, 2H), 2.14 1.(m, 3H), 1.85 - 1.70 (m, 2H), 1.58- 1.52 (m, 1H), 1.51 (s, 3H), 1.01 (d,J=6.3 Hz, 3H).

WO 2024/184461 PCT/EP2024/056026

[00475]The following analog was made by analogous method: Structure Name LCMS 0 ץ Itny Cf FN Compound 24-2 TV1 )-־ -cyanocyclobutyl)-8-methoxy-3-[(27?)-2-methyl-2-[(lS)-2,2,2-trifluoro- 1 -hydroxy-ethyl]pyrrolidine- 1 -carbonyl] -1 -thiazol-5-yl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline- 9-carboxamide RT (M4) = 3.45 min, (ESI+) (M+H)+614.2

[00476] Synthetic Method 25 Scheme for Method 25 [00477] KOH Burgess reagent Cmp 251־ eutomer [00478] Step 1, Method 25

[00479]To a stirring solution of methyl 2-ethyl-l-[8-methoxy-9-(l-methylpyrazol-3-yl)-l-(2- thienyl)-5,6-dihydropyrrolo[2,l-a!]isoquinohne-3-carbonyl]pyrrohdine-2-carboxylate (468 mg, 0.9 mmol, synthesized by method 13) in ethanol (8 mL) and water (3 mL), potassium hydroxide (193 mg, 3.4 mmol CAS 1310-58-3) was added and the reaction was stirred at 80 °C for 4 h. The reaction mixture was cooled to rt and concentrated in vacuo. The aqueous residue was acidified to pH l using 1M aq. HC1 and extracted with DCM (3 x 20 mL). The organics were dried through a WO 2024/184461 PCT/EP2024/056026 phase separator and concentrated to give 2-ethyl-l-[8-methoxy-9-(l-methylpyrazol-3-yl)-l-(2- thienyl)-5,6-dihydropyrrolo[2,l-o ؛]isoquinoline-3-carbonyl]pyrrolidine-2-carboxylic acid (4mg, 84% Yield) as an off white solid. RT (M2) = 0.93 min [M+H]+ (ESI+) 531.2.

[00480] Step 2, Method 25

[00481]Ethyl carbonochloridate (110 uL, 1.1 mmol, CAS 541-41-3) was added dropwise to a stirred solution of 2-ethyl-l-[8-methoxy-9-(l-methylpyrazol-3-yl)-l-(2-thienyl)-5,6- dihydropyrrolo[2,l-a!]isoquinoline-3-carbonyl]pyrrolidine-2-carboxylic acid (465 mg, 0.9 mmol) and N,N-diethylethanamine (240 uL, 1.8 mmol, CAS 121-44-8) in anhydrous THE (6.5 mL) at - °C under N2. The resulting solution was stirred at -20 °C for 40 min. Ammonia (35%, 340 uL, 7.0 mmol, CAS 1336-21-6) was added and the mixture, was allowed to warm to RT over 60 min. The solvent was evaporated in vacuo and the residue dissolved in EtOAc (50 mL). The organic layer was washed with sat. aq. NaHCO3 solution (40 mL) and brine (40 mL), dried (MgSO4) and evaporated under reduced pressure to give the crude product. The crude was purified by acidic prep HPLC (Method P1) to give 2-ethyl-l-[8-methoxy-9-(l-methylpyrazol-3-yl)-l-(2-thienyl)- 5,6-dihydropyrrolo[2,l-o ؛]isoquinoline-3-carbonyl]pyrrolidine-2-carboxamide (60 mg, 12% Yield) as a white solid. RT (M2) = 0.83 min [M+H]+ (ESI+) 530.2.

[00482] Step 3, Method 25

[00483] To a mixture of 2-ethyl-l-[8-methoxy-9-(l-methylpyrazol-3-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a!]isoquinoline-3-carbonyl]pyrrolidine-2-carboxamide (60 mg, 0.1 mmol) in THF (0.5 mL) and DCM (0.5 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (37 mg, 0.157 mmol, CAS 29684-56-8) at 0°C under N2 for 1 h. The mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into water (10 mL) and the aqueous phase extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2S04, filtered and concentrated in vacuo. The crude was purified by acidic prep HPLC (Method Pl) to give 2-ethyl-l-[8-methoxy-9- (1-methylpyrazol-3-yl)-1 -(2-thienyl)-5,6-dihydropyrrolo[2, 1-،2]isoquinoline-3- carbonyl]pyrrolidine-2-carbonitrile (40 mg, 69% Yield) as a white powder.

WO 2024/184461 PCT/EP2024/056026

[00484]Chiral separation on Waters Thar SFC [Column: Chiralpak AD-H (20 x 250mm, 5pm) at 40°C; Isocratic eluent: 70:30 Heptane: EtOH; Flow rate: 18mL/min; Dilution solvent: MeOH, i-PrOH; injection volume: 250pL] to give (27?*)-2-ethyl-l-[8-methoxy-9-(l-methylpyrazol-3-yl)- -(2-thienyl)-5,6-dihydropyrrolo[2, 1 -a ؛]isoquinoline-3-carbonyl]pyrrolidine-2-carbonitrile (compound 25-1) (17 mg, 29% yield) as an off white powder. RT (M4) = 3.92 min, (ESI+) (M+H)+ 512.2; 1HNMR(500 MHz, DMSO) 6 8.09 (s, 1H), 7.61 (d,J=2.2 Hz, 1H), 7.50 (dd, J= 4.3, 2.Hz, 1H), 7.14 - 7.09 (m, 2H), 7.07 (s, 1H), 6.73 (s, 1H), 6.53 (d, J= 2.2 Hz, 1H), 4.52 - 4.43 (m, 1H), 4.27-4.18 (m, 1H), 3.98 - 3.91 (m, 1H), 3.87 (s, 3H), 3.81 -3.75 (m, 4H), 3.07 (t, J = 6.Hz, 2H), 2.44 - 2.31 (m, 2H), 2.21-2.12 (m, 1H), 2.04 - 1.96 (m, 1H), 1.96 - 1.85 (m, 2H), 0.(t, J= 7.4 Hz, 3H). * Denotes unknown stereochemistry, isolated from a diastereomeric mixture using SFC chromatography

[00485] Synthetic Method 26

[00486] Scheme for Method 26 WO 2024/184461 PCT/EP2024/056026 Cmp 26-1 eutomer configuration unknown

[00487] Step 1, Method 26

[00488]Under N2, at 0 °C, 2 M lithium dipropan-2-ylazanide in THF/heptane/ethylbenzene (mL, 26.8 mmol, CAS 4111-54-0) was added to a solution of 07-benzyl 02-ethyl 3-oxopyrrolidine- 1,2-dicarboxylate (7.10 g, 24.4 mmol, CAS 51814-19-8) in THF (150 mL). The reaction mixture was stirred at this temperature for l h. A mixture of iodomethane (2.3 mL, 36.6 mmol, CAS 74- 88-4) in A,A,A',A',A״,A"-hexamethylphosphoric triamide (5.6 mL, 32.4 mmol, CAS 680-31-9) was added to the reaction mixture, and the mixture allowed to warm to rt and stirred overnight. Another portion of iodomethane (390 uL, 6.26 mmol, CAS 74-88-4) was added and the reaction mixture stirred at RT for l h. At 0 °C, sat. aq. NH4C1 (150 mL) was added and the mixture was stirred vigorously for 10 min. Water (100 mL) was added and the suspension was extracted with EtOAc (3 x 80 mL). The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the crude material, which was purified by FCC (silica, eluting with 10-100% EtOAc/heptane) to give O1-benzyl 02-ethyl 2-methyl-3-oxo-pyrrolidine- 1,2-dicarboxylate (2.27 g, 29% yield) as a pale yellow oil. RT (M2) = 0.86 min, (ES1+) (M+H)+ 306.1; 1H NMR (400 MHz, DMSO) 6 7.43 - 7.21 (m, 5H), 5.21 - 5.06 (m, 2H), 4.15 - 3.94 (m, 2H), 3.77 (t, J= 7.8 Hz, 2H), 2.89 - 2.70 (m, 2H), 1.52 (s, 3H), 1.06 (t, J= 7.0 Hz, 3H).

WO 2024/184461 PCT/EP2024/056026

[00489] Step 2, Method 26

[00490]Under N2, at 0 °C, sodium tetrahydroborate (795 mg, 21.0 mmol, CAS 16940-66-2) was added to a solution of 07-benzyl 02-ethyl 2-methyl-3-oxo-pyrrolidine-l,2-dicarboxylate (3.21 g, 10.5 mmol) in MeOH (50 mL). The reaction mixture was stirred at this temperature for h, and sat. aq. NH4C1 (50 mL) was added. Water (50 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 07-benzyl 02-ethyl 3-hydroxy-2-methyl- pyrrolidine-l,2-dicarboxylate (2.93 g, 82% yield) as a colorless oil. RT (M2) = 0.76 min, (ESI+) (M+H)+ 308.3.

[00491] Step 3, Method 26

[00492]At rt, palladium on carbon (10%, 477 mg, 0.4 mmol, CAS 7440-05-3) was added to a solution of 07-benzyl 02-ethyl 3-hydroxy-2-methyl-pyrrolidine-l,2-dicarboxylate (90% purity, 2.93 g, 8.6 mmol) in EtOH (50 mL). The reaction mixture was stirred under H2 (1 atm) overnight. The reaction mixture was filtered through Celite, washing through with MeOH (100 mL) and the filtrate was concentrated in vacuo to give ethyl 3-hydroxy-2-methyl-pyrrolidine-2-carboxylate (1.53 g, 98% yield) as a pale yellow solid. 1H NMR* (400 MHz, DMSO) 6 4.89 (d, J = 5.4 Hz, 1H), 4.15-3.97 (m, 3H), 3.88 (td, J= 5.4, 2.5 Hz, 1H), 3.09 (dt, J= 10.4, 8.2 Hz, 1H), 2.75 (ddd, J = 10.4, 9.1, 4.3 Hz, 1H), 1.96 (dddd, J = 12.9, 9.0, 7.3, 5.4 Hz, 1H), 1.63 (dddd, J = 13.0, 8.4, 4.3, 2.6 Hz, 1H), 1.17 (t, J = 1A Hz, 3H), 1.10 (s, 3H). *NMR shifts for major diastereomers reported.

[00493] Step 4, Method 26

[00494]At rt, HATU (3.34 g, 8.8 mmol, CAS 148893-10-1) was added to a solution of ethyl 3-hydroxy-2-methyl-pyrrolidine-2-carboxylate (1.1 g, 6.1 mmol), 8-methoxy-9-(2-methyltetrazol- 5-yl)-l-propyl-5,6-dihydropyrrolo[2,l-،2]isoquinoline-3-carboxylic acid (2.15 g, 5.9 mmol, synthesized by method 19) and A-ethyl-A-(propan-2-yl)propan-2-amine (3.1 mL, 17.6 mmol, CAS 7087-68-5) in 1,4-dioxane (15 mL) and DCM (15 mL). The reaction mixture was stirred at RT for days. Water (50 mL) was added and the mixture extracted with DCM (3 x 50 mL). The combined extracts were dried over anhydrous MgSO4, filtered and concentrated to give the crude material, -240- WO 2024/184461 PCT/EP2024/056026 which was purified by FCC (silica, eluting with 10-100% EtOAc/heptane then 0-10% MeOH/EtOAc) to give ethyl 3-hydroxy-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-propyl-5,6- dihydropyrrolo[2,l-a!]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carboxylate (2.66 g, 85% Yield) as an off white solid. RT (M2) = 0.88 min, (ESI+) (M+H)+ 523.3; 1H NMR (400 MHz, DMSO) 6 8.07 (s, 1H), 7.22 (s, 1H), 6.54 - 6.46 (m, 1H), 5.69 - 5.52 (m, 1H), 4.43 (s, 4H), 4.- 3.98 (m, 4H), 3.89 (s, 3H), 3.86 - 3.66 (m, 2H), 3.04 (t, J = 6.3 Hz, 2H), 2.68 - 2.62 (m, 2H), 2.19 - 1.78 (m, 2H), 1.69 1.59 (m, 2H), 1.59 - 1.41 (m, 3H), 1.18 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.3 Hz, 3H).

[00495] Step 5, Method 26

[00496]At rt, potassium trimethylsilanolate (90% purity, 2.93 g, 20.6 mmol, CAS 10519-96-7) was added to a solution of ethyl 3-hydroxy-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-propyl-5,6- dihydropyrrolo[2,l-a!]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carboxylate (2.15 g, 4.mmol) in THF (40 mL). The reaction mixture was stirred at 40 °C for 3 h. Water (30 mL) was added and the mixture was concentrated in vacuo to remove organics. The suspension was adjusted to pH 1 with addition of 6 M aq. HCI (5 mL) and was then extracted with DCM/MeOH (4:1, 2 x mL) and DCM (50 mL). The combined extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 3-hydroxy-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-propyl- 5,6-dihydropyrrolo[2,l-o ؛]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carboxylic acid (1.g, 47% yield) as a pale green solid. RT (M2) = 0.78 min, (ES1+) (M+H)+ 495.3.

[00497] Step 6, Method 26

[00498]At tr, ammonium chloride (1.25 g, 23.4 mmol, CAS 12125-02-9) was added to a solution of 3-hydroxy- 1 -[8-methoxy-9-(2-methyltetrazol-5-yl)- 1 -propyl-5,6-dihydropyrrolo[2, 1 - o ؛]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carboxylic acid (55% purity, 2.31 g, 2.mmol) and A-ethyl-A-(propan-2-yl)propan-2-amine (4.9 mL, 28.0 mmol, CAS 7087-68-5) in DCM (22 mL). The mixture was stirred for 5 min and then HATU (2.66 g, 7.0 mmol, CAS 148893- 10-1) was added. The reaction mixture was stirred at room temperature for 3 days. Water (1mL) was added and the mixture was stirred vigorously for 10 min. The aqueous layer was extracted with DCM/MeOH (4:1, 3 x 50 mL). The combined extracts were dried over anhydrous MgSO4, WO 2024/184461 PCT/EP2024/056026 filtered and concentrated in vacuo to give 3-hydroxy-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l- propyl-5,6-dihydropyrrolo[2,l-a!]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carboxamide (22% purity, 5.60 g, assumed quant, yield) as a pale green solid. RT (M2) = 0.68 min, (ESI+) (M+H)+ 494.3.

[00499] Step 7, Method 26

[00500]Under nitrogen, at 0 °C, trifluoroacetic anhydride (0.8 mL, 5.8 mmol, CAS 407-25-0) was added to a solution of 3-hydroxy-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-propyl-5,6- dihydropyrrolo[2,l-a!]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carboxamide (4.80 g, 2.mmol) and A,A-diethylethanamine (1.6 mL, 11.7 mmol, CAS 121-44-8) in THF (40 mL). The reaction mixture was stirred at this temperature for 1 h and then at rt for 1 h. At 0 °C, further portions of A,A-diethylethanamine (1.6 mL, 11.7 mmol, CAS 121-44-8) and trifluoroacetic anhydride (0.8 mL, 5.8 mmol, CAS 407-25-0) were added. The reaction mixture was stirred at this temperature for 1 h. 1 M aqueous NaOH (20 mL) was added to the reaction mixture and stirred vigorously for 10 min. Water (50 mL) was added and the mixture was concentrated to remove THF. The suspension was extracted with EtOAc (3 x 50 mL) and the combined extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give crude material, which was purified by FCC (silica, eluting with 10-100% heptane/EtOAc) and by acidic prep HPLC (Method P2) to give the pairs of enantiomers.

[00501]Chiral separation by chiral HPLC [Column: Chiralpak AD-H (20 x 250mm, 5pm) at 40°C; Isocratic eluent: 70:30 Heptane: i-PrOH; Flow rate: 15 mL/min; Dilution solvent: MeOH, i-PrOH, acetonitrile, formic acid] gave re/-(2R,35)-3-hydroxy-l-[8-methoxy-9-(2-methyltetrazol- 5-yl)-l-propyl-5,6-dihydropyrrolo[2,l-o ؛]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2- carbonitrile (stereoisomer 26-1) (101 mg, 9% yield) as a colorless solid. RT (M4) = 3.27 min, (ES1+) (M+H)+ 476.3. 1H NMR (400 MHz, DMSO) 6 8.07 (s, 1H), 7.23 (s, 1H), 6.59 (s, 1H), 6.(s, 1H), 4.44 - 4.34 (m, 5H), 4.28 (dt, J= 12.9, 6.3 Hz, 1H), 3.88 (s, 3H), 3.84 (t, J= 7.0 Hz, 2H), 3.05 (t, 6.4 Hz, 2H), 2.70-2.61 (m, 2H), 2.14-2.03 (m, 1H), 1.96- 1.86 (m, 1H), 1.69-1.58(m, 5H), 0.96 (t, J= 13 Hz, 3H).

WO 2024/184461 PCT/EP2024/056026

[00502]re/-(2S,37?)-3-hydroxy-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-propyl-5,6- dihydropyrrolo[2,l-a!]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile (steroisomer 26-1) (103 mg, 9% yield) as a colorless solid. RT (M4) = 3.26 min, (ESI+) (M+H)+ 476.3.1HNMR (400 MHz, DMSO) 6 8.07 (s, 1H), 7.23 (s, 1H), 6.59 (s, 1H), 6.06 (s, 1H), 4.44 - 4.35 (m, 5H), 4.28 (dt, J= 13.0, 6.3 Hz, 1H), 3.88 (s, 3H), 3.84 (t, J= 7.0 Hz, 2H), 3.05 (t, J= 6.4 Hz, 2H), 2.(t, J=7.6 Hz, 2H), 2.14-2.04 (m, 1H), 1.96- 1.86 (m, 1H), 1.68 - 1.57 (m, 5H), 0.97 (t, J =Hz, 3H).

[00503]Chiral separation by chiral SFC [Column: Chiralpak AD-H (10 x 250mm, 5pm) at 40°C; Isocratic eluent: 70:30 CO2:MeOH; Flow rate: 15 mL/min; Dilution solvent: methanol, acetonitrile] gave re/-(2R,3R)-3-hydroxy- 1 -[8-methoxy-9-(2-methyltetrazol-5-yl)- 1 -propyl-5,6- dihydropyrrolo[2,l-a!]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile (stereoisomer 26-1) (40 mg, 4% yield) as a colorless solid. RT (M4) = 3.15 min, (ESI+) (M+H)+ 476.3. 1H NMR (500 MHz, DMSO) 6 8.07 (s, 1H), 7.23 (s, 1H), 6.57 (s, 1H), 6.19 (s, 1H), 4.41 (s, 4H), 4.27 (dt, J= 13.0, 6.3 Hz, 1H), 4.08 (dd, J = 8.1, 5.2 Hz, 1H), 3.88 (s, 3H), 3.85 -3.73 (m, 2H), 3.05 (t, J = 6.4 Hz, 2H), 2.68 - 2.63 (m, 2H), 2.14 - 2.07 (m, 1H), 1.88 - 1.78 (m, 1H), 1.70 (s, 3H), 1.68 - 1.58 (m, 2H), 0.96 (t, J= 13 Hz, 3H). - 5,6-3 - hydroxy-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-propyl ،؟(- 3 ', 00504 ] re/-(2،S ]dihydropyrrolo[2,l-a!]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile (stereoisomer 26-1) (48 mg, 4% yield) as a colorless solid. RT (M4) = 3.15 min, (ESI+) (M+H)+ 476.3. 1H NMR (500 MHz, DMSO) 6 8.07 (s, 1H), 7.23 (s, 1H), 6.57 (s, 1H), 6.19 (s, 1H), 4.44 - 4.35 (m, 4H), 4.31 - 4.22 (m, 1H), 4.08 (dd, J= 7.8, 5.3 Hz, 1H), 3.88 (s, 3H), 3.85 - 3.72 (m, 2H), 3.05 (t, J= 6.1 Hz, 2H), 2.66 (t, J= 7.5 Hz, 2H), 2.16-2.04 (m, 1H), 1.88 - 1.78 (m, 1H), 1.70 (s, 3H), 1.- 1.59 (m, 2H), 0.96 (t, J= 13 Hz, 3H).

WO 2024/184461 PCT/EP2024/056026

[00505]The following analogs were made by analogous method: Structure Name LCMS/Ox^X/X Til o y /A / AZ yAOH V Stereoisomer 26-2 re/-(2jyAl-[l-(4-fluorophenyl)-8- methoxy-9-(2-methyltetr azol-5-yl)- 5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carbonyl]-3- hydroxy-2-methyl-pyrrolidine-2- carbonitrile RT (M4) = 3.min, [M+H]+ (ESI+) 528.4 /0XX"T 11 1 0 NxAAvNxJ'ב x>N y TyA / /X X/ ,OH M FZ Stereoisomer 26-2 re/-(25',3R)-1 -[ 1 -(4-fluorophenyl)-8- methoxy-9-(2-methyltetr azol-5-yl)- 5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carbonyl]-3- hydroxy-2-methyl-pyrrolidine-2- carbonitrile RT (M4) = 3.min, [M+H]+ (ESI+) 528.3 /O-x^x/XT 11 1 0 n x/VX/NJ I A y A—y / /x xy-oH FZ Stereoisomer 26-2 rel-Q.R,3RY 1 4)- 1 ]־-fluorophenyl)-8- methoxy-9-(2-methyltetr azol-5-yl)- 5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl]-3- hydroxy-2-methyl-pyrrolidine-2- carbonitrile RT (M4) = 3.min, [M+H]+ (ESI+) 528.3 /0xZx/X I || 1 0 y 2PyA / /X xA*OH FZ Stereoisomer 26-2 rel-(2S,3S)-1 -[ 1 -(4-fluorophenyl)-8- methoxy-9-(2-methyltetr azol-5-yl)- 5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carbonyl]-3- hydroxy-2-methyl-pyrrolidine-2- carbonitrile RT (M4) = 3.min, [M+H]+ (ESI+) 528.3 WO 2024/184461 PCT/EP2024/056026

[00506] Synthetic Method 27 Scheme for Method 27 OEt Pd/C

[00508] Step 1, Method 27

[00509]To a solution of ethyl l-(l-(benzyloxy)-2-methylpropan-2-yl)-8-methoxy-9-(2-methyl- 2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate (900 mg, 1.75 mmol) in THF (10 mL) was added with Pd/C (900mg, 1.75 mmol, 10% purity). The mixture was stirred at 45°C under H2 (15 psi) for 12 hr. The mixture was filtered and concentrated under vacuum to afford ethyl 1 -(1 -hydroxy-2-methylpropan-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate (650 mg, 87.52%) as a white solid. RT (M32) = 0.36 min, [M+H]+ (ESI+) 426.2.

[00510] Step 2, Method 27

[00511]To a solution of ethyl l-(l-hydroxy-2-methylpropan-2-yl)-8-methoxy-9-(2-methyl- 2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate (400 mg, 940.12 umol) in THF (3 mL), H2O (3 mL) and EtOH (3 mL) was added with KOH (131.86 mg, 2.35 mmol). The mixture was stirred at 45OC for 6 hr. The mixture was added with IM HC1 to adjust pH=5. The mixture was extracted with EtOAc (10 mLx3). The combined organic phase was washed with brine (10 mLx2), dried with anhydrous Na2S04, filtered and concentrated in vacuum to afford 1- (l-hydroxy-2-methylpropan-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carboxylic acid (350 mg, 93.68%) as a white solid. RT (M32) = 0.77 min, [M+H]+ (ES1+) 398.1.

[00507] WO 2024/184461 PCT/EP2024/056026

[00512] Synthetic Method 28

[00513] Scheme for Method 28

[00514] Step 1, Method 28

[00515]POC13 (35.03 g, 228.44 mmol) in DCE (100 mL) was dropwise added to DMF (16.g, 228.44 mmol) in DCE (200 mL) at 0°C and stirred at 0°C for 0.5 hr. Then the mixture of ethyl 9-bromo-8-methoxy-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate (20.00 g, 57.11 mmol) in DCE (200 mL) was added to the reaction mixture under N2. The mixture was stirred at 60°C for 2 hr. The mixture was slowly added into sat.Na2CO3 (500 mL) at 0°C until pH = 8 and stirred at 20°C for 1.5 hr. The aqueous phase was extracted with DCM (300 mL x 2). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na2S04, filtered and concentrated in vacuum to give ethyl 9-bromo-l-formyl-8-methoxy-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxylate (19.00 g, 88%) as awhite solid. RT (M13)= 1.93 min [M+H]+(ESI+) 378.1/380.1.

[00516] Step 2, Method 28

[00517]To a solution of ethyl 9-bromo-l-formyl-8-methoxy-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxylate (19.00 g, 50.24 mmol) in nitroethane (99.75 g, 1.33 mol) was added with NH40Ac (7.74 g, 100.47 mmol) at 20°C. The mixture was stirred at 120°C for 2 hr. The residue was poured into water (300 mL) at 0°C. The aqueous phase was extracted with DCM (1mL x 3). The combined organic phase was washed with brine (60 mL x 2), dried with anhydrous WO 2024/184461 PCT/EP2024/056026 Na2SO4, filtered and concentrated in vacuum to give ethyl (E)-9-bromo-8-methoxy-l-(2- nitroprop-l-en-l-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate (21.00 g, 96%) as a yellow solid. RT (M13) = 2.29 min [M+H]+ (ESI+) 435.2/437.2.

[00518] Step 3, Method 28

[00519]To a solution of ethyl (E)-9-bromo-8-methoxy-l -(2-nitroprop-l-en-l-yl)-5, 6- dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate (27.00 g, 62.03 mmol) in AcOH (270 mL) was added with Fe (34.64 g, 620.31 mmol) at 90°C. The mixture was stirred at 130°C for 2 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure. DCM (200 mL) and H20 (100 mL) was added to the reaction mixture. The aqueous phase was extracted with DCM (100 mL x 3). The combined organic phase was washed with brine (100 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1) to give ethyl 9-bromo-8-methoxy-l-(2-oxopropyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate (24.00 g, 84%) as a white solid. RT (M13) = 2.00 min [M+H]+ (ES1+) 406.2/408.1.

[00520] Step 4, Method 28

[00521]To a solution of ethyl 9-bromo-8-methoxy-l-(2-oxopropyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxylate (11.00 g, 27.08 mmol) in DCM (55 mL) was added with DAST (67.10 g, 416.28 mmol) at 0°C and stirred at 80°C for 2 hr. The reaction mixture was poured into the sat. Na2CO3 (300 mL) at 0°C to adjust the mixture pH to 7-8. The aqueous phase was extracted with DCM (60 mL x 2). The combined organic phase was washed with brine (50 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1) to give ethyl 9-bromo-l-(2,2-difluoropropyl)-8-methoxy-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate (10.00 g, 86%) as a yellow solid. RT (M13) = 2.27 min [M+H]+ (ES1+) 428.2/430.2.

WO 2024/184461 PCT/EP2024/056026

[00522] Synthetic Method 29

[00523] Scheme for Method 29

[00524] Step 1 Method 29

[00525]To a solution of (7?)-l-(9-bromo-8-methoxy-l-(thiophen-2-yl)-5,6-dihydropynolo[2,l- a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile (700 mg, 1.45 mmol) in EtOH (7 mL) was added with hypoboric acid (390.28 mg, 4.35 mmol), Pd(dtbpf)C12 (9.46 mg, 14.51 umol) and DIPEA (937.70 mg, 7.26 mmol, 1.26 mL). The mixture was stirred at 60 °C for 2 hr. The reaction mixture containing (7?)-(3-(2-cyano-2-methylazetidine- 1 -carbonyl)-8-methoxy- 1 -(thiophen-2-yl)- 5,6-dihydropyrrolo[2,l-a]isoquinolin-9-yl)boronic acid was cooled and used directly in next step. RT (M32) = 0.47 min [M+H]+ (ESI+) 448.0.

[00526] Synthetic Method 30

[00527] Scheme for Method 30

[00528] Step 1, Method 30

[00529]To a solution of 4-bromo-3-methoxy-benzaldehyde (43 g, 0.2 mol) in AcOH (86 mL) was added with NH40Ac (16.9 g, 0.22 mol) and CH3NO2 (61 g, 1 mol, 54 mL).The mixture was stirred at 80 °C for 12 hr. The reaction mixture was cooled down to ~25°C. H2O (430 mL) was WO 2024/184461 PCT/EP2024/056026 added to the reaction mixture and the mixture was stirred at 25 °C for 15 min, then it was filtered to afford a filter cake. The filter cake was triturated with MeCN (215 mL) at 25 °C for 15 min, filtered to afford filter cake. The filter cake was triturated with Petroleum ether (430 mL) at 25 °C for 15 min, filtered to give a cake, which was dried in vacuum to give (£)-1 -bromo-2-methoxy-4- (2-nitrovinyl)benzene (40 g, 90.43%). 1H NMR (400 MHz, CDCh) 8 = 7.96 (d, J= 13.7 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.58 (s, 1H), 7.05 (dd, J = 1.8, 8.2 Hz, 1H), 7.00 (d, J = 1.7 Hz, 1H), 4.03 - 3.92 (m, 3H).

[00530] Step 2, Method 30

[00531]To a solution of (£)-1-bromo-2-methoxy-4-(2-nitrovinyl)benzene (40 g, 155.00 mmol) in THF (800 mL) was added with MeMgBr (3 M, 55.91 mL) dropwise at -40°C under N2. The mixture was stirred at -40°C for 2 hr. The mixture was poured into NH4C1 (200 mL) at 0-10°C. The mixture was extracted with DCM (200 mL x 3), dried over Na2S04 and organic phase was concentrated. The residue was purified by column (SiO2, PE/EtOAc=3/l to 1/1). l-Bromo-2- methoxy-4-(l-nitropropan-2-yl)benzene (27 g, 64%) was obtained as colorless oil. 1H NMR (4MHz, DMSO-d6) 8 7.49 (d, J= 8.1 Hz, 1H), 7.11 (d,J= 1.4 Hz, 1H), 6.85 (dd, J =8.1, 1.5 Hz, 1H), 4.86 (s, 2H), 3.80 - 3.89 (m, 3H), 3.50 - 3.60 (m, 1H), 1.26 (d, J= 7.0 Hz, 3H)

[00532] Step 3, Method 30

[00533]To a solution of l-bromo-2-methoxy-4-(l-nitropropan-2-yl)benzene (11 g, 40.mmol) in EtOH (110 mL) was added Zn (39.36 g, 601.95 mmol) and HOAc (48.20 g, 802.mmol) at 0°C under N2. The mixture was stirred at 20°C for 12 hours. The mixture was filtered and filtrate was adjusted pH to 13 with 2N NaOH solution. The mixture was extracted with DCM (150 mL x 3), dried over Na2S04 and organic phase was concentrated. The residue was used directly next step without purification. 2-(4-Bromo-3-methoxyphenyl)propan-l -amine (15.1 g, crude) was obtained as yellow oil. RT (Ml 1) = 0.70 min [M+H]+ (ESI+) 244.1/246.1.

[00534] Step 4, Method 30

[00535]To a solution of 2-(4-bromo-3-methoxyphenyl)propan-l-amine (15 g, 61.44 mmol) in DCM (150 mL) was added with DIPEA (23.82 g, 184.33 mmol) and Fmoc-Cl (18.28 g, 70.

WO 2024/184461 PCT/EP2024/056026 mmol) at 0°C under N2. The mixture was stirred at 15 °C for 1 hr. The mixture was poured into M HCI (130 mL) and extracted with DCM (100 mL x 3). The combined organic phase was washed with 1 M HCI (80 mL), dried over Na2S04 and concentrated. The residue was purified by column (SiO2, PE/EtOAc=3/l). (9H-Fluoren-9-yl) methyl (2-(4-bromo-3- methoxyphenyl)propyl)carbamate (28 g, 88%, 90% purity) was obtained as white solid. RT (M14) = 1.04 min) [M+Na] + (ESI+) 488.1/490.1.

Structure Name LCMS H / ךן jp Fmoc (9H-fluoren-9-yl)methyl (1- (4-bromo-3-methoxyphenyl)propan-2 - yl)carbamate RT (M12) = 0.72 min [M+H]+(ESI+) 466.2/468.2

[00536] Synthetic Method 31

[00537] Scheme for Method 31 Pd(OAc)2

[00538] Step 1, Method 31

[00539]To a solution of Pd(OAc)2 (5.02 g, 22.37 mmol) and cyclopropanecarboxylic acid (28.89 g, 335.54 mmol, 26.50 mL) in HFIP (700 mL) was added (S)-N-(l-(dimethylamino)-3- phenylpropan-2-yl)acetamide (9.86 g, 44.74 mmol) and Ag2CO3 (92.52 g, 335.54 mmol, 15.mL), Na2CO3 (35.56 g, 335.54 mmol) and l-bromo-4-iodo-2-methoxy-benzene (70.00 g, 223.mmol). The mixture was stirred at 80o C for 12 h. The solvent was adjusted to pH 2-3 with IM HCI. The mixture was filtered and the filtrate was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with sat.NaHCO3 (100 mL x 2), and the aqueous layer was adjusted to pH 2-3 with IM HCI. The aqueous layer was extracted with ethyl acetate DCM (200-250- WO 2024/184461 PCT/EP2024/056026 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried with anhydrous Na2S04, filtered and concentrated in vacuum. The crude product was purified by reversed-phase HPLC to give (U?,2lS)-2-(4-bromo-3-methoxyphenyl)cyclopropane-l-carboxylic acid (31.50 g, 51.94% yield) was obtained as a brown oil. RT (M27) =1.14 min [M+Na] + (ESI+) 269.1/271.0.

[00540] Step 2, Method 31

[00541]To a solution of (l/?,2.S)-2-(4-bromo-3-methoxyphenyl)cyclopropane-l-carboxylic acid (36.00 g, 132.79 mmol) in toluene (360 mL) was added TEA (14.78 g, 146.07 mmol, 20.mL), DPPA (40.20 g, 146.07 mmol, 31.65 mL) and 9H-fluoren-9-ylmethanol (31.27 g, 159.mmol), then it was stirred at 120°C for 0.5 hr. The mixture was diluted with EtOAc (100 mL), then filtered. The filtrate was poured into H20 (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried with anhydrous Na2S04, filtered and concentrated in vacuum. The organic layers were concentrated under reduced pressure to give a crude product. The crude product was triturated with MeCN (100 mL) at 20°C for min to give the (9H-fluoren-9-yl)methyl((lR,2R)-2-(4-bromo-3methoxyphenyl)cyclopropyl) carbamate (28 g, 45.41%, yield) as a white solid. RT (MH) = 2.06 min [M+Na] + (ESI+) 486.2/488.2.

WO 2024/184461 PCT/EP2024/056026

[00542] Synthetic Method 32 Scheme for Method 32 [00543] TMSOK NH3 CICO2Et DCE, rt Et3N Burgess Reagent

[00544] Step 1, Method 32

[00545]HATU (698.57 mg, 1.84 mmol, 1.5 eq) was added to a solution of 8-methoxy-9-(2- methyltetrazol-5-yl)-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylic acid (450 mg, 1.22 mmol), rac-methyl (17?,6>S)-2-azabicyclo[4.2.0]octane-l-carboxylate hydrochloride, cis (302.31 mg, 1.47 mmol) and triethylamine (433.79 mg, 4.29 mmol, 597.50 pL) in DMF (6 mL, 0.2 M) and the reaction was stirred at 50 °C for 16 h. The reaction was followed by LCMS. When the starting material was consumed, the reaction was quenched with water (5 mL) and diluted with EtOAc (10 mL). The organic layer was washed with water (5 mL) and brine (5 mL), dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography eluting with dichloromethane:methanol to give rac-methyl (1/?,6.S')-2-[8- methoxy-9-(2-methyltetrazol-5-yl)-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]- WO 2024/184461 PCT/EP2024/056026 2-azabicyclo[4.2.0]octane-l-carboxylate, cis (619 mg, 1.04 mmol, 85% yield) as a purple solid. RT (M42) = 1.64 min, [M+H]+ (ESI+) 519.1.

[00546] Step 2, Method 32

[00547]Potassium trimethylsilanolate (111.9 mg, 0.87 mmol, 2 eq) was added to a solution of rac-methyl (lR,6lS)-2-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-propyl-5,6-dihydropynolo[2,l- a]isoquinoline-3-carbonyl]-2-azabicyclo[4.2.0]octane-l-carboxylate, cis (260 mg, 0.44 mmol, eq) in dry THF (11 mL, 0.04 M) and stirred at 50 °C for 16 h. The reaction was followed by LCMS. Water was added and the pH of the mixture was adjusted to 4 by addition of HCI IN. The crude was diluted with EtOAc (60 mL) and washed with H20 (50 mL). The aqueous layer was extracted with CHClz:iPrOH (3:1). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated under vacuum. Crude was used in the next step without further purification. RT (M44) = 1.14 min, [M+Na] +(ESI+) 505.2.

[00548] Step 3, Method 32

[00549]Under argon atmosphere triethylamine (69.89 mg, 0.69 mmol, 96.27 pL, 1 eq) was added to a solution of rac-(lR,6،8]-2-( ؟-methoxy-9-(2-methyltetrazol-5-yl)-l-propyl-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2-azabicyclo[4.2.0]octane-l-carboxylic acid, cis (410 mg, 0.69 mmol, 1 eq) and ethyl chloroformate (149.91 mg, 1.38 mmol, 131.96 pL, 2 eq) in THF (17 mL, 0.04M) at -10°C. Reaction was stirred at -10°C for 30 min. Then, ammonia (g) was bubbled into the reaction for 15 min and the mixture was stirred at rt for l h. The reaction was followed by LCMS. When the starting material was consumed, the reaction was quenched with water (10 mL) and diluted with EtOAc (40 mL). The organic layer was washed with water (mL) and brine (10 mL), dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography eluting with di chloromethane :methanol to give rac-(U?,6 lS)-2-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-propyl-5,6-dihydropynolo[2,l- a]isoquinoline-3-carbonyl]-2-azabicyclo[4.2.0]octane-l-carboxamide, cis (114 mg, 0.22 mmol, 32% yield) was isolated as a blue solid. RT (M44) = 1.07 min, [M+H]+(ESI+) 504.3.

WO 2024/184461 PCT/EP2024/056026

[00550] Step 4, Method 32

[00551]Methyl N-(triethylammoniumsulfonyl)carbamate (Burgess reagent) (107.89 mg, 0.mmol, 2 eq) was added to a solution of rac-(U?,6 lS)-2-[8-methoxy-9-(2-methyltetrazol-5-yl)-l- propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2-azabicyclo[4.2.0]octane-l- carboxamide, cis (114 mg, 0.23 mmol, 1 eq) in DCM (9 mL, 0.03M). The reaction is stirred at rt for 16 h. The reaction was followed by LCMS. When the starting material was consumed, the reaction was quenched with water (10 mL) and diluted with DCM (20 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography eluting with dichloromethane:methanol to give rac-(1R,6S)-2-[8-methoxy-9-(2-methyltetrazol-5-yl)-1-propyl- 5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2-azabicyclo[4.2.0] octane- 1-carbonitrile (1mg, 0.21 mmol, 94%). RT (M44) = 1.25 min, (ES1+) 486.1 [M+H]+. The racemic mixture was separated using prep method 13 (P13) to give the eutomer (compound 32-1) (l،S'*,6R*)-2-(8- methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl)-2-azabicyclo[4.2.0]octane-l-carbonitrile (35.1 mg, 0.07 mmol, 32%) as a white solid. RT (M41) = 3.86 min, [M+H]+(Dual-ESl +) 486.23; 1H-NMR (DMSO-d6, 400 MHz) 6 8.02 (s, 1H), 6.44 (s, 1H), 4.4-4.3 (m, 4H), 4.2-4.0 (m, 2H), 3.83 (s, 3H), 3.02 (br t, J = 6.4 Hz, 4H), 2.8- 2.7 (m, 1H), 2.7-2.6 (m, 2H), 2.1-2.0 (m, 2H), 2.0-1.8 (m, 3H), 1.7-1.5 (m, 5H), 0.93 (t, J = Hz, 3H).

[00552]The following analog was made by analogous method: Structure Name LCMS A—LATN9 W 7 H Compound 32-2 (1S * ,5 S *)-2-(8-methoxy-9-(2- methyl-2H-tetrazol-5 -yl)- 1 - propyl-5,6-dihydropyrrolo[2, 1 - a] isoquinoline-3-carbonyl)-5- methyl-2-azabicyclo[3.2.0]heptane- 1 - carbonitrile RT (M40) = 3.min, [M+H]+ (ES1+)472.2 WO 2024/184461 PCT/EP2024/056026 * Denotes unknown stereochemistry, isolated from a diastereomeric mixture using SFC chromatography

[00553] Synthetic Method 33

[00554] Scheme for Method 33 TBDSCI Imidazole

[00555] Step 1, Method 33

[00556]Under argon atmosphere, imidazole (10.44 g, 153.38 mmol, 2.2 eq) was added portionwise to a solution of 1-(tert-butyl) 2-methyl (27?,4lS)-4-hydroxypynoli dine- 1,2- dicarboxylate (18 g, 69.72 mmol, 1 eq) and tert-butylchlorodimethylsilane (15.76 g, 104.58 mmol, 19.46 mL, 1.5 eq) in dry DCM (108 mL, 0.55M) at 0 °C. Then, the reaction was stirred at rt for h. When the starting material was consumed, the reaction mixture was washed with water (1mL). The aqueous phase was extracted with DCM three times (50 mL). Organics were combined, dried with MgSO4 and concentrated under vacuum. The crude was purified by flash WO 2024/184461 PCT/EP2024/056026 chromatography using heptane/ethyl acetate as eluents. 1-(tert-butyl) 2-methyl (2R,4،S)-4-((tert- butyldimethylsilyl)oxy)pyrrolidine-l,2-dicarboxylate (23.5 g, 64.06 mmol, 92% yield) was obtained as colorless oil. 1H-NMR (DMSO-d6, 400 MHz) 6 4.42 (br s, 1H), 4.2-4.1 (m, 1H), 3.7- 3.6 (m, 3H), 3.25 (brt, J = 11.1 Hz, 1H),2.1-2.O (m, 1H), 2.0-1.9 (m, 1H), 1.4-1.3 (m, 9H), 0.(s, 9H), 0.05 (d, J= 2.1 Hz, 6H).

[00557] Step 2, Method 33

[00558]Under argon atmosphere 1-(tert-butyl) 2-methyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy) pyrrolidine- 1,2-dicarboxylate (6 g, 16.69 mmol, 1 eq) was diluted in dry THF (220 mL, 0.05M) . The mixture was cooled to -78 °C and LiHMDS (IM in hexanes, 66.mmol, 66.75 mL, 4 eq) was added dropwise. The reaction was stirred at that temperature for 4 h. Then iodomethane (18.95 g, 133.51 mmol, 8.31 mL, 8 eq) was added dropwise. The mixture was stirred at -78 °C for 2 h and then at rt for 16 h. The reaction was followed by TLC and LCMS and two diastereoisomers were formed. The reaction was quenched with water and extracted with EtOAc (100 mL x 3). The organics were washed with brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by flash chromatography eluting with heptane :ethyl acetate. The two diastereoisomers were obtained pure.

[00559]Fl: Heptane/AcOEt 95:5. 1-(tert-butyl) 2-methyl (2S',4lS)-4-((tert-butyldimethylsilyl)oxy)-2-methyl- pyrroli dine- 1,2-dicarboxylate (780 mg, 2.09 mmol, 12%) was obtained as a colorless oil. RT (M44) = 1.56 min, [M+Na] + 396.2; 1H-NMR (DMSO-d6,400 MHz) 4.44 (quin, J= 6.5 Hz, 1H), 3.7-3.6 (m, 3H),3.58(s, 1H), 3.0-3.1 (m, 1H), 2.2-1.9(m, 2H), 1.(s, 3H), 1.38 (s, 3H), 1.32 (s, 6H), 0.84 (s, 9H), 0.1-0.0 (m, 6H).

[00560]F2: Heptane/AcOEt 93:7. 1-(tert-butyl) 2-methyl (2R,4S)-4-((tert- butyldimethylsilyl)oxy)-2-methyl-pyrrolidine-l,2-dicarboxylate (2.23 g, 5.84 mmol, 35%) was obtained as a colorless oil.

[00561]LCMS: RT (M44) = 1.56 min, [M+Na] + 396.2; 1H-NMR (DMSO-d6, 400 MHz) 8 4.(m, 1H), 3.63 (s, 2H), 3.6-3.5 (m, 2H), 3.3-3.2 (m, 1H), 2.3-2.2 (m, 1H), 1.9-1.8 (m, 1H), 1.56 (s, 3H), 1.37 (s, 3H), 1.32 (s, 6H), 0.86 (s, 9H), 0.1-0.0 (m, 6H).

WO 2024/184461 PCT/EP2024/056026

[00562] Step 3, Method 33

[00563]Potassium trimethylsilanolate (1.53 g, 11.94 mmol, 2 eq) was added to a solution of 1- (tert-butyl) 2-methyl (2R,4lS)-4-((tert-butyldimethylsilyl)oxy)-2-methylpynolidine- 1,2-dicarboxylate (2.23 g, 5.97 mmol) in dry THF (28 mL, 0.2 M) and stirred at 50 °C for 16 h. The reaction was followed by TLC and LCMS. Water was added and the pH of the mixture was adjusted to 6 by addition of HCI IN. The crude was diluted with ethyl acetate (60 mL) and washed with water (50mL). The aqueous layer was extracted with CHC13:z ’PrOH (3:1). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated under vacuum. Crude was used in the next step without further purification. RT (M44) = 1.38 min, [M+Na] + 382.2.

[00564] Step 4, Method 33

[00565]HATU (6.66 g, 17.52 mmol, 1.5 eq) was added to a solution of (2R,4S)-l-(tert- butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)-2-methylpyrrolidine-2-carboxylic acid (4.2 g, 11.68 mmol, 1 eq), DIPEA (5.28 g, 40.89 mmol, 7.12 mL, 3.5 eq) and NH4CI (937.32 mg, 17.mmol, 1.5 eq) in DMF (34 mL, 0.28 M) and the reaction was stirred at room temperature for 16 h. The reaction was followed by LCMS. When the starting material was consumed the reaction was diluted with EtOAc (100 mL) and washed with water (30 mLx5). The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography eluting with heptane:ethyl acetate to give tert-butyl (2R,4S)-4-((tert- butyldimethylsilyl)oxy)-2-carbamoyl-2-methylpyrrolidine-l-carboxylate (3.41 g, 9.32 mmol, 80% yield) as a white solid. RT (M44) = 1.26 min, [M+Na] + 359.2; 1H-NMR (DMSO-d6, 4MHz) 6 7.1-7.0 (m, 1H), 7.0-6.8 (m, 1H), 4.4-4.3 (m, 1H), 3.68 (br dd, J= 5.0, 11.1 Hz, 1H), 3.2- 3.2 (m, 1H), 2.2-2.1 (m, 1H), 1.8-1.7 (m, 1H), 1.6-1.5 (m, 3H), 1.4-1.3 (m, 9H), 0.85 (s, 9H), 0.(s, 6H).

[00566] Step 5, Method 33

[00567]Hydrogen chloride 4N in dioxane (4 M, 2.90 mmol, 725.15 pL, 2 eq) was added to a solution of tert-butyl(2R,4،S)-4-((tert-butyldimethylsilyl)oxy)-2-carbamoyl-2-methylpyrrolidine- 1-carboxylate (520 mg, 1.45 mmol, 1 eq) in DCM (5 mL, 0.25M) and the reaction was stirred at rt for 16 h. Reaction is followed by LCMS and when all the starting material have reacted the solvent -257- WO 2024/184461 PCT/EP2024/056026 was removed under vacuum and the crude product was used in the next step without further purification. RT (M43) = 0.67 min, [M-C1]+259.2

[00568] Step 6, Method 33

[00569]TCFH (293.26 mg, 1.05 mmol, 1.2 eq) was added to a solution of 8-methoxy-9-(2- methyltetrazol-5-yl)-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylic acid (320 mg, 0.87 mmol, 1 eq), (27?,4lS)-4-[ter/-butyl(dimethyl)silyl]oxy-2-methyl-pynolidine-2- carboxamide;hydrochloride (385.27 mg, 1.31 mmol, 1.5 eq) and 1 -methylimidazole (250.29 mg, 3.05 mmol, 242.76 pL, 3.5 eq) in DMA (1.7 mL, 0.45 M) and stirred at 70 °C for 16 h. The reaction was followed by LCMS, showing the formation of the expected compound (RT (M43) = 1.65 min, 608.5 [M+H]+) and the product resulting from the Boc cleavage (RT (M43) = 0.85 min, 494.[M+H]+). The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with heptane/EtOAc (0-100%) to give (27?,45)-4-[/6^- butyl(dimethyl)silyl]oxy-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-propyl-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carboxamide (100 mg, 0.08 mmol, 9% yield, 50% purity) as a yellowish oil (RT (M43) = 1.65 min, [M+H]+ 608.5) and gradient towards DCM/MeOH (0-10%) to obtain (2R,4،S)-4-hydroxy-l-[8-methoxy-9-(2- methyltetrazol-5-yl)-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2-methyl- pyrrolidine-2-carboxamide (30 mg, 0.06 mmol, 7% yield) as a white solid. RT (M43) = 0.85 min, [M+H]+ 494.4.

[00570] Step 7, Method 33

[00571]Methyl N-(triethylammoniumsulfonyl)carbamate (Burgess reagent) (23.52 mg, 0.mmol, 2 eq) was added to a solution of (2R,4،4-(؟-[/ert-butyl(dimethyl)silyl]oxy-l-[8-methoxy-9- (2-methyltetr azol-5-yl)-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2-methyl- pyrrolidine-2-carboxamide (30 mg, 0.05 mmol, 1 eq) in dichloroethane (2 mL, 0.02M) and the reaction was stirred at rt for 16 h. The reaction was followed by LCMS. When the starting material was consumed, the reaction was quenched with water (5 mL) and diluted with DCM (10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. The WO 2024/184461 PCT/EP2024/056026 crude product was used in the next step without further purification. RT (M43) = 1.87 min, [M+H]+ 590.2.

[00572] Step 8, Method 33

[00573]Tetrabutylammonium fluoride, IM in THF (1 M, 0.10 mmol, 98.34 pL, 2 eq) was added to a solution of (2R,4lS)-4-[ter/-butyl(dimethyl)silyl]oxy-l-[8-methoxy-9-(2-methyltetrazol-5-yl)- l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile (29 mg, 0.05 mmol, 1 eq) in dry THF (2 mL) and the reaction was stirred at rt for 16 h. The reaction was followed by LCMS. When the starting material was consumed, the reaction was quenched with water (5 mL) and diluted with DCM (10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography eluting with dichloromethane:ethyl acetate to give (2R,4lS)-4-hydroxy-l-[8-methoxy-9-(2- methyltetrazol-5-yl)-l-propyl-5,6-dihydropyrro-lo[2,l-a]isoquinoline-3-carbonyl]-2-methyl- pyrrolidine-2-carbonitrile (compound 33-1) (12.6 mg, 0.03 mmol, 53% yield) as a white solid. RT (M41) = 3.27 min, [M+H]+ (Dual-ESI +) 476.2; 1H-NMR (DMSO-d6, 400 MHz) 6 8.09 (s, 1H), 7.24 (s, 1H), 6.59 (s, 1H), 5.42 (br s, 1H), 4.42 (s, 3H), 4.4-4.3 (m, 3H), 4.01 (dd, J= 5.4, 10.4 Hz, 1H), 3.89 (s, 3H), 3.64 (dd, J= 4.6, 10.3 Hz, 1H), 3.07 (brt, J = 6.3 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H), 2.61 (dd, J = 5.2, 13.0 Hz, 1H), 2.13 (dd, J = 5.9, 13.0 Hz, 1H), 1.83 (s, 3H), 1.65 (qd, J = ר A, 15.0 Hz, 2H), 0.98 (t, J= 13 Hz, 3H).

WO 2024/184461 PCT/EP2024/056026

[00574] Synthetic Method 34

[00575] Scheme for Method 34 F F Cmp 34-1

[00576] Step 1, Method 34

[00577]Triethylamine (289.52 mg, 2.86 mmol, 398.79 pL, 3 eq) was added to a solution of 1- (4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxylic acid (400 mg, 0.95 mmol, 1 eq), (2^?,45)-4-[/6^- butyl(dimethyl)silyl]oxy-2-methyl-pyrrolidine-2-carboxamide; hydrochloride (421.87 mg, 1.mmol, 1.5 eq) and 2-chloro- 1-methyl-pyridin- 1-ium iodide (365.49 mg, 1.43 mmol, 1.5 eq) in DMA (3 mL, 0.28 M) and stirred at 70 °C for 16 h. The reaction was followed by LCMS showing the formation of the expected product (m/z 660) and the TBS deprotected product (m/z 546). The reaction was diluted with ethyl acetate (12 mL) and washed with brine (5 mL x 5). The organic layer was dried over MgSO4, filtered and concentrated under vacuo. The crude product was purified by flash chromatography eluting with dichloromethane:methanol to yield (2/?,4.S')-l-[l- (4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl]-4-hydroxy-2-methyl-pyrrolidine-2-carboxamide (85 mg, 0.15 mmol, 21% yield) as a yellow oil. RT (M43): 0.91 min; [M+H]+ 546.4.

WO 2024/184461 PCT/EP2024/056026

[00578] Step 2, Method 34

[00579]Methyl N-(triethylammoniumsulfonyl)carbamate (Burgess reagent) (72.51 mg, 0.mmol, 2 eq) was added to a solution of (2R,4،S)-l-[l-(4-fluorophenyl)-8-methoxy-9-(2- methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-4-hydroxy-2-methyl- pyrrolidine-2-carboxamide (83 mg, 0.15 mmol, 1 eq) in DCM (2 mL, 0.08M) and the reaction was stirred at rt for 4 h. The reaction was followed by LCMS. When the starting material was consumed, the reaction was quenched with water (5 mL) and diluted with DCM (10 mL). The organic layer was dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography eluting with dichloromethane :ethyl acetate to give (2R,4S)-1-[1- (4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl]-4-hydroxy-2-methyl-pyrrolidine-2-carbonitrile (compound 34-1) (21 mg, 0.04 mmol, 26% yield) as a white solid. RT (M41): 3.24 min; m/z [M+H]+ (Dual-ESl +) 528.2; 1H-NMR (DMSO-d6,400 MHz) 6 7.71 (s, 1H), 7.44 (dd, J= 5.6, 8.7 Hz, 2H), 7.24 (s, 1H), 7.2-7.2 (m, 2H), 6.74 (s, 1H), 5.42 (br s, 1H), 4.4-4.3 (m, 2H), 4.33 (s, 3H), 4.06 (dd, J = 5.2, 10.4 Hz, 1H), 3.(s, 3H), 3.70 (dd, J= 4.5, 10.3 Hz, 1H), 3.29 (s, 1H), 3.15 (br t, J= 6.4 Hz, 2H), 2.62 (dd, J= 5.2, 13.1 Hz, 1H), 2.15 (dd, J= 5.7, 13.0 Hz, 1H), 1.85 (s, 3H).

[00580]Additional compounds were prepared as described below.

[00581] INTERMEDIATE 1:(E)-l-bromo-2-methoxy-4-(2-nitrovinyl)benzene

[00582]To a solution of 4-bromo-3-methoxy-benzaldehyde (430 g, 2.00 mol) in AcOH (8mL) was added NH4OAc (169.55 g, 2.20 mol) and CH3NO2 (610.27 g, 10.00 mol, 540.07 mL). The mixture was stirred at 80 °C for 12 hr. The reaction mixture was cooled down to -25 °C. Three batches were combined to work up. H20 (1800 mL) was added to the reaction mixture and stirred at 25 °C for 15 min, then it was filtered to afford a filter cake. The filter cake was triturated with MeCN (900 mL) at 25 °C for 15 min, filtered to afford the solid. The solid was triturated with Petroleum ether (1800 mL) at 25 °C for 15 min, filtered to give a cake, which was dried under -261- WO 2024/184461 PCT/EP2024/056026 reduced pressure to give the title compound (1600 g, 90% yield) as a yellow solid. 1H NMR (4MHz, CDCI) 6 = 7.96 (d, J = 13.7 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.58 (s, 1H), 7.05 (dd, J = 1.8, 8.2 Hz, 1H), 7.00 (d, J = 1.7 Hz, 1H), 4.03 - 3.92 (m, 3H)

[00583] INTERMEDIATE 2:2-(4-bromo-3-methoxyphenyl)ethan-l-amine

[00584]At 0 °C, BH3.THF (1 M, 8.82 L) was added dropwise to a solution of Intermediate (650 g, 2.52 mol) in THF (6500 mL). Then NaBH4 (47.64 g, 1.26 mol) was added in portions at 5-8 °C. The mixture was stirring at 65 °C for 18 hr. The reaction mixture was cooled to 0 °C and added dropwise with HC1 (4.9 L, 4M). After stirring for 1 h at 70 °C, the reaction mixture was cooled to room temperature and MTBE (IL) was added to the mixture. The aqueous layer was separated and extracted with MTBE (IL x 3). The aqueous layer was adjust to pH=13 with solid NaOH at 0-5°C, then extracted with DCM (5L x 3), The combined organic phase was washed with brine (500 mL x 3), dried with Na2S04, filtered and concentrated under reduced pressure to give the title compound (510 g, 2.13 mol, 88% yield) as a yellow oil. 1H NMR (400 MHz, CDCI) 6 = 7.44 (br d, J = 7.9 Hz, 1H), 6.74 (d, J = 1.8 Hz, 1H), 6.68 (dd, J = 1.9, 8.0 Hz, 1H), 3.92 - 3.85 (m, 3H), 3.01 - 2.92 (m, 2H), 2.76 - 2.64 (m, 2H), 1.44 - 1.18 (m, 2H)

[00585] INTERMEDIATE 3:N-(4-bromo-3-methoxyphenethyl)formamide

[00586]To a solution of Intermediate 2 (40 g, 150.06 mmol, HC1) in ethyl formate (200 mL) was added TEA (45.55 g, 450.18 mmol, 62.66 mL) at 20 °C. The mixture was stirred at 70 °C for hr. Two reactions were combined to work up. The reaction mixture was concentrated under reduced pressure to remove the solvent to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 10/1 to 1/1) to give the title WO 2024/184461 PCT/EP2024/056026 compound (74 g, 88% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.04 (br s, 1H), 7.98 (d, J= 1.8 Hz, 1H), 7.50 - 7.42 (m, 1H), 6.97 (d, J= 1.5 Hz, 1H), 6.74 (dd, J= 1.7, 8.Hz, 1H), 3.86 - 3.81 (m, 3H), 3.37 - 3.33 (m, 2H), 2.74 - 2.68 (m, 2H).

[00587] INTERMEDIATE 4:l-bromo-4-(2-isocyanoethyl)-2-methoxybenzene

[00588]To a solution of Intermediate 3 (25 g, 96.86 mmol) in THF (250 mL) was added Burgess Reagent (27.70 g, 116.23 mmol) at 0°C. The mixture was stirred at 20°C for 2 hr. The two reactions was combined to work up. The mixture was added with H20 (500 mL) and extracted with DCM (200 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 10/1 to 1/1) to give the title compound (42 g, 90% yield) as a yellow oil. 1H NMR (4MHz, CDCL) 8 = 7.50 (d, 8.0 Hz, 1H), 6.79 (d, J= 1.5 Hz, 1H), 6.72 (dd,J= 1.8, 8.0 Hz, 1H),3.96 - 3.89 (m, 3H), 3.63 (br t, J= 6.9 Hz, 2H), 2.96 (br t, J= 6.8 Hz, 2H).

[00589] INTERMEDIATE 5:N-(4-bromo-3-methoxyphenethyl)-2-formamido-2-(thiophen- 2-yl)acetamide

[00590]To a solution of Intermediate 4 (20 g, 83.30 mmol) in MeOH (200 mL) was added with ammonium formate (10.51 g, 166.60 mmol) and thiophene-2-carbaldehyde (9.81 g, 87.46 mmol, 8.17 mL) at 20°C. The mixture was stirred at 80°C for 4 hr. The two reactions was combined to work up. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H20 (500 mL) and extracted with warm EtOAc (200 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The crude HN^^O WO 2024/184461 PCT/EP2024/056026 product was triturated by cold EtOAc (100 mL) and filtered to give the title compound (38 g, 57% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.86 (hr d, J= 8.3 Hz, 1H), 8.46 (hr t, J= 5.4 Hz, 1H), 8.02 (s, 1H), 7.47 - 7.36 (m, 2H), 6.98 - 6.85 (m, 3H), 6.66 (dd, J = 0.9, 8.1 Hz, 1H), 5.72 (d, J = 8.3 Hz, 1H), 3.83 - 3.74 (m, 3H), 3.41 - 3.33 (m, 2H), 2.70 (t, J= 6.9 Hz, 2H).

[00591] INTERMEDIATE 6:9-bromo-8-methoxy-l-(thiophen-2-yl)-5,6- dihydroimidazo[5, 1 -a] isoquinoline

[00592]A solution of P2O5 (67.88 g, 478.24 mmol) in methanesulfonic acid (350 mL) at 20 °C was stirred at 75 °C for 0.5 hr. Intermediate 5 was added into the mixture (38 g, 95.65 mmol) at °C and then it was stirred at 75 °C for 1.5 hr. The reaction was poured into ice-H2O (1 L) and the mixture was added Na2CO3 solid slowly to adjust pH = 8, then it was extracted with EtOAc (400 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The crude product was triturated by MTBE (300 mL) and filtered to give the title compound (31 g, 89% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) 8 = 7.84 (s, 1H), 7.78 (s, 1H), 7.54 (br d, J =4.9 Hz, 1H), 7.26 (br d, J= 2.9 Hz, 1H), 7.18 (s, 1H), 7.15 - 7.09 (m, 1H), 4.15 (brt, J= 6.0 Hz, 2H), 3.91 - 3.84 (m, 3H), 3.05 (brt, J= 5.7 Hz, 2H).

[00593] INTERMEDIATE 7:Ethyl 9-bromo-8-methoxy-l-(thiophen-2-yl)-5,6- dihydroimidazo[5, 1 -a]isoquinoline-3-carboxylate WO 2024/184461 PCT/EP2024/056026

[00594]To a solution of Intermediate 6 (15 g, 41.52 mmol) in THF (150 mL) was added LDA (2 M, 24.91 mL) at -70 °C. The mixture was added with ethyl chloroformate (22.53 g, 207.mmol, 19.76 mL) at -70 °C and the mixture was stirred at -70 °C for 2 hr. The mixture was added with H20 (100 mL) and extracted with EtOAc (100 mL x 3). The organic layers were concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 0/1) to give the title compound (9.g, 52% yield) as a yellow solid. 1H NMR (400 MHz, CDCh) 8 = 7.89 (s, 1H), 7.41 - 7.37 (m, 1H), 7.35 - 7.32 (m, 1H), 7.10 (dd, J= 3.6, 5.1 Hz, 1H), 6.82 (s, 1H), 4.69 (t, J= 6.6 Hz, 2H), 4.46 (q, J= 7.1 Hz, 2H), 3.97 - 3.92 (m, 3H), 3.08 (t, J= 6.6 Hz, 2H), 1.49 - 1.42 (m, 3H).

[00595] INTERMEDIATE 8 (From Int 7):ethyl 8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)- l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxylate

[00596]To a solution of Intermediate 7 (400 mg, 923.11 umol) and l-methyl-3-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrazole (230.48 mg, 1.11 mmol) in dioxane (5 mL) and H(1 mL) was added Xphos-Pd-G2 (72.63 mg, 92.31 umol) and C82CO3 (1.20 g, 3.69 mmol) at °C. The mixture was stirred at 80 °C for 2 hr. The mixture was filtered and the filtrate was added with H20 (3 mL) and extracted with EtOAc (2 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 10/1 to 1/1) to give the title compound (350 mg, 87% yield) as a yellow solid. 1H NMR (400 MHz, CDCh) 8 = 8.29 (s, 1H), 7.44 - 7.(m, 1H), 7.35 - 7.33 (m, 2H), 7.08 (m, 1H), 6.88 (s, 1H), 6.56 (s, 1H), 4.70 (t, J = 6.6 Hz, 2H), 4.46 (q, J= 7.1 Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.12 (t, J= 6.6 Hz, 2H), 1.45 (m, 3H).

[00597] INTERMEDIATE 9:Potassium 8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-l- (thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxylate WO 2024/184461 PCT/EP2024/056026

[00598]To a solution of Intermediate 8 (120 mg, 276.17 pmol) in THE (1 mL) was added TMSOK (70.86 mg, 552.35 pmol). The mixture was stirred at 20 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to remove dioxane to use to next step. The title compound (336 mg, crude) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.46 (s, 1H), 7.65 (s, 1H), 7.41 (d, J = 4.8 Hz, 1H), 7.36 (d, J = 4.8 Hz, 1H), 7.08-7.05(m, 2H), 6.63 (s, 1H), 4.61 (t, J= 6.6 Hz, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 2.96 (t, J= 6.6 Hz, 2H).

[00599] INTERMEDIATE 10:8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-l-(thiophen-2-yl)- 5,6-dihydroimidazo[5,l-a]isoquinoline

[00600]To a solution of Intermediate 6 (3 g, 8.30 mmol) and l-methyl-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrazole (2.07 g, 9.97 mmol) in dioxane (0.5 mL) andH2O (0.mL) was added Xphos-Pd-G2 (653.39 mg, 830.44 pmol) and C82CO3 (10.82 g, 33.22 mmol) at °C. The mixture was stirred at 80 °C for 2 hr. The residue was diluted with H2O (10 mL) and extracted with EtOAc (5 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 10/1 to 1/1) to give the title compound (4.5 g, 75% yield) as a yellow solid. 1H NMR (400 MHz, CDCh) 8 = 8.47 (s, 1H), 7.69 (s, 1H), 7.54 (d, J = 4.8 Hz, 1H), 7.35 (d, J = 4.8 Hz, 1H), 7.30 (m, 1H), 7.08-7.05(m, 1H), 6.87 (s, 1H), 6.62 (s, 1H) 4.18 (t, J = 6.6 Hz, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.12 (t, J= 6.6 Hz, 2H).

WO 2024/184461 PCT/EP2024/056026

[00601] INTERMEDIATE 8 (From Int 10):Ethyl 8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxylate

[00602]To a solution of Intermediate 9 (1.75 g, 4.83 mmol) in THF (15 mL) was added LDA (2 M, 3.38 mL) at -60 °C. The mixture was added with ethyl chloroformate (1.12 g, 10.32 mmol) at -60 °C and stirred for 2 hr. The mixture was added with H20 (50 mL) and extracted with EtOAc (20 mL x 3). The organic layers were concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 10/1 to 1/1) to give the title compound (1.3 g, 31% yield) as a yellow solid. 1H NMR (400 MHz, CDCh) 8 = 8.29 (s, 1H), 7.44 - 7.43 (m, 1H), 7.35 - 7.33 (m, 2H), 7.08 (m, 1H), 6.(s, 1H), 6.56 (s, 1H), 4.70 (t, J= 6.6 Hz, 2H), 4.46 (q, J= 1A Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.12 (t, J= 6.6 Hz, 2H), 1.45 (m, 3H).

[00603] INTERMEDIATE 11:(R)-l-(8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carboxamide

[00604]To a solution of Intermediate 9 (1.5 g, 3.69 mmol) and (2R)-2-methylpyrrolidine-2- carboxamide (729.08 mg, 4.43 mmol, HC1) in DMF (15 mL) was added DIEA (1.43 g, 11.mmol) and HATU (1.68 g, 4.43 mmol) at 20 °C. The mixture was stirred at 20 °C for 12 hr. The mixture was diluted with H20 (50 mL) and extracted with EtOAc (20 mL x 3). The organic layers WO 2024/184461 PCT/EP2024/056026 were concentrated under reduced pressure to give a crude product. The crude product was washed by MTBE (5 mL) to give the title compound (1.1 g, 57% yield) as a yellow solid.

[00605] INTERMEDIATE 12:Ethyl 8-methoxy-9-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxylate

[00606]To a solution of Intermediate 7 (900 mg, 2.08 mmol) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (5 g, 19.69 mmol) inn-heptane (10 mL) and dioxane (5 mL) was added KOAc (3.06 g, 31.15 mmol) and Pd(dppf)C12.CH2C(424.04 mg, 519.25 umol) at 20 °C. The mixture was stirred at 80 °C for 2 hr. The reaction was filtered, added with H20 (15 mL) and extracted with EtOAc (10 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 10/1 to 1/1) to give the title compound (580 mg, 58% yield) as a yellow solid. 1H NMR (400 MHz, CDCh) 5 = 8.07 (s, 1H), 7.39 - 7.(m, 2H), 7.07-7.05 (m, 1H), 6.77 (s, 1H), 4.70 (t, J = 6.6 Hz, 2H), 4.44 (q, J = 7.1 Hz, 2H), 3.(s, 3H), 3.32 (t, J= 6.6 Hz, 2H), 1.47 (t, J= 6.6 Hz, 3H), 1.30 (s, 12H).

[00607] INTERMEDIATE 13:Ethyl 8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(thiophen- 2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxylate

[00608]To a solution of Intermediate 12 (560 mg, 1.17 mmol) and 5-bromo-2-methyl-tetrazole (208.99 mg, 1.28 mmol) in dioxane (5 mL) and H20 (1 mL) was added with Xphos-Pd-G2 (91.

WO 2024/184461 PCT/EP2024/056026 mg, 116.57 pmol) and C82CO3 (1.14 g, 3.50 mmol) at 20 °C. The mixture was stirred at 80 °C for hr. The residue was diluted with H20 (10 mL) and extracted with EtOAc (5 mL x 2). The organic layers were concentrated under reduced pressure to give a crude product. The crude product was washed by MTBE (5 mL) and filtered to give the title compound (450 mg, 88% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.27 (s, 1H), 7.58-7.57 (m, 1H), 7.35-7.(m, 2H), 7.11-7.09 (m, 1H), 4.61 (t, J = 6.6 Hz, 2H), 4.39-4.32 (m, 5H), 3.90 (s, 3H), 3.19 (t, J= 6.6 Hz, 2H), 1.34 (t, J= 6.6 Hz, 3H).

[00609] INTERMEDIATE 14:Potassium 8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l- (thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxylate

[00610]To a solution of Intermediate 13 (220 mg, 504.03 pmol) in THE (2.5 mL) was added TMSOK (129.32 mg, 1.01 mmol) at 20 °C. The mixture was stirred at 20 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to remove solvent to give a crude product (2mg, crude) as a yellow solid.

[00611] INTERMEDIATE 15:9-bromo-8-methoxy-l-(thiophen-2-yl)-5,6-dihydroimidazo[5, 1 -a]isoquinoline-3-carboxylate

[00612]To a solution of Intermediate 7 (2 g, 4.62 mmol) in THF (20 mL) was added TMSOK (1.18 g, 9.23 mmol). The mixture was stirred at 20 °C for 1 hr. The mixture was filtered and concentrated under reduced pressure, the crude product was used into the next step. The title WO 2024/184461 PCT/EP2024/056026 compound (2 g, crude) was obtained as a yellow solid. LCMS {Method m, ES+, RT=0.390 min) 405.0/407.0 (M+H) +

[00613] INTERMEDIATE 16:(R)-l-(9-bromo-8-methoxy-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carboxamide

[00614]To a solution of Intermediate 15 (2 g, 4.51 mmol) in DMF (20 mL) was added DIEA (2.33 g, 18.04 mmol, 3.14 mL), (2R)-2-methylpyrrolidine-2-carboxamide (965.47 mg, 5.86 mmol, HC1) and HATU (2.57 g, 6.77 mmol). The mixture was stirred at 20 °C for 1 hr. The mixture was poured into water (20 mL) and pH was adjusted to 7 with 1M HC1. The aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure to afford the title compound (1.5 g, yield:65%) as a yellow solid. 1H NMR (400 MHz, CDCI3) 6 8.00 (s, 1H), 7.36 (t,J = 4.1 Hz, 2H), 7.13 -7.08 (m, 1H), 6.82 (s, 1H),5.31 (s, 1H), 4.59 (br t, J= 5.9 Hz, 2H), 4.40 - 4.20 (m, 2H), 3.93 (s, 4H), 3.04 (br t, J= 6.4 Hz, 2H), 2.50 - 2.43 (m, 1H), 2.08 - 1.98 (m, 3H), 1.77 (s, 3H). LCMS {Method a, ES+, RT=L671 min) 515.1/517.1 (M+H) +

[00615] INTERMEDIATE 17:(R)-l-(9-bromo-8-methoxy-l-(thiophen-2-yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile

[00616]To a solution of Intermediate 16 (1.5 g, 2.91 mmol) in pyridine (15 mL) was added TFAA (4.89 g, 23.28 mmol, 3.24 mL). The mixture was stirred at 20 °C for 2 hr. The mixture WO 2024/184461 PCT/EP2024/056026 was poured into water (15 mL) and pH was adjusted to 7 with IM HCI. The aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 10/1 to 0/1) to afford the title compound (0.8 g, yield: 55%) as a yellow solid. IHNMR (400 MHz, CDCI3) 6 8.- 7.99 (m, 1H), 7.40 - 7.34 (m, 2H), 7.14 - 7.09 (m, 1H), 6.85 - 6.82 (m, 1H), 4.77 - 4.59 (m, 2H), 4.35 - 4.18 (m, 2H), 3.94 (s, 3H), 3.10 - 3.01 (m, 2H), 2.17 - 2.06 (m, 4H), 1.90 - 1.86 (m, 3H). LCMS (Method a, ES+, RT=2.039 min) 497.1/498.9 (M+H) +

[00617] INTERMEDIATE 18:(8-methoxy-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l- a]isoquinolin-9-yl)boronic acid

[00618]To a solution of Intermediate 6 (2.3 g, 6.37 mmol) and hypoboric acid (1.71 g, 19.mmol) in EtOH (10 mL) was added DIEA (4.11 g, 31.83 mmol, 5.54 mL) and Pd(dtbpf)C12 (41.mg, 63.67 umol) at 20 °C. The mixture was stirred at 50 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with H20 (2 mL) and the solid precipitation was filtered. The title compound (4.1 g, crude) was obtained as a yellow solid.

[00619] INTERMEDIATE 19:8-methoxy-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l- a]isoquinolin-9-ol WO 2024/184461 PCT/EP2024/056026

[00620]To a solution Intermediate 18 (4.1 g, 12.57 mmol) in H20 (20 mL) was added NaBO3.4H2O (1.93 g, 12.57 mmol, 2.42 mL) at 20 °C. The mixture was stirred at 20 °C for 12 hr. The mixture was filtered to give the crude product (1.5 g, 40% yield) as a white solid. IHNMR (400 MHz, MeOD-d) 6 = 8.13 (s, 1H), 7.85 (d, J = 6.4 Hz, 1H), 7.49 - 7.48 (m, 1H), 7.27 (d, J = 6.4 Hz, 1H), 7.14 - 7.10 (m, 2H), 6.90 (s, 1H), 4.23 - 4.17 (m, 2H), 3.88 (s, 3H), 3.15 (t, J = 6.Hz, 1H), 3.04 (t, J= 6.4 Hz, 1H)

[00621] INTERMEDIATE 20:9-isopropoxy-8-methoxy-l-(thiophen-2-yl)-5,6- dihydroimidazo[5, 1 -a]isoquinoline

[00622]To a solution of Intermediate 19 (800 mg, 2.68 mmol) and 2-iodopropane (683.71 mg, 4.02 mmol, 402.18 pL) in DMF (5 mL) was added KCO3 (741.15 mg, 5.36 mmol) at 20 °C. The mixture was stirred at 80 °C for 12 hr. The residue was diluted with H20 (15 mL) and extracted with EtOAc (10 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The crude product was triturated by MTBE (10 mL) and filtered to give the title compound (640 mg, 70% yield) as a yellow solid. IHNMR (400 MHz, CDC13) 8 7.60 (s, 1H), 7.35-7.33 (m, 3H), 7.08 - 7.06 (m, 1H), 6.76 (s, 1H), 4.29 - 4.24 (m, 1H), 4.14 (t, J= 6.4 Hz, 1H), 3.88 (s, 3H), 3.04 (t, J= 6.4 Hz, 2H), 1.29 (d, J= 4.4 Hz, 6H).

[00623] INTERMEDIATE 21:Ethyl9-isopropoxy-8-methoxy-l-(thiophen-2-yl)-5,6-dihydroimidazo[5, 1 -a]isoquinoline-3-car boxylate WO 2024/184461 PCT/EP2024/056026

[00624]To a solution of Intermediate 20 (540 mg, 1.59 mmol) in THF (5 mL) was added n- BuLi (2.5 M, 761.37 pL) at -60 °C. The mixture was added with ethyl chloroformate (587.51 mg, 7.93 mmol, 637.91 pL) at -60 °C and the mixture was stirred at -60 °C for 2 hr. The mixture was added with H20 (10 mL) and extracted with EtOAc (5 mL x 3). The organic layers were concentrated under reduced pressure to give the crude product. The crude product was triturated by MTBE (5 mL) to give the title compound (270 mg, 41% yield) as a yellow solid. IHNMR (4MHz,CDC13) 8 7.38 (d, J= 4.8 Hz, 1H),7.31 (d,J=3.2Hz, 1H),7.12(s, 1H), 7.09-7.07 (m, 1H), 6.77 (s, 1H), 4.69 (t, J = 6.8 Hz, 1H), 4.46 (q, J = 6.8 Hz, 2H), 4.16-4.13 (m, 1H), 3.89 (s, 3H), 3.06 (t, J= 6.4 Hz, 2H), 1.45 (t, J= 7.2 Hz, 3H), 1.24 (d, J= 4.4 Hz, 6H).

[00625] INTERMEDIATE 22:9-isopropoxy-8-methoxy-l-(thiophen-2-yl)-5,6- dihydroimidazo[5, 1 -a]isoquinoline-3-carboxylic acid

[00626]To a solution of Intermediate 21 (250 mg, 606.06 pmol) in THF (3 mL) was added TMSOK (155.50 mg, 1.21 mmol). The mixture was stirred at 20 °C for 2 hr. The reaction mixture was concentrated under reduced pressure. The title compound (233 mg, 100% yield) was obtained as a yellow solid. LCMS (Method e, ES+, RT=0.358 min) 385.0 (M+H) +

[00627] INTERMEDIATE 23:Phenyl (R)-3-(2-cyano-2-methylpyrrolidine-l-carbonyl)-8- methoxy-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-9-carboxylate N ,0 WO 2024/184461 PCT/EP2024/056026

[00628]To a solution of Intermediate 17 (370 mg, 703.65 pmol) in DMF (5 mL) was added with phenyl formate (515.58 mg, 4.22 mmol, 460.34 pL) and TEA (427.21 mg, 4.22 mmol, 587.uL), Pd(dppf)C12.CH2C12 (143.66 mg, 175.91 pmol) at 20 °C. The mixture was stirred at 120 °C for 12 hr. The reaction mixture was filtered, then the residue was diluted with H20 (10 mL) and extracted with EtOAc (3 mL x 3). The combined organic layers were washed with brine (3 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 10/1 to 0/1) to give the title compound (300 mg, 79.16% yield) as a brown solid. 1H NMR (400 MHz, CDCh) 8 ppm 1.89 (s, 3 H), 2.06 - 2.18 (m, 3 H), 2.55 - 2.65 (m, 1 H), 3.17 (t, J = 6.50 Hz, 2 H), 3.99 (s, 3 H), 4.30 (br s, 2 H), 4.66 - 4.87 (m, 2 H), 6.98 (s, 1 H), 7.07 (dd, J= 5.13, 3.63 Hz, 1 H), 7.16 (d, J = 7.63 Hz, 2 H), 7.23 - 7.26 (m, 1 H), 7.32 - 7.35 (m, 1 H), 7.38 - 7.44 (m, 3 H), 8.51 - 8.60 (m, 1 H). LCMS {Method m. ES+, RT=0.58 min) 539.2 (M+H)+.

[00629] INTERMEDIATE 24:(R)-3-(2-cyano-2-methylpyrrolidine-l-carbonyl)-8-methoxy- l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-9-carboxylic acid

[00630]To a solution of Intermediate 23 (290 mg, 362.04 pmol) in THE (5 mL) was added TMSOK (92.89 mg, 724.08 pmol) at 20 °C. The mixture was stirred at 20 °C for 2 hr. The reaction mixture was added with HC1 (0.5 M) to adjust pH=3, then mixture was diluted with H20 12 mL and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (300 mg, 89.58% yield) as a brown solid. LCMS {Method m. ES+, RT=0.45 min) 463.(M+H)+

[00631] INTERMEDIATE 25:5-iodo-2-methyl-2H-tetr azole N ,0 WO 2024/184461 PCT/EP2024/056026 N-N

[00632]To a solution of 4-methylbenzenesulfonic acid; hydrate (115.17 g, 605.48 mmol) in ACN (IL) was added 2-methyltetrazol-5-amine (20 g, 201.83 mmol) at 20 °C. The mixture was cooled to 0-5 °C for 10 min. Then a mixture of KI (83.76 g, 504.57 mmol) and NaNO2 (27.85 g, 403.66 mmol) dissolved in H20 (250 mL) was added at 0-5 °C and stirred at 0-5 °C for 2 hr. The mixture was poured into sat. NaHCO3 (IL), Na2S2O3 (2M ,400 mL) at 0 °C and stirred at 20 °C for 10 min. Then it was extracted with MTBE (200 mL x 2). The combined organic phase was washed with brine (500 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=50/l to 2/1). The title compound (15 g, 35.39% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCI3) 6 4.41 (s, 3 H). LCMS (Method a. ES+, RT = 0.753 min) 211.1 (M+H)

[00633] INTERMEDIATE 26:2-methyl-5-(tributylstannyl)-2H-tetrazole N-N

[00634]To a solution of Intermediate 25 (30 g, 142.87 mmol) in THE (600 mL) was added n- BuLi (2.5 M, 71.44 mL) at -78 °C under N2 and stirred at -78 °C for 0.5 hr. Then added tributyl(chloro)stannane (53.15 g, 163.28 mmol, 43.93 mL) at -78 °C and stirred at -78 °C for 0.hr. Then the mixture was warmed to 15 °C and stirred for 1.5 hr. The mixture was quenched with sat. NH4C1 solution (200 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with brine (300 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/0 to 0/1). The title compound (40 g, 75.03% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCI) 6 4.36-4.42 (m, 3 H), 1.53-1.65 (m, 6H), 1.28-1.(m, 7H), 1.19 - 1.26 (m, 5H), 0.89 (t,J=7.3 Hz, 9H) WO 2024/184461 PCT/EP2024/056026

[00635] INTERMEDIATE 27:(2R,4S)-l-(9-bromo-8-methoxy-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-4-hydroxy-2-methylpyrrolidine-2-carboxamide

[00636]To a solution of Intermediate 15 (185 mg, 456.49 umol) in DMF (2 mL) was added Intermediate 256 (98.95 mg, 547.79 umol, HC1 salt), DIEA (235.99 mg, 1.83 mmol, 318.05 pL) and HATU (190.93 mg, 502.14 umol) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into the ice water, IN HCI was added to adjust pH = 5-6. The mixture was extracted with EtOAc (5 mL x 3), then the combined organic layer was washed with brine (mL x 3), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EtOAc = 100/1 to 0/1). The title compound (178 mg, 73% yield) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 7.79 (s, 1H), 7.62 (dd, J= 5.07, ^=0.81 Hz, 1H), 7.31 (dd, J=3.50, 0.88 Hz, 1H), 7.(s, 1H), 7.16 (dd, J=5.07, 3.56 Hz, 2H), 6.86 (br s, 1H), 5.13 (d, J= 3.75 Hz, 1H), 4.40 (br t, .7=6.Hz, 2H), 4.27-4.32 (m, 1H), 4.13-4.19 (m, 1H), 4.02-4.08 (m, 1H), 3.89 (s, 3H), 2.96-3.12 (m, 2H), 2.14-2.25 (m, 1H), 1.77-1.87 (m, 1H), 1.66 (s, 3H) LCMS (Method e. ES+, RT = 0.435 min) 533.1/533.2 (M+H) +

[00637] INTERMEDIATE 28:(2R,4S)-l-(9-bromo-8-methoxy-l-(thiophen-2-yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-4-hydroxy-2-methylpyrrolidine-2-carbonitrile WO 2024/184461 PCT/EP2024/056026

[00638]To a solution of Intermediate 27 (150 mg, 282.26 pmol) in pyridine (1.5 mL) was added TFAA (474.27 mg, 2.26 mmol, 313.88 pL) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into the ice water and IN HCI was added to adjust pH = 2-3. Then suspension was extracted with MTBE (5 mL x 3), combined organic phase was washed with mL brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/l to 0/1). The title compound (105 mg, 72.46% yield) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 7.80 (s, 1H), 7.63 (d, J= 4.50 Hz, 1H), 7.33 (d, J= 2.88 Hz, 1H), 7.22 (s, 1H), 7.17 (dd, J= 5.00, 3.63 Hz, 1H), 5.38 (d, J= 3.38 Hz, 1H), 4.50 (br t, J= 6.32 Hz, 2H), 4.32 - 4.40 (m, 1H), 4.15 - 4.22 (m, 1H), 4.06 (br dd, J= 11.76, 3.13 Hz, 1H), 3.89 (s, 3H), 3.(br t, J= 6.38 Hz, 2H), 2.61 (dd, J=13.13, 5.13 Hz, 1H), 2.19 (br dd, J=13.01, 4.13 Hz, 1H), 1.(s, 3H) LCMS (Method e. ES+, RT = 0.555 min) 513.2/515.2 (M+H) +

[00639] INTERMEDIATE 29:(9-bromo-8-methoxy-l-(thiophen-2-yl)-5,6- dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-3, 3,3-tri fluoro- 1- hydroxypropyl)pyrrolidin- 1 -yl)methanone

[00640]To a solution of Intermediate 15 (90 mg, 222.08 pmol), Intermediate 105 A (62.27 mg, 266.49 pmol, HCI salt) in DMF (2 mL) was added with HATU (92.88 mg, 244.28 pmol) and DIEA (114.80 mg, 888.31 pmol, 154.72 pL). The mixture was stirred at 30 °C for 2 hr. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The title compound (200 mg, 77% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCh) 8 7.98 (s, 1 H), 7.30 - 7.41 (m, 2 H), 7.11 (m, 1 H), 6.82 (s, 1 H), 6.01 (br s, 1 H), 4.61 - 4.71 (m, 1 H), 4.38 - 4.58 (m, 3 H), 3.94 (s, 4 H), 3.05 (br t, WO 2024/184461 PCT/EP2024/056026 7=6.44 Hz, 2 H), 2.24 - 2.38 (m, 2 H), 1.75 - 2.00 (m, 4 H), 1.58 (s, 3 H). LCMS {Method I. ES+, RT = 0.589 min) 584/586 (M+H) +

[00641] INTERMEDIATE 30:(9-bromo-8-methoxy-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinohn-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-l-hydroxypropyl)pyrrolidin- 1 -yl)methanone

[00642]To a solution of Intermediate 15 (90 mg, 222.08 umol). Intermediate 258 (62.27 mg, 266.49 umol, HCI salt) in DMF (0.2 mL) was added HATU (92.88 mg, 244.28 umol) and DIEA (114.81 mg, 888.31 umol, 154.73 uL). The mixture was stirred at 25 °C for 1 h. The mixture was poured into ice water and added with IM HCI to adjust pH=5, and filtered. The filter cake was dissolved with DCM and washed with brine (5 mL x 3), concentrated under reduced pressure to give a crude product. The title compound (120 mg, 92 % yield) was obtained as a brown solid. 1H NMR (400 MHz, DMSO-d6) 8 7.79 (s, 1H), 7.60 (dd, 7=5.13, 0.88 Hz, 1H), 7.30 (d, J=2.15 Hz, H), 7.21 (s, 1 H),7.15 (dd, 7=5.00, 3.63 Hz, 1 H), 5.31 (d, J=6.75 Hz, 1 H),4.71 (brt, 7=8.63 Hz, H), 4.45 - 4.52 (m, 1 H), 4.25 - 4.37 (m, 2 H), 3.89 (s, 3 H), 3.59 - 3.68 (m, 1 H), 3.00 - 3.09 (m, H), 2.08 - 2.24 (m, 2 H), 1.75 - 1.90 (m, 2 H), 1.56 - 1.64 (m, 1 H), 1.44 (s, 3 H) LCMS {Method e. ES+, RT = 0.404 min) 584.1/586.1 (M+H) +

[00643] INTERMEDIATE 31:methyl (S)-2-(9-bromo-8-methoxy-l-(thiophen-2-yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carboxamido)-4,4,4-trifluoro-2-methylbutanoate /0xXvX O HO F WO 2024/184461 PCT/EP2024/056026

[00644]Step A: To a solution of Intermediate 15 (2 g, 4.51 mmol) in DMF (20 mL) was added HATU (3.43 g, 9.02 mmol) at 20 °C. The mixture was stirred at 20 °C for 30 min.

[00645]Step B: To a solution of Intermediate 115 (1.30 g, 5.86 mmol, HC1 salt) in DMF (mL) was added Na2CO3 (1.43 g, 13.53 mmol). The mixture was stirred at 20 °C for 30 min.

[00646]Step C. The mixture of A was added dropwise to the mixture B at 20 °C. The mixture was stirred at 20 °C for 1 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/ EtOAc =100/1 to 25/1). The title compound (1.7 g, 65% yield) was obtained as a yellow solid. 1H NMR (400 MHz, CDCI) 6 8.12 (br s, 1 H), 7.93 (s, 1 H), 7.- 7.44 (m, 2 H), 7.13 (m, 1 H), 6.82 (s, 1 H), 4.71 (t, J=6.57 Hz, 2 H), 3.93 (s, 3 H), 3.84 (s, 3 H), 3.26 (m, 1 H), 3.06 (t, J=6.57 Hz, 3 H), 1.76 (s, 3 H) LCMS (Method h. ES+, RT = 2.613 min) 572.1/574.1 (M+H) +

[00647] INTERMEDIATE 32:(S)-2-(9-bromo-8-methoxy-l-(thiophen-2-yl)-5,6- dihydroimidazo[5, 1 -a]isoquinoline-3-carboxamido)-4,4,4-trifluoro-2-methylbutanoic acid

[00648]To a solution of Intermediate 31 (1.65 g, 2.88 mmol) in THF (17 mL) was addedTMSOK (739.61 mg, 5.77 mmol) at 20 °C. The mixture was stirred at 50 °C for 12 hr. The mixture was added with IM HC1 to adjust pH=3 and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The title compound (1.6 g, 99% yield) was obtained as a yellow solid. 1H NMR (400 MHz, CDCI3) 6 8.30 (br s, 1 H), 7.84 (br d, J=4.41 Hz, H), 7.32 - 7.47 (m, 2 H), 7.13 (br d, J=2.98 Hz, 1 H), 6.82 (br d, .7=4.05 Hz, 1 H), 4.73 (br d, WO 2024/184461 PCT/EP2024/056026 .7=3.93 Hz, 2 H), 3.93 (br d, .7=4.41 Hz, 3 H), 3.00 - 3.24 (m, 4 H), 1.79 (br d, J=3.34 Hz, 3 H). LCMS {Method I. ES+, RT = 0.563 min) 558.1/560.1 (M+H) +

[00649] INTERMEDIATE 33:(S)-N-(l-amino-4,4,4-trifluoro-2-methyl-l-oxobutan-2-yl)- 9-bromo-8-methoxy-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxamide

[00650]To a solution of Intermediate 32 (1.5 g, 2.69 mmol) in THF (15 mL) was added CDI (653.40 mg, 4.03 mmol) and NH3.H20 (1.13 g, 8.06 mmol, 1.24 mL, 25% purity) at 25 °C. The mixture was stirred at 25 °C for 2 hr. The reaction mixture was diluted with H20 (20 ml) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The title compound (1.48 g, 98% yield) was obtained as a yellow solid. 1HNMR (400 MHz, CDCI) 6 7.(s, 1H), 7.74 (br d, .7=3.75 Hz, 1H), 7.41-7.45 (m, 1H), 7.31-7.39 (m, 1H), 7.11-7.16 (m, 2H), 6.(s, 1H), 6.24-6.39 (m, 1H), 5.34-5.45 (m, 1H), 4.60-4.83 (m, 2H), 3.94 (s, 3 H), 3.39 (m, 1 H), 3.07 (br t, .7=6.57 Hz, 2 H), 2.90-3.03 (m, 1 H), 1.75 (s, 3 H) LCMS {Method I. ES+, RT = 0.5min) 557.1/559.1 (M+H) +

[00651] INTERMEDIATE 34:(S)-9-bromo-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8- methoxy-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxamide

[00652]To a solution of Intermediate 33 (500 mg, 897.05 umol) in THF (2.5 mL) was addedBurgess reagent (427.54 mg, 1.79 mmol) in DCM (2.5 mL) at 20 °C. The mixture was stirred at WO 2024/184461 PCT/EP2024/056026 °C for 12 hr. The reaction mixture was diluted with H20 (10 ml) and extracted with DCM (mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The title compound (400 mg, 82% yield) was obtained as a yellow solid. 1H NMR (400 MHz, CDCI3) 6 7.89 (s, 1H), 7.60 (s, 1H), 7.43 (d, .7=4.65 Hz, 1H), 7.34 (d, J=2.81 Hz, 1H), 7.14 (m, 1 H), 6.84 (s, 1 H), 4.60-4.86 (m, 2 H), 3.94 (s, 3 H), 3.01-3.22 (m, 4 H), 1.97 (s, 3 H). LCMS (Method I. ES+, RT = 0.593 min) 539.1/541.1 (M+H) +

[00653] INTERMEDIATE 35:(S)-9-bromo-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8- methoxy-N-methyl- 1 -(thiophen-2-yl)-5,6-dihydroimidazo[5, 1 -a]isoquinoline-3-carboxamide

[00654]DMF (1.5 mL) was charged to the three-necked round bottom flask, then Intermediate (150 mg, 278.10 umol) was added. At 0°C inner temperature, NaH (22.25 mg, 556.21 umol, 60% purity) was added to the reaction mixture at 0 °C. Then CHI (59.21 mg, 417.16 umol, 25.pL, 1.5 eq) was added. After the addition, the mixture was stirred at 70 °C for 2 hr. The reaction was cooled and quenched with water (5 mL), extracted with ethyl acetate (5 mL). The organic layer was washed with H20 (3x2 mL), brine (5 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/0 to 80/20). The title compound (70 mg, 45.48% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCh) 8 7.97 (s, 1H), 7.39 (d, J=5.01 Hz, 1H), 7.35 (d, J=3.Hz, 1H), 7.13 (m, 1H), 6.81-6.86 (m, 1H), 4.66-4.86 (m, 1H), 4.41-4.58 (m, 1H), 3.94 (s, 3H), 3.(s, 2H), 3.35 (m, 1H), 2.99-3.22 (m, 4H), 1.96 - 2.08 (m, 2H), 1.98 (s, 1H) LCMS (Method! ES+, RT = 0.601 min) 553.2/555.2 (M+H) + WO 2024/184461 PCT/EP2024/056026

[00655] INTERMEDIATE 36:(2R,4S)-l-((R)-9-bromo-8-methoxy-5-methyl-l -(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-4-hydroxy-2- methylpyrrolidine-2-carboxamide.

[00656]To a solution of (R)-9-bromo-8-methoxy-5-methyl-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carboxylic acid (1.7 g, 4.06 mmol) in DMF (10 mL) was added HATU (1.85 g, 4.88 mmol) and DIEA (2.10 g, 16.26 mmol, 2.83 mL). The mixture was stirred at 20 °C for 1 hr. And then the mixture was added Intermediate 256 (954.55 mg, 5.mmol, HCI) and stirred at 20 °C for 2 hr. The reaction mixture was poured into ice-water (50 mL) and added with 1 M HC1 to pH = 7. The reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1.6 g, 72% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCI3) 6 7.74 - 7.68 (m, 1H), 7.32 - 7.25 (m, 1H), 6.87 - 6.79 (m, 1H), 6.60 - 6.49 (m, 1H), 5.43 - 5.34 (m, 1H), 4.66 - 4.54 (m, 1H), 4.09 - 4.00 (m, 1H), 4.00 - 3.93 (m, 3H), 3.92 - 3.82 (m, 1H), 3.64 - 3.46 (m, 2H), 3.31 (br dd, J = 5.7, 15.5 Hz, 1H), 2.86 - 2.66 (m, 2H), 2.11 - 2.05 (m, 1H), 2.03 - 1.95 (m, 1H), 1.94 - 1.88 (m, 3H), 1.22 - 1.09 (m, 3H). LCMS (Method I. ES+, RT = 0.441 min) 544.2/546.1 (M+H) +.

[00657] INTERMEDIATE 37:(2R,4S)-l-((R)-9-bromo-8-methoxy-5-methyl-l -(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-4-hydroxy-2- methylpyrrolidine-2-carbonitrile WO 2024/184461 PCT/EP2024/056026

[00658]To a solution of Intermediate 36 (2 g, 3.67 mmol) in pyridine (20 mL) was added TFAA (6.17 g, 29.39 mmol, 4.09 mL). The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into ice-water (50 mL) and added 1 M HC1 to pH = 3-4. The reaction mixture was extracted with MTBE (50 mL x 3). The combined organic phase was washed with brine (50 mL x 3), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the title compound (1.75 g, 90% yield) as brown solid. LCMS (Method 1. ES+, RT = 0.5min) 526.2/528.2 (M+H) +.

[00659] INTERMEDIATE 38:(2R,4S)-4-hydroxy-l-((R)-8-methoxy-5-methyl-9-(4,4,5,5- tetramethyl- 1,3,2-dioxa borolan-2-yl)-1 -(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-car bonyl)-2-methylpyrrolidine-2-carbonitrile

[00660]A mixture of Intermediate 37 (723.68 mg, 2.85 mmol), KOAc (419.53 mg, 4.27 mmol) in n-heptane (2.5 mL) and dioxane (0.5 mL) was degassed and purged with N2 for 3 times, then the mixture was added with Pd(dppf)C12.CH2C12 (46.55 mg, 57.00 umol) and degassed and purged with N2 for 3 times. The mixture was stirred at 95 °C for 12 hr. The reaction mixture was filtered, added with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum WO 2024/184461 PCT/EP2024/056026 ether/Ethyl acetate=2/l to 1/1) to give the title compound (180 mg, 55% yield) as a brown solid. 1H NMR (400 MHz, CDCI3) 6 7.85 - 7.80 (m, 1H), 6.70 (s, 1H), 6.55 - 6.44 (m, 1H), 5.59 - 5.(m, 1H), 4.62 - 4.51 (m, 1H), 4.11 - 3.98 (m, 2H), 3.80 (s, 3H), 3.73 - 3.65 (m, 1H), 3.59 - 3.(m, 2H), 3.29 (dd, J = 5.7, 15.6 Hz, 1H), 2.78 - 2.60 (m, 2H), 2.14 (dd, J = 6.8, 13.2 Hz, 1H), 1.- 1.82 (m, 4H), 1.34 - 1.26 (m, 12H), 1.22 - 1.16 (m, 2H), 1.10 - 0.99 (m, 3H). LCMS (Methodi. ES+, RT= 0.545 min) 574.3/575.4 (M+H) +.

[00661] INTERMEDIATE 39:7-bromo-2-(2-ethoxy-2-oxoacetyl)-6-methoxy-l,2,3,4- tetrahydroisoquinoline- 1 -carboxylic acid

[00662]To a solution of 7-bromo-6-methoxy- 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (2.8 g, 8.68 mmol, HC1) in THE (30 mL) was added ethyl 2-chloro-2-oxo-acetate (1.54 g, 11.mmol, 1.26 mL) at 20 °C. The mixture was stirred at 20 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a crude product without purification. The title compound (3.3 g, crude) was obtained as an orange oil. LCMS (Method 1. ES+, RT = 0.421 min) 386.1/388.0 (M+H) +.

[00663] INTERMEDIATE 40:Ethyl l-(2-acetoxy-2-methylpropyl)-9-bromo-8-methoxy- 5,6-dihydropyrrolo[2, 1-a]isoquinoline-3-carboxylate

[00664]To a solution of Intermediate 39 (3.3 g, 8.54 mmol) in Ac20 (35 mL) was added 2- methylpent-4-yn-2-01 (1.01 g, 10.25 mmol) at 20 °C. The mixture was stirred at 140 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove Ac20. The residue was WO 2024/184461 PCT/EP2024/056026 diluted with H20 (100 mL) and adjusted pH to 8 with aq. Na2CO3. The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (1mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 3/1). The title compound (1.7 g, 85.69% yield) were obtained as yellow solid. 1H NMR (4MHz, CDCI) 6 8.19 (s, 1H), 6.87 (s, 1H), 6.80 (s, 1H), 4.60 (t, J = 6.4 Hz, 2H), 4.30 (q, J = 7.Hz, 2H), 3.93 (s, 3H), 3.12 (s, 2H), 2.97 (t, J = 6.4 Hz, 2H), 1.90 (s, 3H), 1.56 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H). LCMS {Method h. ES+, RT = 2.20 min) 404.2/406.2 (M+H) +.

[00665] INTERMEDIATE 41:Ethyl 9-bromo-l-(2-hydroxy-2-methylpropyl)-8-methoxy- 5,6-dihydropyrrolo[2, 1-a]isoquinoline-3-carboxylate /Ox

[00666]To a solution of Intermediate 40 (900 mg, 1.94 mmol) in EtOH (20 mL) was added EtONa (131.90 mg, 1.94 mmol) at 20 °C. The mixture was stirred at 60 °C for 12 hr. The reaction mixture was added with 0.5M HC1 (4 mL), then diluted with H20 (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was triturated with PE (5 mL) at 20 °C for 20 min and filtered. The title compound (1.g, 73% yield) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.33 (s, 1H), 7.12 (s, 1H), 6.83 (s, 1H), 4.47 (br t, J = 6.4 Hz, 2H), 4.43 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.(s, 3H), 2.95 (br t, J = 6.4 Hz, 2H), 2.72 (s, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.16 (s, 6H). LCMS {Method I. ES+, RT = 0.589 min) 422.2/424.2 (M+H) +.

[00667] INTERMEDIATE 42:Ethyl 9-bromo-8-methoxy-l-(2-methylprop-l-en-l-yl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylate WO 2024/184461 PCT/EP2024/056026

[00668]To a solution of Intermediate 41 (1.2 g, 2.84 mmol)inTHF (12 mL) was added Burgess reagent (1.35 g, 5.68 mmol) in DCM (12 mL) at 20 °C. The mixture was stirred at 20 °C for 2 hr. The reaction mixture was diluted with H20 (50 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Method 18). The title compound (700 mg, 60.93% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCh) 5 = 7.91 (s, 1H), 6.91 (s, 1H), 6.79 (s, 1H), 6.18 (s, 1H), 4.60 (t, J = 6.6 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 3.00 (t, J = 6.6 Hz, 2H), 1.(d, J= 1.0 Hz, 3H), 1.84 (d, J = 0.6 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H). LCMS (Methodi. ES+, RT = 0.728 min) 404.2/406.1 (M+H) +.

[00669] INTERMEDIATE 43:ethyl 8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2- methylprop- 1 -en- 1 -yl)-5,6-dihydropyrrolo[2, 1 -a] isoquinoline-3-carboxylate /Ox N O

[00670]To a solution of Intermediate 42 (700 mg, 1.73 mmol ) and Intermediate 25 (2.58 g, 6.93 mmol) in DMF (7 mL) was added Xphos-Pd-G2 (272.45 mg, 346.28 umol) at 20 °C. The mixture was stirred at 120 °C for 1 hr. The reaction mixture was added with H2O (50 mL) at 0 °C, then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, PE/EtOAc= 10/1 to 1 /1). The WO 2024/184461 PCT/EP2024/056026 title compound (400 mg, 56%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) = 8.19 (s, 1H), 7.25 (s, 1H), 6.81 (s, 1H), 6.19 (s, 1H), 4.55 (br t, J = 6.5 Hz, 2H), 4.41 (s, 3H), 4.24 (q, J = 7.0 Hz, 2H), 3.89 (s, 3H), 3.12 (br t, J = 6.5 Hz, 2H), 1.88 (s, 3H), 1.76 (s, 3H), 1.(t, J = 7.1 Hz, 3H). LCMS {Method I. ES+, RT = 0.594 min) 408.2/409.2 (M+H) +.

[00671] INTERMEDIATE 44:8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2-methylprop- l-en-l-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylic acid

[00672]To a solution of Intermediate 43 (50 mg, 122.71 pmol)inTHF (0.5 mL) was added TMSOK (62.97 mg, 490.84 umol) at 20 °C. The mixture was stirred at 70 °C for 12 hr. The reaction mixture was cooled to room temperature and filtered to give the title compound (mg, crude) as a yellow solid. LCMS {Method 1. ES+, RT = 0.455 min) 380.2/381.2 (M+H) +.

[00673] INTERMEDIATE 45:(2R,4S)-4-hydroxy-l-(8-methoxy-9-(2-methyl-2H-tetrazol- 5-yl)- 1 -(2-methylprop- 1 -en- 1 -yl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carbonyl)-2- methylpyrrolidine-2-carboxamide

[00674]To a solution of Intermediate 44 (94 mg, 247.75 umol) and Intermediate 256 (53.mg, 297.30 umol, HC1) in DMF (I mL) was added HATU (141.30 mg, 371.63 umol) and DIEA (128.08 mg, 991.01 umol, 172.62 pL) at 20 °C. The mixture was stirred at 60 °C for 12 hr. The reaction mixture was added with H20 (5 mL) at 0 °C, then extracted with EtOAc (2 mL x 3). The WO 2024/184461 PCT/EP2024/056026 combined organic layers were washed with brine (3 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (80 mg, 63%) as a brown solid. LCMS (Methodi. ES+, RT = 0.369 min) 506.3/507.3 (M+H) +.

[00675] INTERMEDIATE 46:Methyl (S)-4,4,4-trifluoro-2-(8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-1 -(2-methylprop- 1 -en- 1 -yl)-5,6-dihydropyrrolo[2, 1 -a] isoquino line-3- carboxamido)-2-methylbutanoate

[00676]To a solution of Intermediate 44 (250 mg, 658.92 umol) in DMF (2.5 mL) was added with HATU (300 mg, 790.70 umol) andDIEA (340.64 mg, 2.64 mmol, 459.08 pL) at °C for 1 h. The mixture was added with Intermediate 115 (189.82 mg, 856.59 umol, HC1) and stirred at 60 °C for 11 hr. The reaction mixture was added H20 (20 mL) at 0 °C and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 3/1). The title compound (240 mg, 66 %) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) = 8.46 (s, 1H), 8.14 (s, 1H), 7.22 (s, 1H), 6.97 (s, 1H), 6.20 (s, 1H), 4.57 - 4.43 (m, 2H), 4.41 (s, 3H), 3.88 (s, 3H), 3.65 (s, 3H), 3.30 - 3.15 (m, 1H), 3.09 - 3.05 (m, 2H), 2.84 (qd, J = 11.3, 15.Hz, 1H), 1.89 (s, 3H), 1.81 (s, 3H), 1.57 (s, 3H). LCMS (Method a. ES+, RT = 1.920 min) 547.3/548.3 (M+H) +.

[00677] INTERMEDIATE 47:(S)-4,4,4-trifluoro-2-(8-methoxy-9-(2-methyl-2H-tetrazol-5- yl)- 1 -(2-methylprop- 1 -en- 1 -yl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxamido)-2- methylbutanoic acid WO 2024/184461 PCT/EP2024/056026

[00678]To a solution of Intermediate 46 (220 mg, 402.53 pmol) in THF (2 mL) was added TMSOK (103.28 mg, 805.06 pmol) at 20°C. The mixture was stirred at 20 °C for 2 hr. The reaction mixture was diluted with H20 (10 mL) and adjusted pH to 3-4, which was extracted with EtOAc (3 mL x 3). The combined organic layers were washed with brine (5 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The title compound (200 mg, 93%) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 812.(br s, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 7.22 (s, 1H), 6.92 (br s, 1H), 6.20 (s, 1H), 4.61 - 4.37 (m, 5H), 3.88 (s, 3H), 3.30 - 3.16 (m, 1H), 3.06 (br t, J = 6.1 Hz, 2H), 2.92 - 2.74 (m, 1H), 1.89 (s, 3H), 1.81 (s, 3H), 1.60 - 1.50 (m, 3H). LCMS (Method 1). ES+, RT = 0.482 min) 533.4/534.(M+H) +.

[00679] INTERMEDIATE 48:(S)-N-(l-amino-4,4,4-trifluoro-2-methyl-l-oxobutan-2-yl)- 8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 1 -(2-methylprop- 1 -en- 1 -yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carboxamide HN-sj

[00680]To a solution of Intermediate 47 (180 mg, 338.02 pmol) in THF (2 mL) was added CDI (82.21 mg, 507.03 pmol) at 20 °C and stirred for 1 hr. Then the mixture was added NHJ.HO (142.15 mg, 1.01 mmol, 156.21 pL, 25% purity) at 20 °C and stirred for 1 h. The reaction mixture was added H20 (5 mL) at 0 °C,then extracted with DCM (2 mL x 3). The combined organic layers were washed with brine (3 mL x 2), dried over Na2SO4, filtered and concentrated under reduced HN—(S) N ,0 O, WO 2024/184461 PCT/EP2024/056026 pressure to give a crude product. The title compound (200 mg, crude) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.14 (s, 1H), 8.05 (s, 1H), 7.43 (br s, 1H), 7.22 (s, 1H), 7.10 (br s, 1H), 6.90 (s, 1H), 6.21 (s, 1H), 4.56 - 4.44 (m, 2H), 4.41 (s, 3H), 3.88 (s, 3H), 3.31 - 3.18 (m, 1H), 3.07 (br d, J = 6.4 Hz, 2H), 3.01 - 2.86 (m, 1H), 1.89 (s, 3H), 1.81 (s, 3H), 1.55 (s, 3H). LCMS (Method 1). ES+, RT = 0.467 min) 532.3/533.3 (M+H) +.

[00681] INTERMEDIATE 49:(S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8-methoxy-9-(2- methyl-2H-tetrazol-5-yl)- 1 -(2-methylprop- 1 -en- 1 -yl)-5,6-dihydropyrrolo[2, 1 -a] isoquinoline-3- carboxamide

[00682]To a solution of Intermediate 48 (180 mg, 338.65 umol) in THF (2 mL) was added Burgess reagent (161.40 mg, 677.29 umol) in DCM (2 mL) at 20 °C. The mixture was stirred at 20 °C for 2 hr. The reaction mixture was diluted with H20 (5 mL) and extracted with DCM (2 mL x 3). The combined organic layers were washed with brine (3 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 1/1) to give the title compound (120 mg, 69.01%) as a white solid. 1H NMR (400 MHz, CDCI3) 8 = 8.39 (s, 1H), 6.95 (s, 1H), 6.53 (s, 1H), 6.25 (s, 1H), 5.94 (s, 1H), 4.67 (t, J = 6.6 Hz, 2H), 4.44 (s, 3H), 4.01 - 3.97 (m, 3H), 3.23 - 3.04 (m, 4H), 1.95 (s, 6H), 1.80 (s, 3H). LCMS (Method I). ES+, RT= 0.5min) 514.3/515.3 (M+H) +.

[00683] INTERMEDIATE 50:ethyl l-(2-(benzyloxy)-2-methylpropyl)-8-methoxy-9- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carboxylate WO 2024/184461 PCT/EP2024/056026 OBn

[00684]To a solution of Intermediate 70 (2.5 g, 4.88 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (12.39 g, 48.79 mmol) in n-heptane (mL) and dioxane (5 mL) was added with KOAc (7.18 g, 73.18 mmol) and Pd(dppf)C12.CH2C(79.68 mg, 97.57 umol). The mixture was stirred at 950C for 12 hr. The mixture was filtered and the filtrate was added with 10 mL H2O. The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=92/l to 8/1) to give the title compound (2.g, 91% yield) as a white solid. 1H NMR (400 MHz, CDCh) 8 = 8.31 (s, 1H), 7.39 - 7.35 (m, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.26 - 7.21 (m, 1H), 7.02 (s, 1H), 6.75 (s, 1H), 5.31 (s, 1H), 4.61 - 4.(m, 3H), 4.31 - 4.24 (m, 2H), 3.89 - 3.86 (m, 2H), 3.14 (s, 1H), 3.01 - 2.96 (m, 1H), 1.37 (d, J = 2.1 Hz, 2H), 1.34 (s, 4H), 1.33 (s, 8H), 1.27 (d, J= 3.5 Hz, 12H), 1.25 (s, 2H). LCMS (Method I. ES+, RT = 0.739 min) 506.3 (M+H) +

[00685] INTERMEDIATE 51:ethyl l-(2-(benzyloxy)-2-methylpropyl)-8-methoxy-9-(2- methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate

[00686] To a solution of Intermediate 50 (2 g, 3.57 mmol), 5-bromo-2-methyl-tetrazole (640.84mg, 3.93 mmol) in dioxane (2 mL) and H20 (1 mL) was added with C82CO3 (3.49 g, 10.72 mmol) WO 2024/184461 PCT/EP2024/056026 and XPH0S-Pd-G2 (140.63 mg, 178.73 pmol). The mixture was stirred at 70 °C for 2 hr under N2. The mixture was filtered and the filtrate was added with 10 mL H2O. The aqueous layer was extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with brine (mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=88/l to 12/1). The title compound (1.1 g, 59% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCh) 8 = 8.64 - 8.58 (m, 1H), 7.34 - 7.30 (m, 2H), 7.25 - 7.19 (m, 1H), 7.07 (s, 1H), 6.97 - 6.(m, 1H), 5.31 (s, 1H), 4.69 - 4.61 (m, 2H), 4.59 - 4.53 (m, 2H), 4.40 (s, 3H), 4.34 - 4.26 (m, 2H), 3.99 (s, 3H), 3.15 (s, 2H), 3.05 (br t, J = 6.3 Hz, 2H), 1.62 - 1.55 (m, 1H), 1.41 - 1.30 (m, 9H). LCMS(Method I. ES+, RT = 0.625 min) 516.3/517.3 (M+H)+

[00687] INTERMEDIATE 52:l-(2-(benzyloxy)-2-methylpropyl)-8-methoxy-9-(2-methyl- 2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylic acid

[00688]To a solution of Intermediate 51 (1.1 g, 2.13 mmol) in EtOH (4 mL), THE (4 mL) and H2O (4 mL) was added with KOH (359.09 mg, 6.40 mmol). The mixture was stirred at 30 °C for hr. The mixture was added with IM HC1 to adjust pH=5 and added with ethyl acetate (10 mL x 3). The organic layer was washed with brine 10 mL and concentrated under reduced pressure. The title compound (0.85 g, 81.72% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO- d6) 8 = 8.50 - 8.47 (m, 1H), 7.18 (s, 5H), 6.89 - 6.85 (m, 1H), 4.56 - 4.49 (m, 3H), 4.48 - 4.44 (m, 2H), 4.41 (s, 3H), 3.88 (s, 3H), 3.33 (s, 6H), 1.27 (s, 6H). LCMS {Methodi. ES+, RT = 0.494 min) 488.2 (M+H) + WO 2024/184461 PCT/EP2024/056026

[00689] INTERMEDIATE 53:(R)-l-(l-(2-(benzyloxy)-2-methylpropyl)-8-methoxy-9-(2- methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbox amide OBn

[00690]To a solution of Intermediate 52 (200 mg, 410.22 umol), (2R)-2-methylpyrrolidine-2- carboxamide (81.04 mg, 492.26 umol, HC1) inDMF (2 mL) was added HATU (171.57 mg, 451.umol) and DIEA (212.07 mg, 1.64 mmol, 285.81 uL). The mixture was stirred at 30 °C for 2 hr. The mixture was poured into ice water, filtered and the solid was dissolved with EtOAc (10 ml). The combined organic phase was washed with brine (5 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=70/l to 30/1). The title compound (200 mg, 81% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.42 (s, 1H), 7.- 7.18 (m, 6H), 7.13 - 7.07 (m, 1H), 6.81 - 6.75 (m, 1H), 6.58 - 6.54 (m, 1H), 4.48 (s, 2H), 4.41 (s, 3H), 4.28 - 4.20 (m, 2H), 3.87 (s, 3H), 3.59 - 3.51 (m, 1H), 3.06 - 2.96 (m, 4H), 2.06 - 1.97 (m, 2H), 1.84 - 1.75 (m, 3H), 1.49 (s, 3H), 1.28 (br d, J= 1.9 Hz, 6H) LCMS {Method n. ES+, RT = 0.563 min) 598.5/599.5 (M+H)+

[00691] INTERMEDIATE 54:(R)-l-(l-(2-hydroxy-2-methylpropyl)-8-methoxy-9-(2- methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2- methylpyrrolidine-2-carboxamide WO 2024/184461 PCT/EP2024/056026 OH

[00692]To a solution of Intermediate 53 (180 mg, 301.15 umol) in THF (2 mL) was added with Pd/C (360 mg, 338.28 umol, 10% purity). The mixture was stirred at 50 °C for 12 hr under H2 (psi). The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The title compound (120 mg, 78.50% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.44 - 8.38 (m, 1H), 7.18 (s, 1H), 7.13 - 7.08 (m, 1H), 6.87 (s, 1H), 6.81 - 6.75 (m, 1H), 6.65 - 6.63 (m, 1H), 6.56 - 6.52 (m, 1H), 5.78 - 5.74 (m, 1H), 4.42 (s, 2H), 4.29 - 4.20 (m, 2H), 3.97 - 3.90 (m, 1H), 3.88 - 3.83 (m, 2H), 3.79 - 3.69 (m, 1H), 3.04 - 2.(m, 1H), 2.86 - 2.78 (m, 1H), 2.21 - 2.15 (m, 1H), 2.11 - 2.01 (m, 1H), 1.93 - 1.82 (m, 2H), 1.(s, 2H), 1.35 (s, 6H), 1.15 (d, J = 5.5 Hz, 5H) LCMS (Method 1. ES+, RT = 0.350 min) 508.3/509.(M+H) +

[00693] INTERMEDIATE 55:ethyl l-(2-hydroxy-2-methylpropyl)-8-methoxy-9-(2- methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate

[00694]To a solution of Intermediate 51 (1.6 g, 3.10 mmol) in THF (7.5 mL) and EtOH (7.mL) was added Pd/C (1.6 g, 1.50 mmol, 10% purity). The mixture was stirred at 45OC for 12 hr under H2 (15 Psi). The reaction mixture was filtered. The filtrate was and concentrated under reduced pressure to give a residue. The title compound (1.1 g, 83.31% yield) was obtained as a gray solid. 1H NMR (400 MHz, DMSO-d6) 8 8.44-8.50 (m, 1H), 7.19-7.26 (m, 1H), 6.85-6.91 (m, WO 2024/184461 PCT/EP2024/056026 1H), 4.52 (br t, J=625 Hz, 2H), 4.42 (s, 3H), 4.29 - 4.33 (m, 1H), 4.23 (q, J=7.09 Hz, 2H), 3.(s, 3H), 3.06 (brt, J=6.32 Hz, 2H), 2.76-2.86 (m, 2H), 1.28 (t, J=7.07 Hz, 3H), 1.12-1.17 (m, 6H). LCMS (Method a. ES+, RT = 1.635 min) 425.2/426.2 (M+H) +

[00695] INTERMEDIATE 56:Ethyl 8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2- methylprop- 1 -en- 1 -yl)-5,6-dihydropyrrolo[2, 1 -a] isoquinoline-3-carboxylate

[00696]To a solution of Intermediate 55 (200 mg, 0.47 mmol) in THE (2 mL) was added with Burgess reagent (224 mg, 0.940 mmol) in DCM (1 mL). The mixture was stirred at 20 °C for 2 h. The mixture was added with H20 (2 mL) and the pH was adjusted to 5-6 with 1M HC1, extracted with DCM (2 mL x 3). The combined organic phase was washed with brine (2 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=10/l to 0/1) to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.19 (s, 1H), 8.06 - 7.98 (m, 1H), 7.25 (s, 1H), 6.81 (s, 1H), 6.78 - 6.77 (m, 1H), 6.19 (s, 1H), 4.82 - 4.76 (m, 1H), 4.65 (br s, 1H), 4.58 - 4.52 (m, 2H), 4.41 (s, 3H), 4.27 - 4.19 (m, 2H), 3.89 (s, 3H), 3.15 - 3.08 (m, 2H), 1.88 (s, 3H), 1.80 - 1.74 (m, 3H), 1.(t, J = 7.1 Hz, 3H). LCMS (Method a. ES+, RT = 2.063 min) 408.2/409.2 (M+H)+.

[00697] INTERMEDIATE 57:8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l -(2-methylprop- l-en-l-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylic acid WO 2024/184461 PCT/EP2024/056026

[00698]To a solution of Intermediate 56 (100 mg, 245.42 umol) in THF (1 mL) was added with TMSOK (62.97 mg, 490.84 umol). The mixture was stirred at 20 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (102 mg, crude) as a yellow solid. LCMS (Method g. ES+, RT = 0.450 min) 380.2 (M+H) +

[00699] INTERMEDIATE 58:(R)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2-methylprop- 1 -en- 1 -yl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carboxamide

[00700]To a solution of Intermediate 57 (102 mg, 268.84 umol) and Intermediate 124 (60.mg, HCI) in DMF (2 mL) was added with HATU (153.33 mg, 403.26 umol) and DIEA (138.mg, 1.08 mmol, 187.30 pL) at 20 °C. The mixture was stirred at 20 °C for 1 hr. The mixture was diluted with H20 (5 mL) and extracted with EtOAc (2 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The crude product was triturated by MTBE (2 mL) to give the title compound (80 mg, 63% yield) as a yellow solid. LCMS (Method g. ES+, RT = 0.44 min) 476.3 (M+H)+

[00701] INTERMEDIATE 59:N-(4-bromo-3-methoxyphenethyl)-2-formamido-3,3- dimethylbutanamide

[00702]To a solution of Intermediate 4 (25.00 g, 104.12 mmol) and 2,2-dimethylpropanal (9.g, 109.33 mmol, 12.09 mL) in MeOH (250 mL) was added HCOONH4 (13.13 g, 208.25 mmol) at -296- WO 2024/184461 PCT/EP2024/056026 °C. The mixture was stirred at 80°C for 2 hr. The reaction mixture was diluted with H20 (5mL) and extracted with DCM (200 mLx3). The combined organic layers were washed with brine (200 mLx2), dried over Na2S04, filtered and concentrated under reduced pressure to give a crude product. The crude product was triturated with PE (200 mL) at 20°C for 20 min and filtered. The title compound (30 g, 78%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.20 - 8.10 (m, 2H), 8.01 (d, J = 1.4 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 1.7 Hz, 1H), 6.73 (dd, J = 1.8, 8.1 Hz, 1H), 4.20 (d, J = 9.9 Hz, 1H), 3.83 (s, 3H), 3.41 - 3.33 (m, 1H), 3.31 - 3.22 (m, 1H), 2.70 (dt, J = 2.4, 7.1 Hz, 2H), 0.84 (s, 9H). LCMS (Method m. ES+, RT = 0.42 min) 371.2/373.2 (M+H) +

[00703] INTERMEDIATE 60:9-bromo-l-(tert-butyl)-8-methoxy-5,6-dihydroimidazo[5,l- a]isoquinoline

[00704]To a solution of PPA (49.68 g, 107.74 mmol, 85% purity) in toluene (100 mL) was added Intermediate 59 (10 g, 26.93 mmol) at 20 °C. The mixture was stirred at 110 °C for 2 hr. The reaction mixture was added by H2O (300 mL) at 20 °C, then adjust pH=8, extracted with DCM (100 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Method 16). The title compound (4.00 g, 44 %) was obtained as a white solid. 1HNMR (400 MHz, CDCh) 8 = 7.95 (s, 1H), 7.42 (s, 1H), 6.79 (s, 1H), 4.04 (t, J = 6.2 Hz, 2H), 3.92 (s, 3H), 2.96 (t, J = 6.2 Hz, 2H), 1.48 (s, 9H) LCMS (Method m. ES+, RT = 0.min)335.0/337.0 (M+H) +

[00705] INTERMEDIATE 61:Ethyl 9-bromo-l-(tert-butyl)-8-methoxy-5,6- dihydroimidazo[5, 1 -a]isoquinoline-3-carboxylate WO 2024/184461 PCT/EP2024/056026

[00706]To a solution of Intermediate 60 (4 g, 11.93 mmol) in THF (35 mL) was added LDA (2 M, 8.95 mL) at -70°C for 1 hr under N2. At -70°C, the mixture was added with Ethyl chloroformate (12.95 g, 119.32 mmol, 11.41 mL) and stirred at -70°C for 1 hr. The mixture was poured into H20 (100 mL) at -70°C and extracted with EtOAc (50 mLx3). The organic layers were washed with brine (100 mLx2), filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 0/1). The title compound (2 g, 82%) was obtained as a yellow solid. 1H NMR (400 MHz, CDCI) 6 = 8.00 (s, 1H), 6.83 (s, 1H), 4.64 - 4.55 (m, 2H), 4.44 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 2.94 (t, J = 6.4 Hz, 2H), 1.51 (s, 9H), 1.45 (t, J = 7.1 Hz, 3H) LCMS {Method m. ES+, RT = 0.52 min) 407.0/409.0 (M+H) +

[00707] INTERMEDIATE 62:9-bromo-l-(tert-butyl)-8-methoxy-5,6-dihydroimidazo[5,l- a]isoquinoline-3-carboxylic acid

[00708]To a solution of Intermediate 61 (400 mg, 982.08 umol) in THF (4 mL) was added TMSOK (251.98 mg, 1.96 mmol) at 20°C. The mixture was stirred at 20°C for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The title compound (375 mg, crude) was obtained as a yellow solid. LCMS {Method m. ES+, RT = 0.40 min 379.0/381.1 (M+H) WO 2024/184461 PCT/EP2024/056026

[00709] INTERMEDIATE 63:(9-bromo-l-(tert-butyl)-8-methoxy-5,6-dihydroimidazo[5,l- a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-l-hydroxypropyl)pyrrolidin-l- yl)methanone

[00710]To a solution of Intermediate 62 (280.00 mg, 738.30 umol) and Intermediate 2(207.01 mg, 885.96 umol, HC1) in DMF (3 mL) was added HATU (308.80 mg, 812.13 umol) and DIEA (381.68 mg, 2.95 mmol, 514.40 pL) at 20°C. The mixture was stirred at 20°C for 2 hr. The reaction mixture was added with H20 (30 mL) at 0°C, then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 3/1). The title compound (350 mg, 85%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 = 7.80 (s, 1H), 7.17 (s, 1H), 5.46 (d, J = 6.6 Hz, 1H), 4.84 - 4.74 (m, 1H), 4.30 - 4.15 (m, 3H), 3.93 - 3.77 (m, 4H), 2.(br t, J= 6.1 Hz, 2H), 2.40 - 2.28 (m, 1H), 2.27 - 2.15 (m, 1H), 2.13 - 2.03 (m, 1H), 1.84 - 1.(m, 2H), 1.66 - 1.56 (m, 1H), 1.51 (s, 3H), 1.39 (s, 9H). LCMS (Method m. ES+, RT = 0.55 min) 558.3/560.2 (M+H) +

[00711] INTERMEDIATE 64:N-(4-bromo-3-methoxyphenethyl)-2-formamido-4- methylpentanamide N ,0 WO 2024/184461 PCT/EP2024/056026

[00712]To a solution of Intermediate 4 (5.00 g, 20.82 mmol) in MeOH (50 mL) was added with 3-methylbutanal (3.59 g, 41.65 mmol, 4.57 mL), HCOONH4 (2.63 g, 41.65 mmol) at 20°C. The mixture was stirred at 80°C for 4 hr. The reaction mixture was diluted with H20 (100 ml) and extracted with EtOAc (100 mLx3). The combined organic layers were washed with brine (1mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by Method 6. The title compound (1.50 g, 19%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 12.37 (br s, 1 H), 4.14 (m, 1 H), 3.33 (br s, 1 H), 2.05 - 2.17 (m, 1 H), 1.68 - 1.80 (m, 3 H), 1.40 (s, 6 H), 1.32 (s, 5 H), 1.25 - 1.29 (m, 3 H) LCMS (Method i. ES+, RT = 0.42 min) 371.1/373.1 (M+H) +

[00713] INTERMEDIATE 65:9-bromo-l-isobutyl-8-methoxy-5,6-dihydroimidazo[5,l- a]isoquinoline

[00714]A solution of P205 (2.49 g, 17.51 mmol, 1.08 mL) in methanesulfonic acid (13 mL) was heated to 75°C and stirred for 0.5 hr. Intermediate 64 (1.30 g, 3.50 mmol) was added at 75°C. The mixture was stirred at 75°C for 12 hr. The mixture was cooled, added with sat.NaHCO3 to adjust pH=8, diluted with H20 (100 mL) and extracted with DCM (50 mLx3). The combined organic layers were washed with brine (50 mLx2), dried over Na2S04, filtered and concentrated under reduced pressure. The title compound (1 g, 85%) was obtained as a white solid. 1H NMR (400 MHz, CDC13) 8 ppm 8.03 (br s, 1 H), 6.78 (s, 1 H), 6.34 (s, 1 H), 3.83 (br t, J=6.32 Hz, 2 H), 3.45 (s, 3 H), 2.59 (br t, J=6.32 Hz, 2 H), 2.30 (d, J=7.27 Hz, 2 H), 1.64 - 1.76 (m, 1 H), 0.55 (d, J=6.68 Hz, 6 H) LCMS (Method m. ES+, RT=0.39 min) 335.0/337.0 (M+H) +

[00715] INTERMEDIATE 66:ethyl 9-bromo-l-isobutyl-8-methoxy-5,6- dihydroimidazo[5, 1 -a]isoquinoline-3-carboxylate WO 2024/184461 PCT/EP2024/056026

[00716]Step A: To a solution of Intermediate 65 (800.00 mg, 2.39 mmol) in THF (8 mL) was added LDA (2 M, 1.43 mL) at -70°C for 30 min under N2.

[00717]Step B: A solution of ethyl chloroformate (1.29 g, 11.93 mmol, 1.14 mL) in THF (mL) was stirred at -70°C under N2.

[00718]Step C: The solution A was added dropwise to the solution B mixture at -70°C for 1.hr. The mixture was added with NaHCO3 (10 mL) and extracted with EtOAc (50 mLx3). The organic layers were concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/l to 80/20). The title compound (150 mg, 15%) was obtained as a yellow solid. 1H NMR (400 MHz, CDC13) ppm 7.85 (s, 1 H), 6.83 (s, 1 H), 4.66 (t, J=6.57 Hz, 2 H), 4.45 (m, 2 H), 3.94 (s, 3 H), 3.02 (br t, J=6.57 Hz, 2 H), 2.78 (d, J=7.25 Hz, 2 H), 2.03 - 2.22 (m, 1 H), 1.44 (t, J=7.13 Hz, 3 H), 1.00 (d, J=6.63 Hz, 6 H) LCMS {Method a. ES+, RT = 1.57 min) 407.1/409.1 (M+H) +

[00719] INTERMEDIATE 67:9-bromo-l-isobutyl-8-methoxy-5,6-dihydroimidazo[5,l- a]isoquinoline-3-carboxylic acid

[00720]To a solution of Intermediate 66 (130 mg, 319.17 umol) in THF (1.5 mL) was added TMSOK (81.89 mg, 638.35 umol). The mixture was stirred at 20°C for 1 hr. The mixture was concentrated under reduced pressure. The title compound (130.00 mg, crude) was obtained as a white solid. LCMS {Method m. ES+, RT = 0.41 min) 379.2/381.2 (M+H) +.

WO 2024/184461 PCT/EP2024/056026

[00721] INTERMEDIATE 68:(R)-l-(9-bromo-l-isobutyl-8-methoxy-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carboxamide

[00722]To a solution 1 of Intermediate 67 (130 mg, 311.50 umol) in DMF (1 mL) was added with HATU (130.29 mg, 342.65 umol) at 20°C. The mixture was stirred at 20°C for 30 min.

[00723]To a solution 2 of (2R)-2-methylpyrrolidine-2-carboxamide (61.54 mg, 373.80 umol, HC1) in DMF (1 mL) was added with Na2CO3 (66.03 mg, 623.00 umol). The mixture was stirred at 20°C for 30 min. The solution I was added dropwise to the solution 2 mixture at 20°C. The mixture was stirred at 20°C for 1 hr. The reaction mixture was poured into ice water (5 ml), filtered and the solid was dissolved with EtOAc (25 ml). The organic phase was washed with brine (mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The title compound (110 mg, 72%) was obtained as a white solid. LCMS (Method a. ES+, RT = 1.49 min) 489.4/491.0 (M+H) +.

[00724] INTERMEDIATE 69:(R)-l-(9-bromo-l-isobutyl-8-methoxy-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile /Ox

[00725]To a solution of Intermediate 68 (110.00 mg, 224.76 umol) in THF (1 mL) was added Burgess Reagent (107.12 mg, 449.53 umol). The mixture was stirred at 20°C for 2 hr. The reaction mixture was diluted with H20 (5 ml) and extracted with DCM (5 mLx3). The combined organic N N WO 2024/184461 PCT/EP2024/056026 layers were washed with brine (5 mL*2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The title compound (80 mg, 76%) was obtained as a white solid.

[00726] INTERMEDIATE 70:ethyl l-(l-(benzyloxy)-2-methylpropan-2-yl)-9-bromo-8-methoxy-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate

[00727]To a solution of Intermediate 39 (5 g, 12.95 mmol) in Ac20 (100 mL) was added 2,2- dimethylbut-3-ynoxymethylbenzene (2.92 g, 15.54 mmol). The mixture was stirred at 140°C for hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H20 50 mL and quenched with Na2CO3 100 mL. Then extracted with DCM (100 mLx3). The combined organic layers were washed with brine 200 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=20/l to 10/1). The title compound (5.50 g, 41%) as colorless oil. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.28 (t, J=7.Hz, 3 H), 1.34 (s, 6 H), 2.88 (br t, J=6.13 Hz, 2 H), 3.54 (s, 2 H), 3.89 (s, 3 H), 4.23 (d, J=7.13 Hz, H), 4.37 - 4.43 (m, 2 H), 4.48 (s, 2 H), 6.90 (s, 1 H), 7.13 (s, 1 H), 7.29 (br d, J=4.75 Hz, 5 H), 8.05 (s, 1 H) LCMS (Method h. ES+, RT = 0.73 min) 408.0/410.0 (M+H) +.

[00728] INTERMEDIATE 71:Ethyl 9-bromo-8-methoxy-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxylate

[00729]To a solution of Intermediate 39 (23.94 g, 61.99 mmol) in Ac2O (120 mL) was addedethynyl (trimethyl) silane (7.92 g, 80.59 mmol, 11.16 mL). The mixture was stirred at 140 °C for OBn WO 2024/184461 PCT/EP2024/056026 1 hr. The reaction mixture was concentrated to dryness. The residue was diluted with DCM (1mL) and adjusted to pH 8 with sat.Na2CO3, then extracted with DCM (100 mLx2). The combined organic layers were washed with brine (100 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with PE (200 mL) at 250C for min, filtered and concentrated under reduced pressure. The title compound (18.08 g, 79%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.28 (t, J=7.07 Hz, 3 H) 3.05 (t, J=6.75 Hz, H) 3.87 (s, 3 H) 4.19 - 4.26 (m, 2 H) 4.51 (t, J=6.75 Hz, 2 H) 6.66 - 6.70 (m, 1 H) 6.89 - 6.(m, 1 H) 7.09 - 7.13 (m, 1 H) 7.90 (s, 1 H) LCMS (Method m. ES+, RT = 0.62 min) 350.1/352.(M+H) +

[00730] INTERMEDIATE 72:Ethyl l-(l-(benzyloxy)-2-methylpropan-2-yl)-8-methoxy-9- (2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate

[00731]To a solution of Intermediate 70 (2.50 g, 4.88 mmol) in DMF (50 mL) was added with Intermediate 26 (3.64 g, 9.76 mmol) and XPHOS-Pd-G2 (767.71 mg, 975.74 umol) at 20°C. The mixture was stirred at 120 °C for 12 h. The reaction mixture was poured into H2O (80 mL) and extracted with EtOAc (20 mLx3). The combined organic layers were washed with brine (mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 50/to 0/1). The title compound (3.40g, 68 %) as a white solid. 1H NMR (400 MHz, DMSO—d6) ppm 1.27 - 1.32 (m, 3 H), 1.38 (s, 6 H), 2.98 (br t, J=5.84 Hz, 2 H), 3.60 (s, 2 H), 3.90 (s, 3 H), 4.23 (q, J=7.03 Hz, 2 H), 4.39 (s, 3 H), 4.43 - 4.49 (m, 4 H), 6.92 (s, 1 H), 7.21 - 7.32 (m, 6 H), 8.44 (s, 1 H) LCMS (Method m. ES+, RT = 0.54 min) 416.4/417.3 (M+H) +.

WO 2024/184461 PCT/EP2024/056026

[00732] INTERMEDIATE 73:Ethyl l-(l-hydroxy-2-methylpropan-2-yl)-8-methoxy-9-(2- methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate

[00733]To a solution of Intermediate 72 (3.30 g, 6.40 mmol) in THE (45 mL) and EtOH (mL) was added Pd/C (50 mg, 10% purity) under H2 (15 psi). The mixture was stirred at 45OC for hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. 77ze hz/e compount/ (2.70 g, 99%) as a white solid. 1H NMR (400 MHz, CDCI3) 6 ppm 1.36- 1.(m, 3 H), 1.47 (s, 6 H), 1.60 - 1.70 (m, 1 H), 2.96 - 3.04 (m, 2 H), 3.87 (s, 2 H), 4.01 (s, 3 H), 4.(q, J=7.13 Hz, 2 H), 4.42 - 4.46 (m, 3 H), 4.54 - 4.65 (m, 2 H), 6.95 (s, 1 H), 7.05 (s, 1 H), 8.52 (s, H) LCMS (Method m. ES+, RT = 0.48 min) 426.2/427.3 (M+H) +.

[00734] INTERMEDIATE 74:ethyl 1-(1 -((tert-butyldimethylsilyl)oxy)-2-methylpropan-2- yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carboxylate

[00735]To a solution of Intermediate 73 (1.30 g, 3.06 mmol) in DCM (10 mL) was added with imidazole (416.00 mg, 6.11 mmol) and TBSC1 (552.61 mg, 3.67 mmol, 451.11 pL)at20°C. The mixture was stirred at 20°C for 2 hr. The reaction was diluted with DCM (20 mL) and washed with H20 (10 mL x3). The organic layers were concentrated under reduced pressure. The title compound (3.20 g, 97%) as a white solid. 1H NMR (400 MHz, CDCI3) 6 8.51 (s, 1H), 7.09 (s, WO 2024/184461 PCT/EP2024/056026 1H), 6.94 (s, 1H), 4.62 - 4.56 (m, 2H), 4.45 - 4.41 (m, 3H), 4.30 (q, J = 7.1 Hz, 2H), 4.03 - 3.(m, 3H), 3.77 (s, 2H), 2.99 (brt, J = 6.3 Hz, 2H), 1.44 - 1.41 (m, 6H), 1.39 - 1.35 (m, 3H), 0.87 - 0.83 (m, 9H), -0.02 - -0.09 (m, 6H) LCMS (Method/ ES+, RT = 0.75 min) 540.2/541.2 (M+H) +.

[00736] INTERMEDIATE 75:l-(l-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-8- methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylic acid

[00737]To a solution of Intermediate 74 (1.00 g, 1.85 mmol) in THF (10 mL) was added with TMSOK (713.07 mg, 5.56 mmol). The mixture was stirred at 20°C for 12 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (1.02 g, crude) as a yellow solid. LCMS (Method/ ES+, RT=0.61 min) 380.2/381.2 (M+H)+.

[00738] INTERMEDIATE 76:methyl (S)-2-(l-(l-((tert-butyldimethylsilyl)oxy)-2- methylpropan-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxamido)-4,4,4-trifluoro-2-methylbutanoate

[00739]To a solution of Intermediate 75 (1.00 g, 1.95 mmol) and Intermediate 115 (519.mg, 2.35 mmol, HC1) in DMF (10 mL) was added HATU (1.49 g, 3.91 mmol) and DIEA (1.01 g, 7.82 mmol, 1.36 mL) at 80°C. The mixture was stirred at 80°C for 12 hr. The mixture was diluted with H20 (40 mL) and extracted with EtOAc (20 mLx3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by column WO 2024/184461 PCT/EP2024/056026 chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 1/1). The title compound (550.mg, 41%) as a yellow solid. 1H NMR (400 MHz, CDCI3) 6 = 8.49 (s, 1H), 6.93 (s, 1H), 6.81 - 6.71 (m, 2H), 4.51 (s, 2H), 4.45 - 4.42 (m, 3H), 4.03 - 3.99 (m, 3H), 3.87 - 3.83 (m, 3H), 3.80 - 3.75 (m, 2H), 3.48 - 3.39 (m, 1H), 3.02 - 2.93 (m, 3H), 1.76 (s, 3H), 1.44 - 1.42 (m, 6H), 0.87 - 0.85 (m, 9H), -0.02 - -0.07 (m, 6H). LCMS (Method m. ES+, RT=0.68 min) 679.4/680.4 (M+H)+.

[00740] INTERMEDIATE 77:(S)-2-(l-(l-((tert-butyl dimethylsilyl)oxy)-2-methylpropan-2- yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carboxamido)-4,4,4-trifluoro-2-methylbutanoic acid

[00741]To a solution of Intermediate 76 (500.00 mg, 736.58 umol) in THE (5 mL) was added with TMSOK (283.49 mg, 2.21 mmol). The mixture was stirred at 70°C for 6 hr. The mixture was diluted with H20 (10 mL) and adjust pH = 6 with 0.5N HC1, then it was extracted with EtOAc (10 mLx3). The organic layers were concentrated under reduced pressure. The title compound (480 mg, 98%) was obtained as a yellow solid. IHNMR (400 MHz, CDCI3) 6 8.50 (s, 1H), 6.(s, 1H), 6.77 (s, 1H), 6.62 (s, 1H), 4.56 - 4.49 (m, 3H), 4.45 - 4.41 (m, 3H), 4.03 - 3.97 (m, 3H), 3.81 - 3.75 (m, 2H), 3.25 - 3.22 (m, 1H), 3.03 - 2.95 (m, 2H), 2.86 - 2.81 (m, 1H), 1.81 (s, 3H), 1.45 -1.41 (m, 7H), 1.22 - 1.20 (m, 2H), 0.88 - 0.84 (m, 9H), -0.03 - -0.08 (m, 6H) LCMS (Method m. ES+, RT=0.62 min) 665.5/666.4 (M+H)+.

[00742] INTERMEDIATE 78:(S)-N-(l-amino-4,4,4-trifluoro-2-methyl-l-oxobutan-2-yl)- l-(l-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-8-methoxy-9-(2-methyl-2H-tetr azol-5- yl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxamide WO 2024/184461 PCT/EP2024/056026

[00743]To a solution of Intermediate 77 (430.00 mg, 645.86 umol) in THF (5 mL) was added with CDI (157.09 mg, 968.79 pmol) at 20°C. The mixture was stirred at 20°C for 0.5 hr. The mixture was added NHJ.HO (271.62 mg, 1.94 mmol, 298.48 pL, 25% purity) at 20°C. The mixture was stirred at 20°C for 1 h. The reaction was diluted with H20 (10 mL) and extracted with EtOAc (10 mL x3). The organic layers were concentrated under reduced pressure to give a crude product. The crude product was triturated by MTBE (3 mL) to give the title compound (300.00 mg, 70%) as a yellow solid. 1H NMR (400 MHz, CDCh) 8 = 8.51 (s, 1H), 6.95 (s, 1H), 6.79 (s, 1H), 6.26 (s, 2H), 4.61 - 4.48 (m, 3H), 4.44 (s, 3H), 4.00 (s, 3H), 3.82 - 3.71 (m, 2H), 3.(hr dd, J= 11.6, 15.9 Hz, 1H), 3.22 (s, 1H), 3.11 - 2.92 (m, 3H), 1.74 (s, 3H), 1.36 - 1.23 (m, 2H), 1.20 (s, 2H), 0.91 - 0.84 (m, 10H), -0.01 - -0.08 (m, 5H) LCMS (Method f, ES+, RT = 0.59 min) 664.6/665.4 (M+H)+.

[00744] INTERMEDIATE 79:(S)-l-(l-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2- yl)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxamide

[00745]To a solution of Intermediate 78 (260.00 mg, 391.68 pmol) in THF (3 mL) was added burgess reagent (186.68 mg, 783.36 pmol) at 20°C. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with H20 (10 mL) and extracted with MTBE (10 mLx3). The organic layers were concentrated under reduced pressure to give the title WO 2024/184461 PCT/EP2024/056026 compound (230.00 mg, 91%) as a yellow solid. 1HNMR (400 MHz, CDC13) 6 = 8.56 (s, 1H), 7.(s, 1H), 6.78 (s, 1H), 4.74 - 4.57 (m, 2H), 4.48 (s, 3H), 4.09 - 4.04 (m, 3H), 3.81 (s, 2H), 3.30 - 3.09 (m, 2H), 3.04 (t, J = 6.3 Hz, 2H), 2.00 (s, 3H), 1.60 (s, 4H), 1.50 - 1.45 (m, 7H), 0.93 - 0.(m, 8H), 0.03 - -0.02 (m, 6H) LCMS (Method f ES+, RT = 0.65 min) 646.4/647.4 (M+H)+.

[00746] INTERMEDIATE 80:(S)-l-(l-((tert-butyl dimethylsilyl)oxy)-2-methylpropan-2- yl)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8-methoxy-N-methyl-9-(2-methyl-2H-tetrazol-5-yl)- 5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamide

[00747]To a solution of Intermediate 79 (230.00 mg, 356.15 umol) in DMF (3 mL) was added NaH (21.37 mg, 534.23 umol, 60% purity) at 0°C under N2. The mixture was stirred at 20°C for 0.5 hr. CHI (101.10 mg, 712.31 umol, 44.34 pL) was dropwise added at 20°C and the mixture was stirred at 70°C for 2 hr under N2. The reaction was poured into sat. NH4C1 (10 mL) at 0°C and extracted with EtOAc (5 mLx3). The organic layers were concentrated under reduced pressure to give the title compound (200 mg, 85%) as a yellow solid. LCMS (Method m, ES+, RT = 1.min) 440.3 (M+H)+.

[00748] INTERMEDIATE 81:ethyl l-(2,2-difluoropropyl)-8-methoxy-9-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylate ס, ­ ­ ,ס N WO 2024/184461 PCT/EP2024/056026

[00749]To a solution of ethyl 9-bromo-l-(2,2-difluoropropyl)-8-methoxy-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate (2.00 g, 4.67 mmol) in n-heptane (14 mL) and dioxane (7 mL) was added KOAc (6.87 g, 70.05 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)-l, 3,2-dioxaborolane (11.86 g, 46.70 mmol), Pd(dppf)C12. CH2C12 (762.74 mg, 934.00 umol). The mixture was stirred at 95°C for 12 hr. The residue was poured into water (20 mL). The aqueous phase was extracted with EtOAc(20 mLx3). The combined organic phase was washed with brine (20 mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=10/l to 0/1) to give the title compound (1.40 g, 63 %) as a white solid. 11HNMR (400 MHz, CDCh) 8 = 8.10 - 8.00 (m, 1H), 7.00 - 6.96 (m, 1H), 6.81 - 6.74 (m, 1H), 4.65 - 4.(m, 2H), 4.33 - 4.25 (m, 2H), 3.88 (s, 3H), 3.35 (t, J = 15.6 Hz, 2H), 3.00 (br t, J = 6.4 Hz, 2H), 1.74 - 1.56 (m, 3H), 1.36 (s, 12H), 1.29 - 1.24 (m, 3H). LCMS (Method a, ES+, RT = 2.25 min 476.0/477.2 (M+H)+.

[00750] INTERMEDIATE 82:ethyl l-(2,2-difluoropropyl)-8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate N ,0

[00751]To a solution of Intermediate 81 (1.30 g, 2.73 mmol) in dioxane (10 mL) and H20 (mL) was added C82CO3 (3.56 g, 10.94 mmol), 5-iodo-2-methyl-tetrazole (746.55 mg, 3.56 mmol) and XPHOS-Pd-G2 (430.37 mg, 546.99 umol). The mixture was stirred at 80°C for 2 hr. The residue was poured into water (15 mL). The aqueous phase was extracted with EtOAc(15 mLx3). The combined organic phase was washed with brine (15 mLx2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=10/l to 0/1) to give the title compound (760.00 mg, 64%) as white solid. 1 HNMR (400 MHz, CDCh) 8 = 8.35 (s, 1H), 7.02 - 6.97 (m, 2H), 4.69 - 4.63 (m, 2H), 4.-310- WO 2024/184461 PCT/EP2024/056026 (s, 3H), 4.34 - 4.28 (m, 2H), 4.00 (s, 3H), 3.44 - 3.34 (m, 2H), 3.07 (br t, J = 6.5 Hz, 2H), 1.76 - 1.65 (m, 3H), 1.41 - 1.35 (m, 3H). LCMS (Method m, ES+, 1.64 min 432.3.7433.2 (M+H )+.

[00752] INTERMEDIATE 83:l-(2,2-difluoropropyl)-8-methoxy-9-(2-methyl-2H-tetrazol- 5-yl)-5,6-dihydropyrrolo [2,1-a]isoquinoline-3-carboxylic acid

[00753]To a solution of Intermediate 82 (760 mg, 1.76 mmol) in THF (5 mL) and EtOH (mL) was added KOH (296.50 mg, 5.28 mmol) in H20 (5 mL). The mixture was stirred at °C for 2 hr. The solvent was evaporated and the pH was adjusted to 3-4 with 1M HC1. The aqueous phase was extracted with EtOAc(8 mLx3). The combined organic phase was washed with brine (10 mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure to give the title compound (650 mg, 91 %) as a yellow solid. 1H NMR (400 MHz, DMSO- d6) 5 = 12.42 - 12.32 (m, 1H), 8.21 - 8.17 (m, 1H), 7.30 - 7.23 (m, 1H), 6.85 (s, 1H), 4.61 - 4.(m, 2H), 4.45 - 4.39 (m, 3H), 3.89 (s, 3H), 3.12 - 3.03 (m, 2H), 1.73 - 1.59 (m, 3H). LCMS (Method m, ES+ 1.64 min) 432.3.743 3.2 (M+H)+.

[00754] INTERMEDIATE 84:methyl (S)-2-(l-(2,2-difluoropropyl)-8-methoxy-9-(2- methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2, l-a]isoquinoline-3-carboxamido)-4, 4,4-tri fluoro- 2-methylbutanoate WO 2024/184461 PCT/EP2024/056026

[00755]To a solution of Intermediate 83 (800 mg, 1.98 mmol)inDMF (8 mL) was added HATU (905 mg, 2.38 mmol) and DIEA (1.03 g, 7.93 mmol, 1.38 mL) at 20°C for 1 hr. Then it was added with Intermediate 115 (571.34 mg, 2.58 mmol, HC1). The mixture was stirred at 80°C for 4 hr. The residue was poured into water (10 mL) and the pH was adjusted to 5 with IM HCI. The aqueous phase was extracted with EtOAc(10 mLx3). The combined organic phase was washed with brine (10 mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=10/l to 0/1) to give title compound (600 mg, 53%) as a brown solid. 1H NMR (400 MHz, CDC13) 8 = 8.32 (s, 1H), 6.99 - 6.96 (m, 1H), 6.80 (s, 1H), 6.67 (s, 1H), 4.63 - 4.57 (m, 2H), 4.45 (s, 3H), 4.- 3.97 (m, 3H), 3.47 - 3.33 (m, 3H), 3.06 (t, J= 6.4 Hz, 2H), 2.82 (s, 1H), 2.06 - 2.04 (m, 1H), 1.- 1.59 (m, 8H). LCMS {Method m, ES+ 0.52 min 571.3.7572.3 (M+H)+.

[00756] INTERMEDIATE 85:(S)-2-(l-(2,2-difluoropropyl)-8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamido)-4,4,4-trifluoro-2- methylbutanoic acid

[00757]To a solution of Intermediate 84 (600 mg, 1.05 mmol) in THE (7 mL) was added TMSOK (269 mg, 2.10 mmol). The mixture was stirred at 50 °C for 3 hr. The residue was added with water (8 mL) and the pH was adjusted to 4-5 with 1M HCI. The aqueous phase was extracted withEtOAc(8 mLx3). The combined organic phase was washed with brine (8 mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure to give the title compound (620.00 mg, crude) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 = 12.88 - 12.(m, 1H), 8.37 - 8.28 (m, 1H), 8.16 (s, 1H), 7.27 - 7.20 (m, 1H), 7.01 - 6.91 (m, 1H), 4.54 - 4.(m, 5H), 3.89 (s, 3H), 3.38 - 3.23 (m, 4H), 3.03 (br t, J = 6.0 Hz, 2H), 2.89 - 2.76 (m, 1H), 1.(brt,J= 18.7 Hz, 3H), 1.56 (s,3H). LCMS {Method m, ES+ RT = 0.46 min 557.3.7558.3 (M+H)+.-312- N ,0 O, WO 2024/184461 PCT/EP2024/056026

[00758] INTERMEDIATE 86:(S)-N-(l-amino-4,4,4-trifluoro-2-methyl-l-oxobutan-2-yl)- l-(2,2-difluoropropyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxamide

[00759]To a solution of Intermediate 85 (570 mg, 1.02 mmol) in THF (6 mL) was added CD I (249.13 mg, 1.54 mmol). The mixture was stirred at 25OC for lb , then it was added NH3.H20 (4mg, 3.07 mmol, 473.37 pL, 25% purity) . The mixture was stirred at 25OC for 1 hr. The mixture was diluted with H20 (6 mL), extracted with DCM (5 mLx3). The combined organic layer was washed with 5 mL H2O, 5 mL brine, dried over Na2S04, filtered and the filtrate was concentrated to give the title compound (580.00 mg, crude) as a brown solid. 1H NMR (400 MHz, CDCh) 8 = 8.35 - 8.26 (m, 1H), 7.81 - 7.67 (m, 1H), 7.19 - 7.08 (m, 1H), 7.02 - 6.95 (m, 1H), 6.(s, 1H), 6.49 - 6.41 (m, 1H), 5.46 - 5.33 (m, 1H), 4.75 - 4.65 (m, 1H), 4.59 - 4.48 (m, 1H), 4.44 (s, 3H), 3.99 (s, 3H), 3.46 - 3.24 (m, 3H), 3.11 - 2.98 (m, 3H), 1.79 - 1.70 (m, 5H). LCMS {Method m, ES+ RT =0.44 min 556.3/557.3 (M+H) +.

[00760] INTERMEDIATE 87:(S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-l-(2,2- difluoropropyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxamide WO 2024/184461 PCT/EP2024/056026

[00761]To a solution of Intermediate 86 (530 mg, 954.10 umol) in THF (3 mL) was added with Burgess Reagent (909.46 mg, 3.82 mmol) in DCM (3 mL). The mixture was stirred at 25 °C for hr. The mixture was diluted with H20 (6 mL), extracted with DCM (5 mLx3). The combined organic layer was washed with 5 mL H2O, 5 mL brine, dried over Na2S04, filtered and the filtrate was concentrated to give a crude product. The residue was purified by column chromatography (SiO2, PE/EA=10/l to 0/1) to give the title compound (340 mg, 66 %) as a yellow solid. IHNMR (400 MHz, CDCh) 8 = 8.31 (s, 1H), 7.03 - 6.96 (m, 1H), 6.65 (s, 1H), 6.04 - 5.99 (m, 1H), 4.70 - 4.61 (m, 2H), 4.45 (s, 3H), 4.05 - 3.97 (m, 3H), 3.44 - 3.32 (m, 2H), 3.21 - 3.05 (m, 4H), 1.96 (s, 2H), 1.71 (brt, J= 18.4 Hz, 3H), 1.57 (brs,2H). LCMS (Methodm. ES+RT0.51 min 538.3/539.(M+H)+.

[00762] INTERMEDIATE 88:ethyl 8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(l,3,4- thiadiazol-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate

[00763]To a solution of ethyl 8-methoxy-9-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l- (l,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate (5.00 g, 11.51 mmol) and Intermediate 26 (8.59 g, 23.03 mmol) in DMF (50 mL) was added XPHOS-Pd-G2 (1.81 g, 2.30 mmol) at 20°C. The mixture was stirred at 120°C for 12 hr. The reaction mixture was diluted with H20 (50 mL) and KF (10% w/w, 20 mL). The reaction mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with (50 mL x 4), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/l to 0/1) to give the title compound (2.20 g, 44%) as a white solid. 1H NMR (400 MHz, CDCh) 8 = 9.06 - 8.96 (m, 1H), 8.67 - 8.56 (m, 1H), 7.21-7.16 (m, 1H), 6.94 - 6.85 (m, 1H), 4.70 - 4.56 (m, 2H), 4.32 (s, 3H), WO 2024/184461 PCT/EP2024/056026 4.27 (q, J = 7.2 Hz, 2H), 3.95 - 3.88 (m, 3H), 3.07 (t, J = 6.6 Hz, 2H), 1.36 - 1.26 (m, 3H). LCMS (Method h. ES+ RT 0.46 min 438.2/439.2 (M+H)+.

[00764] INTERMEDIATE 89:8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(l,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylic acid

[00765]To a solution of Intermediate 88 (2.20 g, 5.03 mmol) in THF (10 mL), EtOH (10 mL) and H20 (10 mL) was added with KOH (846.44 mg, 15.09 mmol) at 20°C. The mixture was stirred at 80°C for 2 hr. The reaction mixture was poured into ice-water (50 mL) and added 1 M HC1 to pH=5-6. The reaction mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with PE (20 mL) at 20°C for 5 min and filtered to give the title compound (1.40 g, 68%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 = 9.59 (s, 1H), 8.61 - 8.49 (m, 1H), 7.34 - 7.28 (m, 1H), 7.25 - 7.17 (m, 1H), 4.68 - 4.55 (m, 2H), 4.45 - 4.36 (m, 3H), 3.91 (s, 3H), 3.24 - 3.11 (m, 2H), 1.41 - 1.33 (m, 1H). LCMS (Method m. ES+ RT 0.34 min 410.2/411.2 (M+H) +.

[00766] INTERMEDIATE 90:methyl(S)-4,4,4-trifluoro-2-(8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-l-(l,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamido)-2- methylbutanoate N ,0 WO 2024/184461 PCT/EP2024/056026

[00767]To a solution of Intermediate 89 (1.10 g, 2.69 mmol) and Intermediate 115 (774.mg, 3.49 mmol, HC1) in DMF (11 mL) was added HATU (1.23 g, 3.22 mmol) and DIEA (1.39 g, 10.75 mmol, 1.87 mL). The mixture was stirred at 20°C for 2 hr. The reaction mixture was poured into ice-water (20 mL) and added 1 M HC1 to pH=5-6. The reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/l to 1/2) to give the title compound (1.00 g, 65%) as a white solid. 1H NMR (400 MHz, CDC13) 8 = 9.(s, 1H), 8.66 - 8.57 (m, 1H), 7.36 - 7.29 (m, 1H), 7.17 - 7.12 (m, 1H), 7.09 - 7.00 (m, 2H), 4.75 - 4.62 (m, 2H), 4.45 (s, 3H), 4.05 (s, 3H), 3.98 - 3.88 (m, 3H), 3.60 - 3.41 (m, 1H), 3.23 - 3.14 (m, 2H), 3.09 - 3.00 (m, 1H), 1.89 - 1.79 (m, 3H). LCMS {Method m. ES+, RT= 0.46 min 577.3/578.(M+H) +

[00768] INTERMEDIATE 91:(S)-4,4,4-trifluoro-2-(8-methoxy-9-(2-methyl-2H-tetrazol-5- yl)-l-(l,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamido)-2- methylbutanoic acid

[00769]To a solution of Intermediate 90 (800 mg, 1.39 mmol) in THE (4 mL) and MeOH (mL) was added LiOH.H2O (87.33 mg, 2.08 mmol) in H20 (4 mL) at 20°C. The mixture was stirred at 45OC for 6 hr. The reaction mixture was poured into ice-water (20 mL) and added 1 M HC1 to pH=3-4. The reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (600 mg, 77%) as a white solid. 1H NMR (4MHz, CDCh) 8 9.04 - 8.94 (m, 1H), 8.25 - 8.15 (m, 1H), 7.67 - 7.61 (m, 1H), 7.51 (s, 1H), 6.(s, 1H), 4.93 - 4.78 (m, 1H), 4.55 - 4.41 (m, 1H), 4.38 - 4.29 (m, 3H), 3.99 - 3.87 (m, 3H), 3.69 - WO 2024/184461 PCT/EP2024/056026 3.51 (m, 1H), 3.17 - 2.99 (m, 2H), 2.97 - 2.82 (m, 1H), 1.86 - 1.79 (m, 3H). LCMS (Method m. ES+, RT= 0.40 min 563.2/664.3 (M+H) +

[00770] INTERMEDIATE 92:(S)-N-(l-amino-4,4,4-trifluoro-2-methyl-l-oxobutan-2-yl)- 8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(l,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxamide

[00771]To a solution of Intermediate 91 (600 mg, 1.07 mmol) in THF (8 mL) was added CDI (259.43 mg, 1.60 mmol). The mixture was stirred at 20 °C for 2 hr and added with NHJ.HO (448.57 mg, 3.20 mmol, 492.93 pL, 25% purity). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was poured into ice-water (20 mL) and added 1 M HCI to pH = 5-6. The reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/l to 0/1) to give the title compound (400 mg, 67%) as a white solid. 1H NMR (400 MHz, CDCh) 5 = 9.08 - 8.95 (m, 1H), 8.47 - 8.27 (m, 1H), 7.14 - 7.06 (m, 1H), 6.96 - 6.75 (m, 2H), 4.71 - 4.61 (m, 1H), 4.47 - 4.38 (m, 1H), 4.34 - 4.27 (m, 3H), 3.94 - 3.83 (m, 3H), 3.34 - 3.16 (m, 1H), 3.10 - 2.92 (m, 3H), 1.98 (s, 2H), 1.75 - 1.66 (m, 3H). LCMS (Method n.. ES+, RT= 0.38 min 562.3/563.4 (M+H) +

[00772] INTERMEDIATE 93:(S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8-methoxy-9-(2- methyl-2H-tetrazol-5-yl)- 1 -(1,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo [2,1 -a] isoquinoline-3 - carboxamide WO 2024/184461 PCT/EP2024/056026 HN—(S)

[00773]To a solution of Intermediate 92 (400 mg, 712.33 umol) in DCM (2 mL) was added burgess reagent (339.50 mg, 1.42 mmol) in THF (2 mL) .The mixture was stirred at 20 °C for hr. The reaction mixture was diluted with H20 10 mL and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/l to 1/2) to give the title compound (3mg, 77%) as a white solid. 1H NMR (400 MHz, CDCh) 5 = 9.04 (s, 1H), 8.33 (s, 1H), 7.26 (s, 2H), 7.11 - 7.07 (m, 1H), 6.94 - 6.84 (m, 2H), 4.66 - 4.51 (m, 2H), 4.65 - 4.51 (m, 1H), 4.42 - 4.(m, 3H), 3.97 - 3.86 (m, 3H), 3.12 - 2.96 (m, 4H), 1.92 - 1.83 (m, 3H) LCMS (Method m. ES+, RT = 0.44 min 544.3/545.3 (M+H) +

[00774] INTERMEDIATE 94:Tert-butyl (S)-2-(hydroxymethyl)-2-methylpyrrolidine- 1 - carboxylate

[00775]To a solution of (2S)-l-tert-butoxycarbonyl-2-methyl -pyrrolidine-2-carboxylic acid (20 g, 87.23 mmol) in THF (100 mL) was added with BH3.THF (1 M, 104.68 mL) dropwise for 0.5 hr at 0 °C. The mixture was stirred at 25 °C for 15 hr. The mixture was quenched by addition MeOH (25 mL) slowly at 0 °C during 0.5 hr. Then the mixture was stirred at 80 °C for 1 hr. The mixture was cooled to 20 °C and concentrated to give the residue, which was dissolved with ethyl acetate (300 mL), washed with saturated NaHCO3 solution (300 mL), water (300 mL), dried over anhydrous Na2S04 and filtered, the filtrate was concentrated to give the title compound (16 g, 85%) as a white solid. 1H NMR (400 MHz, CDCI3) 6 ppm 3.62 - 3.70 (m, 1H), 3.54 - 3.61 (m, N ,0 N WO 2024/184461 PCT/EP2024/056026 1H), 3.50 (br t, J = 8.13 Hz, 1H), 3.25 - 3.37 (m, 1H), 1.72 - 1.91 (m, 2H), 1.62 - 1.71 (m, 2H),1.45 (s, 9H), 1.35 (brs, 3H).

WO 2024/184461 PCT/EP2024/056026

[00776] INTERMEDIATE 95:Tert-butyl (S)-2-formyl-2-methylpyrrolidine-l-carboxylate Boc.

[00777]To a solution of Intermediate 94 (8 g, 37.16 mmol) in DCM (80 mL) was added Dess- Martin Periodinane (20.49 g, 48.31 mmol) at 20°C. The mixture was stirred at 20°C for 6 hr. The mixture was added with sat. NaHCO3 solution (300 mL) slowly and filtered using kieselguhr. The filtrate was diluted with H20 (100 mL) and extracted with DCM (100 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 7/1). The title compound (12 g, 76%) was obtained as a colorless solid. 1H NMR (400 MHz, CDCI) 6 ppm 9.28 - 9.49 (m, 1H), 3.40 - 3.77 (m, 2H), 1.97 (br dd, J = 6.36, 4.28 Hz, 3H), 1.62 - 1.71 (m, 1H), 1.46 (s, 3H), 1.36- 1.44 (m, 9H).

[00778] INTERMEDIATE 96:tert-butyl (S)-2-methyl-2-(2-methylprop-l-en-l-yl)pyrrolidine- 1 -carboxylate Boc

[00779]Isopropyl (triphenyl) phosphonium; bromide (13.55 g, 35.17 mmol) was dissolved with THE (30 mL), thent-BuOK (1 M, 35.17 mL) was added dropwise, then Intermediate 95 (5 g, 23.mmol) was added. The mixture was stirred at 30°C for 12 hr. The mixture was filtered. The filter cake was triturated with MTBE at 20°C for 15 min, then filtered. All of the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate= 100/0 to 97/3). The title compound (8 g, 71%) was obtained as a colorless oil. 1H NMR (400 MHz, DMSO-d6) 8 ppm 5.25 - 5.37 (m, 1H), 3.38 (br dd, J = 6.75, 3.75 Hz, 1H), 3.29 (brt, J= 8.19 Hz, 1H), 1.69 -2.00 (m, 4H), 1.61 - 1.67 (m, 3H), 1.54 (s, 3H), 1.30- 1.40 (m, 12H).

WO 2024/184461 PCT/EP2024/056026

[00780] INTERMEDIATE 97:tert-butyl (S)-2-((R)-l,2-dihydroxy-2-methylpropyl)-2-methylpyrrolidine- 1 -carboxylate

[00781]To a solution of Intermediate 96 (7 g, 29.25 mmol) in acetone (50 mL) and H20 (5 mL) was added NMO (5.14 g, 43.87 mmol, 4.63 mL) and KOs04.2HO (323.27 mg, 877.37 umol) at °C. The mixture was stirred at 20 °C for 12 hr. The mixture was poured into sat. Na2S203 (mL). The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=70/l to 30/1) to give the title compound (6 g, 75%) as a yellow oil. 1H NMR (400 MHz, CDC13) 8 ppm 3.49 - 3.72 (m, 2H), 3.28 (dt, J = 10.88, 7.50 Hz, 1H), 2.30 (br d, J = 1.63 Hz, 1H), 1.67 - 1.85 (m, 3H), 1.40 - 1.54 (m, 12H), 1.30 (s, 6H). LCMS {Method t), ES+, RT = 1.74 min) 274.2 (M+H) +.

[00782] INTERMEDIATE 98:tert-butyl (S)-2-((R)-l,2-dihydroxy-2-methylpropyl)-2- methylpyrrolidine- 1 -carboxylate

[00783]Intermediate 97 (6 g, 21.95 mmol) was separated by SFC {SFC method A). The title compound (0.6 g, 10%) was obtained as yellow solid. 1H NMR (400 MHz, CDC13) 8 ppm 5.13 - 5.90 (m, 1H), 3.48 - 3.72 (m, 2H), 3.30 (dt, J = 10.91, 7.99 Hz, 1H), 2.44 - 2.60 (m, 1H), 1.78 - 1.86 (m,2H), 1.67- 1.75 (m, 1H), 1.37- 1.55 (m, 12H), 1.32 (s,3H), 1.25(s,3H). LCMS {Method t), ES+, RT = 1.79 min) 274.2 (M+H) +.

WO 2024/184461 PCT/EP2024/056026

[00784] INTERMEDIATE 99:(R)-2-methyl-l-((S)-2-methylpyrrolidin-2-yl)propane-l,2- diol

[00785]To a solution of Intermediate 98 (100 mg, 365.81 umol) in MeOH (0.5 mL) was added HCl/MeOH (4 M, 1 mL). The mixture was stirred at 20°C for 1 hr. The reaction was concentrated directly under reduced pressure to give the title compound (75 mg, 357.63 umol, 97.76% yield, HCI) as a white solid.

[00786] INTERMEDIATE 100:tert-butyl (2S)-2-(l-hydroxyethyl)-2-methylpyrrolidine-l- carboxylate Boc s

[00787]To a solution of Intermediate 95 (20 g, 93.78 mmol) in THF (200 mL) was added MeMgBr (3 M, 34.38 mL) at 0°C. The mixture was stirred at 20°C for 2 hr. The reaction was quenched with H20 (300 mL) and extracted with EtOAc (100 mL x 3). The organic layers were concentrated under reduced pressure to give the title compound (20 g, 93%) as a colorless oil. 1H NMR (400 MHz, CDC13) 8 ppm 6.39 (s, 1H), 5.09 (br d, J = 9.76 Hz, 1H), 3.88 (q, J = 6.34 Hz, 1H), 3.58 (brt, J = 8.50 Hz, 1H), 3.26 (td, J = 10.22, 7.07 Hz, 1H), 1.63 - 1.90 (m, 4H), 1.46 (s, 9H), 1.26 - 1.40 (m, 3H), 1.10 - 1.15 (m, 3H).

[00788] INTERMEDIATE 101:tert-butyl (S)-2-acetyl-2-methylpyrrolidine- 1 -carboxylate Boc I L N-V^O WO 2024/184461 PCT/EP2024/056026

[00789]To a solution of Intermediate 100 (20 g, 87.22 mmol) in DCM (200 mL) was added Dess-Martin Periodinane (44.39 g, 104.66 mmol) at 20°C. The mixture was stirred at 20°C for hr. The mixture was filtered using kieselguhr. The filtrate was diluted with H20 (300 mL) and extracted with DCM (100 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 7/1) to give the title compound (19 g, 96%) was obtained as a colorless oil. 1H NMR (400 MHz, CDCh) 5 ppm 3.44 - 3.76 (m, 2H), 2.11 (s, 3H), 1.90 - 2.02 (m, 3H), 1.71-1.80 (m, 1H), 1.45 (s, 3H), 1.41 (s, 9H).

[00790] INTERMEDIATE 102:tert-butyl (S)-2-methyl-2-(l-(((trifluoromethyl)sulfonyl) oxy)vinyl)pyrrolidine- 1 -carboxylate OTf

[00791]To a solution of Intermediate 101 (7 g, 30.80 mmol) in THE (70 mL) was dropwise added with LDA (2 M, 23.10 mL) at -70°C. The mixture was added 1,1,1-trifluoro-N-phenyl-N- (trifluoromethyl sulfonyl)methanesulfonamide (12.10 g, 33.88 mmol) at -70°C. The mixture was stirred at 50°C for 12 hr. The residue was diluted with H20 (300 mL) and extracted with EtOAc (200 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 10/1 to 1/1) to give the title compound (14 g, 63%) as a colorless oil. 1H NMR (4MHz, CDCh) 8 ppm 5.20 - 5.28 (m, 1H), 5.01 - 5.13 (m, 1H), 3.40 - 3.65 (m, 2H), 2.17 - 2.32 (m, 1H), 1.76 - 1.94 (m, 3H), 1.56 - 1.67 (m, 3H), 1.45 (s, 8H).

[00792] INTERMEDIATE 103:tert-butyl (S)-2-methyl-2-(3,3,3-trifluoropropanoyl) pyrrolidine- 1 -carboxylate WO 2024/184461 PCT/EP2024/056026

[00793]To a solution of Intermediate 102 (2.8 g, 7.79 mmol) in t-BuOH (25 mL) and H20 (mL) was added with AgNO3 (13.24 mg, 77.92 pmol) and (NH4)2S2O8 (355.61 mg, 1.56 mmol) at 20°C. The reaction was stirred at 30°C for 12 hr. The reaction mixture was diluted with EtOAc (20 mL). The organic layer was separated and the aqueous layer was washed with EtOAc (3xmE). The combined organic layers were dried over Na2S04. The solvent was removed under reduced pressure and the residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 1/1) to give the title compound (2.1 g, 46%) as a colorless oil. 1H NMR (400 MHz, CDC13) 8 ppm 3.60 - 3.80 (m, 1H), 3.35 - 3.55 (m, 2H), 3.17 - 3.29 (m, 1H), 1.94 - 2.11 (m, 3H), 1.72- 1.89 (m, 1H), 1.37 - 1.53 (m, 12H).

[00794] INTERMEDIATE 104A&104B:tert-butyl (S)-2-methyl-2-((R)-3, 3,3-trifluoro-l- hydroxypropyl)pyrrolidine- 1 -carboxylate; tert-butyl (S)-2-methyl-2-((S)-3 ,3,3-trifluoro- 1 - hydroxypropyl)pyrrolidine- 1 -carboxylate

[00795]To a solution of Intermediate 103 (300 mg, 1.02 mmol) in MeOH (3 mL) was added NaBH4 (115.30 mg, 3.05 mmol) at 0 °C. The mixture was stirred at 30 °C for 1 hr. 2 bateces were combined for work up. The mixture was added with H20 (5 mL) and extracted with EtOAc (2 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by prep-TLC (SiO2, PE:EtOAc= 3:1) to give Intermediate 104A (50 mg, 66%) with the lower polarity , the other one is Intermediate 104B (40 mg, 53%) as a yellow oil.

[00796] INTERMEDIATE 105A:(R)-3,3,3-trifluoro-l-((S)-2-methylpyrrolidin-2-yl)propan-l-ol / WO 2024/184461 PCT/EP2024/056026

[00797]To a solution of Intermediate 104A (50 mg, 168.17 pmol) in MeOH (0.5 mL) was added HCl/MeOH (4M, 1 mL). The mixture was stirred at 20 °C for ihr. The mixture was concentrated under reduced pressure to give the title compound (39 mg, 99%, HC1) as a white solid. 1HNMR(400MHz,METHANOL-d4)6ppm4.00(m, 1H), 3.32 - 3.39 (m, 2H), 2.31 - 2.(m, 2H), 2.03 - 2.28 (m, 2H), 1.86 - 1.95 (m, 2H), 1.35 (s, 3H).

[00798] INTERMEDIATE 105B:(S)-3,3,3-trifluoro-l-((S)-2-methylpyrrolidin-2-yl)propan- 1-01

[00799]To a solution of Intermediate 104B (40 mg, 134.54 umol) in MeOH (0.5 mL) was added HCl/MeOH (4M, 1 mL). The mixture was stirred at 20 °C for ihr. The mixture was concentrated under reduced pressure to give the title compound (31 mg, 98%, HC1) as a white solid. 1HNMR(400MHz,METHANOL-d4)6ppm4.00(m, 1H), 3.32 - 3.39 (m, 2H), 2.31 - 2.(m, 2H), 2.03 - 2.28 (m, 2H), 1.86 - 1.95 (m, 2H), 1.35 (s, 3H).

[00800] INTERMEDIATE 106:(R)-3-((benzyloxy)carbonyl)-4-methyloxazolidine-4- carboxylic acid Cbz^ N/X

[00801](2R)-2-amino-3-hydroxy-2-methyl-propanoic acid (2 g, 16.79 mmol) was dissolved inNaOH (2 M, 8.39 mL) at 20 °C. Then, an aqueous solution of formaldehyde (5.45 g, 67.mmol, 37% purity) was added drop wise under vigorous stirring and the resulting solution was stirred for 48h at 20°C, after which time the pH was 8-9. NaHCO3 (3.37 g, 40.mmol) and acetone (20 mL) was added to the reaction mixture, and the solution was cooled to 0- 5°C. Benzyl carbonochloridate (4.27 g, 25.05 mmol) was added dropwise under vigorous stirring, while the pH was adjusted to 9 with sat. NaHCO3. The reaction mixture was stirred at 5°C for WO 2024/184461 PCT/EP2024/056026 min and at 20°C for 12 hr. Acetone was evaporated, the reaction mixture was diluted with 30 mL H20 and extracted with MTBE (30 mL x 3). The MTBE phase extracts were discarded. After cooling to 0°C, the solution was acidified with IN HC1 to pH = 2. The suspension was extracted withEtOAc(50 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (3.3 g, crude) was obtained as a yellow oil. 1H NMR (400 MHz, CDCI3) 6 ppm 7.28 - 7.43 (m, 5H), 5.(s, 2H), 5.05 (br s, 1H), 4.98 - 5.03 (m, 1H), 4.26 - 4.42 (m, 1H), 3.85 - 3.95 (m, 1H), 1.58 - 1.(m, 3H). LCMS (Method u) ES+, RT =1.164 min) 265.9 (M+H) +.

[00802] INTERMEDIATE 107:Benzyl (R)-4-carbamoyl-4-methyloxazolidine-3- carboxylate

[00803]To a solution of Intermediate 106 (2.8 g, 10.56 mmol) in THE (28 mL) was added with GDI (2.57 g, 15.83 mmol). The mixture was stirred at 20 °C for 5 hr. Then GDI (855.79 mg, 5.mmol) was added to the reaction mixture and stirred at 30 °C for 2 hr. Then NH3.H2O (6.61 g, 52.78 mmol, 28% purity) was added to the reaction mixture. The mixture was stirred at 20 °C for hr. IN HCI was added to the reaction mixture until the pH was 4-5. Then the reaction mixture was extracted with DCM (30 mL x 3), the combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 10/1 to 1/1) to give the title compound (2.2 g, 80%) was obtained as a colorless oil. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 7.27 - 7.41 (m, 5H), 5.13 (br s, 3H), 4.95 (d, J=3.81 Hz, 1H), 4.22 (br d, J=8.70 Hz, 1H), 3.85 (br s, 1H), 1.59 (br s, 3H). LCMS (Method u. ES+, RT =1.00 min) 264.(M+H) +.

WO 2024/184461 PCT/EP2024/056026

[00804] INTERMEDIATE 108:(R)-4-methyloxazolidine-4-carboxamide

[00805]To a solution of Intermediate 107 (700 mg, 2.65 mmol)inEtOAc (35 mL) was added Pd/C (140.00 mg, 131.55 pmol, 10% purity) under H2 (1 atm). The mixture was stirred at 20°C for 2 hr. The reaction mixture was filtered, and the organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (368 mg, 95%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 7.40 (br s, 1H), 7.(br s, 1H), 4.48 (br s, 1H), 4.07 (br s, 1H), 3.83 (d, J=7.75 Hz, 1H), 3.63 (br s, 1H), 3.18 (d, J=7.Hz, 1H), 1.30 (s, 3H). LCMS (Method u. ES+, RT =0.153 min) 130.9 (M+H).

[00806] INTERMEDIATE 109:(R)-3-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4- carboxamide

[00807]To a solution of l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carboxylic acid (hit 109B) (60 mg, 143.06 pmol)inDMF (1.2 mL) was added HATU (59.83 mg, 157.36 pmol) and DIEA (73.96 mg, 572.24 pmol) strried at 20°C for 0.5hr. Intermediate 108 (27.93 mg, 214.59 pmol) was added at 20°C. The mixture was stirred at 50°C for 12 hr. The reaction was added to ice-water (20 mL), then was filtered. The filter cake was dissolved with EtOAc (10mL). The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=5/l to WO 2024/184461 PCT/EP2024/056026 0/1) to give the title compound (93 mg, 32%) was a pink solid. 1H NMR (400 MHz, CDC13) ppm 7.75 - 7.85 (m, 1H), 7.39 (ddd,J= 8.66, 5.47, 3.13 Hz, 2H), 7.01 -7.11 (m, 3H), 6.94 (s, 1H), 6.69 - 6.73 (m, 1H), 6.47 (s, 1H), 5.47 - 5.64 (m, 1H), 5.39 (d, J= 4.25 Hz, 1H), 5.31 (d, J= 4.Hz, 1H), 4.52 - 4.72 (m, 2H), 4.41 - 4.48 (m, 1H), 4.34 (s, 3H), 3.94 - 3.98 (m, 3H), 3.86 (d, J = 9.13 Hz, 1H), 3.06 - 3.18 (m, 2H), 1.76 - 1.84 (m, 2H), 1.67 (s, 1H). LCMS {Method a), ES+, RT = 1.476 min 531.2 (M+H) +.

[00808] INTERMEDIATE 110:(R)-3-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl- 5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4-carboxamide

[00809]To a solution of 8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carboxylic acid {Int 110B) (200 mg, 544.36 umol) in DMF (2 mL) was added HATU (227.68 mg, 598.80 umol) and DIEA (281.42 mg, 2.18 mmol) at 20°C, stirred at 20°C for 1 hr. The mixture was added Intermediate 108 (85.02 mg, 653.24 umol) at 20°C, stirred at 70°C for 11 hr. The reaction mixture was added H20 (15 mL) at 0°C, and then extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/ethyl acetate = 5/1 to 1/1) to give the title compound (120 mg, 25%, 55% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.07 (br s, 1H), 7.48 (br s, 1H), 7.23 (br s, 2H), 7.02 (br s, 1H), 6.74 (d, J= 1.2 Hz, 1H), 6.46 (d, J = 1.7 Hz, 1H), 5.36 (br s, 1H), 5.19 (br s, 1H), 4.99 (br d, J = 2.3 Hz, 1H), 4.55 - 4.46 (m, 1H), 4.45 - 4.30 (m, 4H), 4.30 - 4.18 (m, 1H), 4.08 (br d, J = 8.9 Hz, 1H), 3.88 (s, 3H), 3.80 (br dd, J = 1.5, 8.3 Hz, 1H), 3.75 - 3.68 (m, 1H), 3.03 (br s, 3H), 2.72 - 2.61 (m, 2H), 1.72 - 1.58 (m, 2H), 1.51 (br d, J = 1.8 Hz, 2H), 1.45 - 1.32 (m, 2H), 1.03 - 0.95 (m, 3H), -0.06 (br s, 1H). LCMS {Method I), ES+, RT = 0.406 min 480.3 (M+H)+.

WO 2024/184461 PCT/EP2024/056026

[00810] INTERMEDIATE 111:L((3aS,6R,7aR)-8,8-dimethyl-2,2-dioxidotetrahydro-3H-3a,6-methanobenzo[c]iso thiazol- 1 (4H)-yl)-2-methylprop-2-en- 1 -one

[00811]To a solution of(lS,5R,7R)-10,10-dimethyl-3thia-4-azatricyclo[5.2.L01,5]decane 3,3-dioxide (45 g, 209.00 mmol)inTHF (450 mL) at -20°C was added LiCl (9.75 g, 229.mmol) and TEA (27.49 g, 271.70 mmol). The mixture was stirred for 10 min. 2-methylprop-2- enoyl 2-methylprop-2-enoate (38.66 g, 250.80 mmol) in THE (135 mL) was then added. The thick white mixture was stirred within the cooling bath and allowed to reach 20°C. The mixture was stirred at 20 °C for 2 hr. The reaction mixture was poured into 2 L H20 and stirred for 10 min, then filtered. The filter cake was dissolved with 500 mL DCM, washed with H20 (300 mL x 2), brine (300 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the title compound (56 g, 95%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 5.65 (s, 1H), 5.54 (s, 1H), 3.93 - 4.00 (m, 1H), 3.83 (d, J = 14.01 Hz, 1H), 3.61 (d, J = 13.88 Hz, 1H), 1.71 - 1.94 (m, 8H), 1.42 - 1.54 (m, 1H), 1.22 - 1.33 (m, 1H), 1.13 (s, 3H), 0.95 (s, 3H). LCMS (Method a), ES+, RT = 1.675 min 284.2 (M+H)+.

[00812] INTERMEDIATE 112:(S)-2-azido-l-((3aS,6R,7aR)-8,8-dimethyl-2,2- dioxidotetrahydro-3H-3a,6-methano benzo[c]isothiazol-l(4H)-yl)-4,4,4-trifluoro-2-methylbutan- l-one

[00813]Togni ’s Reagent (3,3-dimethyl-l-(trifluoromethyl)-l,2-benziodoxole, 101.34 g, 307.mmol) and [(CH3CN)4Cu]PF6 (3.81 g, 10.23 mmol) were dissolved in DMA (290 mL). Intermediate 111 (29 g, 102.33 mmol) andTMSN3 (23.58 g, 204.67 mmol) were added at WO 2024/184461 PCT/EP2024/056026 °C~25°C. Under N2 atmosphere, the mixture was stirred at 50°C for 16 hr. The reaction mixture was diluted with 200 mL MTBE and 500 mL H2O, the organic layer was extracted with MTBE (200 mL x 3) and the combined organic phase was washed with brine (500 mL x 3), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Method 19) to give the title compound (25 g, 62%) as a white solid. 1H NMR (400 MHz, CDCI3) 6 ppm 4.02 - 4.12 (m, 1H), 3.55 - 3.65 (m, 1H), 3.44 - 3.52 (m, 1H), 2.77 - 2.94 (m, 2H), 1.84 - 2.07 (m, 5H), 1.72 (s, 3H), 1.30 - 1.45 (m, 2H), 1.19 (s, 3H), 1.00 (s, 3H). LCMS (Method a), ES+, RT = 1.987 min 417.1 (M+Na) +.

[00814] INTERMEDIATE 113:(S)-2-azido-4,4,4-trifluoro-2-methylbutanoic acid

[00815]To a solution of Intermediate 112 (10 g, 25.35 mmol) in THE (50 mL) was added LiOH.H2O (2.13 g, 50.71 mmol) in H20 (50 mL) at 0 °C. The mixture was stirred at °C for 2 hr. The reaction mixture was concentrated under reduced pressure to remove THF, then extracted with EtOAc (80 mL x 3), the aqueous layer was acidified to pH = 1 by the addition of IM HC1 and then was extracted with EtOAc (50 mL x 3). The organic layer was washed with 1mL brine and dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the title compound (4.5 g, 90%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) 8 ppm 13.- 14.21 (m, 1H), 2.73 - 2.97 (m, 2H), 1.55 (s, 3H).

[00816] INTERMEDIATE 114:methyl (S)-2-azido-4, 4,4-trifluoro-2-methylbutanoate N3z0Me F3C^^،

[00817]To a solution of Intermediate 113 (4.5 g, 22.83 mmol)inDMF (45 mL) was added CH3I (6.48 g, 45.66 mmol) and K2CO3 (6.31 g, 45.66 mmol) at 0 °C under N2 atmosphere. The mixture was stirred at 20 °C for 12 hr. The reaction mixture was added to 100 mL ice-water and extracted with EtOAc (80 mL x 3), the combined organic phase was washed with 100 mL WO 2024/184461 PCT/EP2024/056026 brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the title compound (4.1 g, 85%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) 8 ppm 3.77 (s, 3H), 2.89-3.01 (m, 2H), 1.58 (s, 3H).

[00818] INTERMEDIATE 115:methyl (S)-2-amino-4, 4,4-trifluoro-2-methylbutanoate xnh 2 hci F3C^/،،0Me O

[00819]To a solution of Intermediate 114 (4.1 g, 19.42 mmol) in THF (82 mL) was added HCI (1 M, 21.36 mL) and Pd/C (1.37 g, 1.28 mmol, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (1 atm) at 20°C for 12 hr. The reaction mixture was filtered under kieselguhr. The filtrate was concentrated under reduced pressure to give a residue. 50 mL of toluene was added to the crude and co-evaporated under reduced pressure to remove H2O. It was repeated for 6 times. The title compound (4 g, crude, HCI) was obtained as a yellow oil. 1H NMR (400 MHz, DMSO-d6) 8 ppm 9.23 (br s, 3H), 3.77 (s, 3H), 3.02 - 3.24 (m, 2H), 1.63 (s, 3H).

[00820] INTERMEDIATE 116:9-bromo-8-methoxy-l-propyl-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxylic acid

[00821]Ethyl 9-bromo-8-methoxy-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carboxylate (5 g, 12.75 mmol) was dissolved in EtOH (35 mL) and THF (15 mL). Then the mixture was added KOH (2.15 g, 38.24 mmol) in H20 (15 mL). The mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 16 hr under N2 atmosphere. The reaction mixture was added with H2O 20 mL and adjust pH = 4 with 1M HCI. The reaction mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with -331- WO 2024/184461 PCT/EP2024/056026 brine (30 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (4 g, 86%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 12.22 (br s, 1H), 7.66 (s, 1H), 7.15 (s, 1H), 6.74 (s, 1H),4.48 (t, J=6.44 Hz, 2H),3.88 (s, 3H), 2.97 (brt, J= 6.44 Hz, 2H), 2.62 (t, J = 7.63 Hz, 2H), 1.54 - 1.68 (m, 2H), 0.97 (t, J = 7.32 Hz, 3H). LCMS (Method e), ES+, RT = 0.566 min 364.0 (M+H) +.

[00822] INTERMEDIATE 117:methyl (S)-2-(9-bromo-8-methoxy-l-propyl-5, 6- dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxamido) -4,4,4-trifluoro-2-methylbutanoate

[00823]To a solution of Intermediate 116 (2 g, 5.49 mmol) in DMF (30 mL) was added HATU (2.71 g, 7.14 mmol) and DIEA (2.84 g, 21.96 mmol). The mixture was stirred at 80°C for 2 hr. Then Intermediate 115 (1.70 g, 7.69 mmol, HC1) was added and stirred at 80°C for 12 hr. The reaction mixture was cooled and added into H20 30 mL, adjust pH = 5 with 1M HC1 at 0 - 5°C. The mixture was filtered and the solid was dissolved in EtOAc (30 mL). The organic layer was washed with H20 (30 mL x 2) and brine (30 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate= 100/0 to 80/20) to give the title compound (1.6 g, 55%) as an orange solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.37 (s, 1H), 7.64 (s, 1H), 7.13 (s, 1H), 6.91 (s, 1H), 4.31 - 4.47 (m, 2H), 3.87 (s, 3H), 3.63 (s, 3H), 3.22 (br dd, J = 15.26, 12.28 Hz, 1H), 2.88 - 3.01 (m, 2H), 2.75 - 2.88 (m, 1H), 2.63 (t, J= 7.57 Hz, 2H), 1.60 - 1.71 (m, 2H), 1.53 - 1.58 (m, 3H), 1.00 (t, J= 133 Hz, 3H). LCMS (Method e), ES+, RT = 0.630 min 531.(M+H) +.

[00824] INTERMEDIATE 118:(S)-2-(9-bromo-8-methoxy-l-propyl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxamido)-4,4,4-trifluoro-2-methylbutanoic acid 0 °،OMe WO 2024/184461 PCT/EP2024/056026

[00825]To a solution of Intermediate 117 (2 g, 3.76 mmol) inTHF (20 mL) was added TMSOK (965.72 mg, 7.53 mmol). The mixture was stirred at 50°C for 12 hr. IM HCI was added to the reaction solution and adjust pH = 4. The mixture was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (1.65 g, 85%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.20 (s, 1H), 7.64 (s, 1H), 7.13 (s, 1H), 6.89 (s, 1H), 4.- 4.49 (m, 2H), 3.87 (s, 3H), 3.27 (br s, 1H), 2.89 - 2.97 (m, 2H), 2.71 - 2.87 (m, 1H), 2.56 - 2.(m, 2H), 1.58 - 1.72 (m, 2H), 1.54 (s, 3H), 1.00 (t, J= 134 Hz, 3H). LCMS (Method e), ES+, RT = 0.563 min 517.1 (M+H) +.

[00826] INTERMEDIATE 119:(S)-N-(l-amino-4,4,4-trifluoro-2-methyl-l-oxobutan-2-yl)- 9-bromo-8-methoxy-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamide

[00827]To a solution of Intermediate 118 (1.3 g, 2.51 mmol) in THE (13 mL) was added CD I (611.19 mg, 3.77 mmol) at 25OC for 1 hr, then NHJ.HO (1.06 g, 7.54 mmol, 25% purity) was added to the mixture. The mixture was stirred at 25OC for 1 hr. The residue was poured into water (30 mL). The aqueous phase was extracted with DCM (30 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure to give the title compound (1.25 g, 96%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 7.94 (s, 1H), 7.64 (s, 1H), 7.42 (br s, 1H), 7.13 (s, 2H), 6.82 (s, 1H), 4.43 (br d, J= 2.88 Hz, 2H), 3.87 (s, 3H), 3.30 (s, 1H), 2.87 - 3.06 (m, 3H), 2.63 (br t, J= 7.50 Hz, 2H), 1.-333- WO 2024/184461 PCT/EP2024/056026 (dq, J= 14.85, 7.26 Hz, 2H), 1.54 (s, 3H), 1.00 (br t, J = 7.25 Hz, 3H). LCMS (Method e), ES+, RT = 0.549 min 517.1 (M+H) +.

[00828] INTERMEDIATE 120:(S)-9-bromo-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8- methoxy- 1 -propyl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxamide

[00829]To a solution of Intermediate 119 (1.2 g, 2.32 mmol) in THF (12 mL) was added burgess reagent (1.11 g, 4.65 mmol) in DCM (12 mL). The mixture was stirred at 25 °C for 1 hr. The residue was poured into water (30 mL). The aqueous phase was extracted with DCM (30 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1 g, 86%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.45 (s, 1H), 7.66 (s, 1H), 7.16 (s, 1H), 6.91 (s, 1H), 4.49 (br t, J= 6.48 Hz, 2H), 3.88 (s, 3H), 3.16 - 3.32 (m, 2H), 2.96 (br t, J= 6.42 Hz, 2H), 2.63 (t, J= 7.58 Hz, 2H), 1.81 (s, 3H), 1.56 - 1.72 (m, 2H), 1.00 (t, J= 134 Hz, 3H). LCMS (Method e), ES+, RT = 0.605 min 498.1 (M+H) +.

[00830] INTERMEDIATE 121:(S)-9-bromo-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8- methoxy-N-methyl- 1 -propyl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxamide

[00831]DMF (30 mL) was charged to the three-necked round bottom flask, then Intermediate 120 (1 g, 2.00 mmol) was added to the mixture at 25OC for 5min under Ar balloon. At 0°C inner temperature NaH (120.38 mg, 3.02 mmol, 60% purity) was added in portions to the reaction WO 2024/184461 PCT/EP2024/056026 mixture at 0°C within 15 min under Ar balloon. Then CH3I (569.64 mg, 4.02 mmol) was added. After the addition, the mixture was stirred at 70°C for 2 hr. The residue was poured into NH4C(20 mL). The aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with H20 (20 mL x 2) and brine (20 mL x 3), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate= 100/0 to 84/16) to give the title compound (0.70 g, 68%) as a yellow solid. 1H NMR (400 MHz, CDCh) 5 ppm 7.76 (s, 1H), 6.80 (s, 1H), 6.41 (s, 1H), 4.23 - 4.39 (m, 2H), 3.93 (s, H), 3.39 (s, 3H), 3.12 - 3.37 (m, 2H), 2.98 (t, J= 6.50 Hz, 2H), 2.65 - 2.(m, 2H), 2.00 - 2.08 (m, 3H), 1.63 - 1.76 (m, 2H), 1.05 (t, J = 7.38 Hz, 3H). LCMS (Method e), ES+, RT = 0.650 min 512.1 (M+H) +.

[00832] INTERMEDIATE 122:phenyl (S)-3-((2-cyano-4,4,4-trifluorobutan-2-yl)(methyl)carbamoyl)-8-methoxy- 1 -propyl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxylate

[00833]A mixture of Intermediate 121 (400 mg, 780.70 umol), phenyl formate (572.04 mg, 4.68mmol), TEA (473.99 mg, 4.68 mmol), Pd(dppf)C12.CH2C12 (63.75 mg, 78.07pmol) in DMF (4 mL) was degassed and purged with N2 for 3 times at 20°C, and then the mixture was stirred at 120°C for 12 hr under N2 atmosphere. The reaction mixture was diluted with H20 10 mL and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=2/l to 1/1) to give the title compound (400 mg, 92%) as a white solid. 1H NMR (400 MHz, CDCh) 8 = 8.- 8.21 (m, 1H), 7.43 - 7.33 (m, 2H), 7.24 - 7.13 (m, 4H), 6.89 - 6.84(m, 1H), 6.40 - 6.31 (m, 1H), 4.38 - 4.19 (m, 2H), 3.98 - 3.80 (m, 3H), 3.36 - 3.31 (m, 3H), 3.27 - 3.19 (m, 1H), 3.14 -3.07 (m, WO 2024/184461 PCT/EP2024/056026 1H), 3.04 - 2.97 (m, 2H), 2.70 - 2.61 (m, 2H), 1.97 (s, 3H), 1.71 - 1.56 (m, 2H), 1.12 (s, 2H), 0.(t, J= 7.3Hz, 3H). LCMS (Method /), ES+, RT = 0.619 min 554.0 (M+H) +.

[00834] INTERMEDIATE 123:(S)-3-((2-cyano-4,4,4-trifluorobutan-2-yl)(methyl)carbamoyl)-8-methoxy- 1 -propyl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxylic acid

[00835]To a solution of Intermediate 122 (380 mg, 686.45 umol) in THF (4 mL) was added TMSOK (176.13 mg, 1.37 mmol) at 20°C. The mixture was stirred at 20 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to remove THF and EtOH, diluted with H20 (mL) and adjusted pH to 3 - 4, which was extracted with EtOAc (3 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (400 mg, crude) as a yellow solid. 1H NMR (4MHz, DMSO-d6) 8 = 12.76 - 12.38 (m, 1H), 9.33 (br s, 1H), 7.92 (s, 1H), 7.20 - 7.11 (m, 3H), 6.- 6.71 (m, 2H), 6.50 (s, 1H), 4.31 - 4.10 (m, 2H), 3.85 (s, 3H), 3.28 - 3.16 (m, 4H), 3.09 - 2.98 (m, 2H), 2.70 - 2.60 (m, 2H), 1.92 (s, 3H), 1.63 (sxt, J= 1A Hz, 2H), 0.98 (t, J= 13 Hz, 3H). LCMS (Method Z), ES+, RT = 0.510 min 478.0 (M+H) +.

WO 2024/184461 PCT/EP2024/056026

[00836] INTERMEDIATE 124:(R)-2-methylazetidine-2-carboxamide MCIHN- NH2

[00837]To a solution of tert-butyl (R)-2-carbamoyl-2-methylazetidine-l-carboxylate (2 g, 9.mmol) in EtOAc (10 mL) was added HCl/EtOAc (4M, 20 mL). The mixture was stirred at 20°C for 1 hr. The mixture was concentrated under reduced pressure to give the title compound (1.4 g, 99% yield, HCI salt) as a white solid.

[00838] INTERMEDIATE 125:(R)-l-(9-bromo-8-methoxy-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carboxamide

[00839]To a solution of Intermediate 116 (1 g, 2.75 mmol)inDMF (10 mL) was added Intermediate 124 (496.19 mg, 3.29 mmol, HCI), DIEA (1.42 g, 10.98 mmol) and HATU (1.15 g, 3.02 mmol). The mixture was stirred at 20°C for 1 hr. The reaction mixture was added to the ice water, IM HCI was added to adjust the pH was 5-6. Filtered and the aqueous phase was extracted with EtOAc(20 mL x 3), the combined organic phase was washed with brine (20 mL x 6) to remove DMF, dried by Na2S04, and filtered, then concentrated under reduced pressure to give the title compound (1.24 g, 98%) as a white solid. 1H NMR (400 MHz, CDC13) 8 ppm 8.27 - 8.41 (m, 1H), 7.76 (s, 1H), 6.81 (s, 1H), 6.47 (s, 1H), 5.35 (br s, 1H), 4.46 - 4.69 (m, 2H), 4.26 - 4.38 (m, 2H), 3.93 (s, 3H), 2.90 - 3.01 (m, 3H), 2.64 - 2.74 (m, 2H), 2.15 (ddd, J = 11.59, 8.97, 5.78 Hz, 1H), 1.88 (s, 3H), 1.65 - 1.74 (m, 2H), 1.05 (t, J= 133 Hz, 3H). LCMS (Method e), ES+, RT = 0.5min 462.0 (M+H) +.

WO 2024/184461 PCT/EP2024/056026

[00840] INTERMEDIATE 126:(R)-l-(9-bromo-8-methoxy-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile

[00841]Intermediate 125 (1.1 g, 2.39 mmol) was dissolved in THF (6 mL). Then Burgess Reagent (1.14 g, 4.78 mmol) in DCM (6 mL) was added to the mixture. The mixture was stirred at 20°C for 1 hr. The reaction mixture was added with water (10 mL x 3). The organic layers were washed with brine (15 mL x 3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EtOAc=20/l to 1/1) to give the title compound (930 mg, 88%) as a white solid. 1HNMR (4MHz, CDC13) 8 ppm 7.74 - 7.78 (m, 1H), 6.81 (s, 1H), 6.44 (s, 1H), 4.63 (br t, J= 6.48 Hz, 2H), 4.36 - 4.46 (m, 2H), 3.93 (s, 3H), 2.96 (t, J = 6.48 Hz, 2H), 2.83 (ddd, J = 11.58, 8.89, 5.81 Hz, 1H), 2.69 (t, J = 7.70 Hz, 2H), 2.43 (dt,J= 11.43,7.98 Hz, 1H), 1.91 (s, 3H), 1.69 (sxt, J=7.Hz, 2H), 1.04 (t, J= 134 Hz, 3H). LCMS (Method e), ES+, RT = 0.596 min 444.0 (M+H) +.

[00842] INTERMEDIATE 127:Phenyl(R)-3-(2-cyano-2-methylazetidine-l-carbonyl)-8- methoxy- 1 -propyl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxylate

[00843]To a solution of Intermediate 126 (400 mg, 904.27 umol) in DMF (4 mL) was added phenyl formate (662.58 mg, 5.43 mmol) and TEA (549.01 mg, 5.43 mmol). Then the suspension was degassed and purged with a stream of N2. Then Pd(dppf)C12.CH2C12 (184.61 mg, 226.umol) was added to the reaction mixture at 20°C. The mixture was stirred at 120°C for 12 hr. The reaction mixture was partitioned between EtOAclO mL and H20 (10 mL). The organic phase was -338- WO 2024/184461 PCT/EP2024/056026 separated, washed with brine (15 mL x 6) to remove DMF, dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 20/1 tol/1) to give the title compound (360 mg, 82%) as a white solid. 1H NMR (400 MHz, CDCh) 5 ppm 8.33 (s, 1H), 7.40 - 7.48 (m, 2H), 7.29 (s, 1H), 7.25 (d, J= 7.58 Hz, 2H), 6.95 (s, 1H), 6.46 (s, 1H), 4.68 (br t, J= 6.54 Hz, 2H), 4.37 - 4.47 (m, 2H), 3.(s, 3H), 3.07 (t, J = 6.48 Hz, 2H), 2.80 - 2.90 (m, 1H), 2.71 - 2.78 (m, 2H), 2.40 - 2.49 (m, 1H), 1.92 (s, 3H), 1.71 (sxt, J= 7.51 Hz, 2H), 1.02 (t, J= 134 Hz, 3H). LCMS (Method Z), ES+, RT = 0.587 min 484.3 (M+H) +.

[00844] INTERMEDIATE 128:(R)-3-(2-cyano-2-methylazetidine-l-carbonyl)-8-methoxy- -propyl-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxylic acid

[00845]To a solution of Intermediate 127 (700 mg, 1.45 mmol) in THE (7 mL) was added TMSOK (371.42 mg, 2.90 mmol). The mixture was stirred at 20°C for 1 hr. The reaction mixture was stirred at 30°C in oil bath for 1 hr. The reaction mixture was added to the ice water, IM HCI was added to adjust pH =5 - 6. The reaction mixture was extracted with EtOAc(15 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (630 mg, crude) as a white solid. 1H NMR (400 MHz, CDCh) 8 ppm 10.64 (br s, 1H), 8.43 (s, 1H), 6.96 - 6.97 (m, 1H), 6.(s, 1H), 4.67 (br t, J = 6.63 Hz, 2H), 4.37 - 4.48 (m, 2H), 4.12 (s, 3H), 3.06 (t, J = 6.50 Hz, 2H), 2.81 - 2.88 (m, 1H), 2.73 - 2.79 (m, 2H), 2.44 (ddd, J = 11.66, 8.72, 7.13 Hz, 1H), 1.92 (s, 3H), 1.66 - 1.75 (m, 2H), 1.05 (t, J = 13% Hz, 3H). LCMS (Method /), ES+, RT = 0.461 min 408.(M+H) +.

WO 2024/184461 PCT/EP2024/056026

[00846] INTERMEDIATE 129:methyl (S)-4,4,4-trifluoro-2-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamido)- 2-methylbutanoate

[00847]To a solution of l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carboxylic acid (500 mg, 1.19 mmol) and Intermediate 1(317.03 mg, 1.43 mmol, HCl)inDMF (10 mL) was added HATU (906.59 mg, 2.mmol) and DIEA (616.30 mg, 4.77 mmol) at 80°C. The mixture was stirred at 80°C for 12 hr. The mixture was diluted with H20 (40 mL) and extracted with EtOAc (20 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 1/1) to give the title compound (1 g, 71%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.48 (s, 1H), 7.70 (s, 1H), 7.43 (dd, J= 5.8, 8.2 Hz, 2H), 7.24 -7.17 (m, 3H), 7.08 (s, 1H), 4.61 - 4.42 (m, 2H), 4.33 (s, 3H), 3.86 (s, 3H), 3.68 - 3.63 (m, 3H), 3.28 - 3.17 (m, 1H), 3.12 (br t, J= 6.3 Hz, 2H), 2.93 - 2.(m, 1H), 1.56 (s, 3H). LCMS (Method g), ES+, RT = 0.553 min 587.3 (M+H) +.

[00848] INTERMEDIATE 130:(S)-4,4,4-trifluoro-2-(l-(4-fluorophenyl)-8-methoxy-9-(2- methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamido)-2- methylbutanoic acid N ,0 O, WO 2024/184461 PCT/EP2024/056026

[00849]To a solution of Intermediate 129 (900 mg, 1.53 mmol)inTHF (10 mL) was added TMSOK (393.70 mg, 3.07 mmol) at 20°C. The mixture was stirred at 20°C for 2 hr. The mixture was added with IN HCI to adjust pH = 5 and the reaction was diluted with H20 (20 mL) and extracted with EtOAc (10 mL x 3). The organic layers were concentrated under reduced pressure to give the title compound (800 mg, 91%) as a white solid. 1H NMR (400 MHz, DMSO- d6)8ppm 12.74- 12.89 (m, 1H), 8.29 (s, 1H), 7.68-7.71 (m, 1H), 7.39 - 7.46 (m, 2H), 7.17-7.(m, 3H), 7.07 (s, 1H), 4.55 - 4.63 (m, 1H), 4.43 - 4.52 (m, 1H), 4.33 (s, 3H), 3.86 (s, 3H), 3.20 - 3.29 (m, 1H), 3.12 (hr t, J= 6.44 Hz, 2H), 2.72 - 2.90 (m, 1H), 1.56 (s, 3H). LCMS (Method e), ES+, RT = 0.476 min 573.2 (M+H) +.

[00850] INTERMEDIATE 131:(S)-N-(l-amino-4,4,4-trifluoro-2-methyl-l-oxobutan-2-yl)- l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxamide

[00851]To a solution of Intermediate 130 (700 mg, 1.22 mmol) in THE (10 mL) was added CDI (297.39 mg, 1.83 mmol) at 20°C. The mixture was stirred at 20°C for 0.5 hr. The mixture was added NH3.H2O (514.26 mg, 3.67 mmol, 25% purity) at 20°C. The mixture was stirred at 20°C for 1 hr. The reaction was diluted with H20 (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The crude product was triturated by MTBE (3 mL) and filtered to give the title compound (6mg, 98%) as a yellow solid. 1H NMR (400 MHz, CDCh) 8 = 7.81 (s, 1H), 7.74 (s, 1H), 7.42 - 7.36 (m, 2H), 7.13 (d, J= 0.6 Hz, 3H), 7.09 - 7.03 (m, 2H), 6.93 (s, 1H), 6.67 (s, 1H), 6.49 (s, 1H), 4.77 - 4.57 (m, 2H), 4.36 - 4.31 (m, 3H), 3.98 - 3.91 (m, 3H), 3.32 - 3.09 (m, 4H), 1.75 (s, 3H). LCMS (Method e), ES+, RT = 0.482 min 572.1 (M+H) +.

WO 2024/184461 PCT/EP2024/056026

[00852] INTERMEDIATE 132:(S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinohne- 3-carboxamide

[00853]To a solution of Intermediate 131 (340 mg, 594.90 umol) in THF (3 mL) was added burgess reagent (354.43 mg, 1.49 mmol) at 20°C. The mixture was stirred at 20°C for 2 hr. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with H20 (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were concentrated under reduced pressure to give the title compound (520 mg, 78%) as a yellow solid. 1H NMR (400 MHz, CDCh) 5 ppm 7.75 - 7.78 (m, 1H), 7.29 - 7.36 (m, 2H), 7.05 (t, J = 8.70 Hz, 2H), 6.93 (s, 1H), 6.53 - 6.58 (m, 1H), 6.22 (s, 1H), 4.68 - 4.77 (m, 1H), 4.51 - 4.61 (m, 1H), 4.35 (s, 3H), 3.96 (s, 3H), 3.00 - 3.26 (m, 4H), 1.96 (s, 3H). LCMS (Method e), ES+, RT = 0.5332 min 554.1 (M+H) +.

[00854] INTERMEDIATE 133:tert-butyl( 1 -((4-bromo-3 -methoxyphenethyl)amino)- 1 - oxopentan-2-yl) carbamate

[00855]To a solution of 2-(tert-butoxycarbonylamino)pentanoic acid (5.19 g, 23.mmol) in DCM (50 mL) was added CD 1 (4.23 g, 26.08 mmol) at 20°C for 10 min, then added with Intermediate 2 (5 g, 21.73 mmol). The mixture was stirred at 20°C for 30 min. The mixture was added with sat. NaHCO3 to adjust pH=8. The aqueous phase was extracted with DCM (mLx3). The combined organic phase was washed with brine (10 mLx2), dried with anhydrous WO 2024/184461 PCT/EP2024/056026 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=55/l to 45/1) to give the title compound (2.g, 46%) as a white solid. 1H NMR (400 MHz, CDCh) 8 ppm 7.45 (d, J=7.88 Hz, 1 H) 6.75 (d, J=1.50 Hz, 1 H) 6.67 (dd, J=8.00, 1.63 Hz, 1 H) 6.14 (hr s, 1 H) 4.89 (hr d, J=2.63 Hz, 1 H) 3.- 4.01 (m, 1 H) 3.90 (s, 3 H) 3.43 - 3.59 (m, 2 H) 2.79 (t, J=7.00 Hz, 2 H) 1.72 - 1.83 (m, 1 H) 1.- 1.60 (m, 2 H) 1.43 (s, 8 H) 1.25 - 1.37 (m, 2 H) 0.91 (t, 3=131 Hz, 3 H) LCMS (Method i. ES+, RT = 0.756 min) 452.3/453.3 (M+Na) +

[00856] INTERMEDIATE 134:2-amino-N-(4-bromo-3-methoxyphenethyl)pentanamide

[00857]To a solution of Intermediate 133 (5 g, 11.65 mmol)inEtOAc (10 mL) was added HCl/EtOAc (4 M, 50 mL). The mixture was stirred at 20°C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (3.8 g, 99 %) as a colorless oil. 1HNMR (400 MHz, CDCh) 8 ppm 8.02 - 8.28 (m, 4 H) 7.39 (d, .7=8.00 Hz, 1 H) 6.81 (s, H) 6.67 (br d, .7=7.88 Hz, 1 H) 4.20 (hr s, 1 H) 3.86 (s, 3 H) 3.59 (brd,J=5.75 Hz, 1 H)3.35(brs, H) 2.81 (br s, 2 H) 1.81 (br s, 2 H) 1.15 - 1.33 (m, 2 H) 0.84 (br t, .7=6.88 Hz, 3 H) LCMS (Method g. ES+, RT = 0.348 min) 329.0/331.0 (M+H) +

[00858] INTERMEDIATE 135:N-(4-bromo-3-methoxyphenethyl)-2- formamidopentanamide

[00859]To a solution of Intermediate 134 (500 mg, 1.37 mmol, HC1) in ethyl formate (4.61 g, 62.16 mmol) and MeOH (1 mL) was added Et3N (276.70 mg, 2.73 mmol). The mixture was stirred -343- HN.

HN^O WO 2024/184461 PCT/EP2024/056026 at 70°C for 16 hr. The reaction mixture was added with 2 mL H20 and adjust pH=5 with HC1 (0.M. The aqueous layer was extracted with ethyl acetate (5 mL) and the combined phase was washed with brine 10 mL and concentrated under reduced pressure to give the title compound (800 mg, 82%) as a white solid. 1H NMR (400 MHz, DMSO-dg) 6 ppm 8.17 (br d, ^=8.13 Hz, 1 H) 8.(br t, J=5.57 Hz, 1 H) 7.98 (d, J=0.75 Hz, 1 H) 7.43 (d, J=8.00 Hz, 1 H) 6.95 (d, J=1.88 Hz, 1 H) 6.72 (dd, J=8.07, 1.81 Hz, 1 H) 4.21 - 4.28 (m, 1 H) 3.83 (s, 3 H) 3.34 - 3.39 (m, 1 H) 3.23 - 3.(m, 1 H) 2.69 (t, J=6.94 Hz, 2 H) 1.33 - 1.53 (m, 2 H) 1.06 - 1.24 (m, 2 H) 0.75 - 0.84 (m, 3 H) LCMS {Method g. ES+, RT = 0.407 min) 357.0/359.1 (M+H) +

[00860] INTERMEDIATE 136:9-bromo-8-methoxy-l-propyl-5,6-dihydroimidazo[5,l- a]isoquinoline

[00861]A mixture ofP2O5 (794.67 mg, 5.60 mmol) in methanesulfonic acid (2.5 mL) was stirred at 75°C for 0.5 hr, then was added Intermediate 135 (500 mg, 1.40 mmol). The mixture was stirred at 90°C for 12 hr. The mixture was cooled and quenched with ice water, then added with Na2CO3 to adjust pH=8, extracted with EtOAc (5 mLx2). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate= 100/1) to give the title compound (280 mg, 62%) as a white solid. 1H NMR (400 MHz, DMSO-t/6) 5 ppm 7.58 (d, Hz, 2 H) 7.15 (s, 1 H) 4.05 - 4.13 (m, 2 H) 3.86 (s, 3 H) 2.98 (t, J=6.38 Hz, 2 H) 2.67 (t, J=1.51 Hz, 2 H) 1.66 (sxt, J=1.45 Hz, 2 H) 0.87 - 0.99 (m, 3 H) LCMS {Method e. ES+, RT = 0.355 min) 322.9/321.9 (M+H) +

[00862] INTERMEDIATE 137:8-methoxy-l-propyl-9-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline WO 2024/184461 PCT/EP2024/056026

[00863]To a solution of Intermediate 136 (3 g, 9.34 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethy l-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (23.72 g, 93.40 mmol) in DMSO (mL) was added KOAc (13.75 g,140.09 mmol) and Pd(dppf)C12.CH2C12 (152.54 mg, 186.umol) at 20°C. The mixture was stirred at 95OC for 12 hr under N2 atmosphere. The reaction mixture was diluted with 30 mL EtOAc and filtered, the filtrate was washed with brine (20 mLx6) to remove DMSO, dried by Na2S04, and filtered, then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give the title compound (3.4 g, crude) as a brown solid. 1H NMR (400 MHz, CDCh) 5 7.73 - 7.78 (m, 1 H) 6.76 - 6.79 (m, 1 H) 4.56 - 4.66 (m, 2 H) 4.34 - 4.45 (m, 2 H) 3.85 - 3.90 (m, 3 H) 3.59 - 3.74 (m, 2 H) 2.91 - 3.00 (m, H) 1.33 - 1.41 (m, 3 H) LCMS {Method a. ES+, RT = 1.314 min) 369.4/370.3 (M+H) +

[00864] INTERMEDIATE 138:8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6- dihydroimidazo[5, 1 -a] isoquinoline

[00865]To a solution of Intermediate 137 (3.38 g, 9.18 mmol) and 5-bromo-2-methyl-tetrazole (1.50 g, 9.18 mmol) in dioxane (30 mL) and H20 (6 mL) was added C82CO3 (8.97 g, 27.mmol) and XPHOS-Pd-G2 (361.06 mg, 458.89 umol) at 20 °C. Then the mixture was stirred at 70°C for 2 hr under N2 atmosphere. The reaction mixture was added 30 mL water and extracted with DCM (30 mLx3). The combined organic layers were washed with brine (25 mLx3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was WO 2024/184461 PCT/EP2024/056026 purified by column chromatography (SiO2, EA/DCM/MeOH) to give the title compound (940 mg, 32%) as a brown solid. LCMS (Method a. ES+, RT = 0.097 min) 325.3/326.2 (M+H) +

[00866] INTERMEDIATE 139:ethyl 8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxylate

[00867]THE (45 mL) was charged to the 25 mL three-necked round bottom flask, then Intermediate 138 (1.4 g, 4.32 mmol) was added at 20°C. At -60°C inner temperature, EDA (2 M, 2.81 mL) was added dropwise to the reaction mixture at -60°C within 2 min. The mixture was stirred at -60°C for 0.5 hr. At -60°C inner temperature, ethyl chloroformate (2.34 g, 21.mmol) was added dropwise to the reaction mixture. After the addition, the mixture was stirred at -60°C for 0.5 hr. The reaction mixture was stirred at 20°C for 1.5 hr. The reaction mixture was added to 15mL NaHCO3 at 0°C. The mixture was extracted by DCM (30 mLx2). Then organic phase was washed by brine (15mLx2). The organic layers were dried over Na2S04, filtered. The organic phase was concentrated under reduced pressure at 40°C to give a residue. The residue was purified by column chromatography to give the title compound (270 mg, 16%) as a yellow solid. 1H NMR (400 MHz, CDCI) 6 ppm 8.33 (s, 1 H) 6.98 - 7.02 (m, 1 H) 4.73 (t, J=6.62 Hz, 2 H) 4.-4.51 (m, 5 H) 4.01 (s, 3 H) 3.14 (br t, J=6.50 Hz, 2 H) 2.91 - 3.01 (m, 2 H) 1.78 - 1.88 (m, 2 H) 1.44- 1.48 (m, 4 H) 1.07 (t, .7=7.33 Hz, 3 H) LCMS (Method e. ES+, RT = 0.338 min) 397.1/398.(M+H) + WO 2024/184461 PCT/EP2024/056026

[00868] INTERMEDIATE 140:8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6-dihydroimidazo[5, 1 -a]isoquinoline-3-carboxylic acid

[00869]To a solution of Intermediate 139 (80 mg, 201.79 umol) in THF (0.8 mL) was added TMSOK (51.78 mg, 403.59 umol). The mixture was stirred at 20°C for 2 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (74 mg, crude) as a yellow solid. LCMS {Method e. ES+, RT =0.302 min) 369.0/370.0 (M+H) +

[00870] INTERMEDIATE 141:(R)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl- 5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carboxamide

[00871]To a solution of Intermediate 140 (120 mg, 325.74 umol) in DMF (1.2 mL) was added (2R)-2-methylpyrrolidine-2-carboxamide (64.35 mg, 390.89 umol, HC1), DIEA (168.mg, 1.30 mmol) and HATU (136.24 mg, 358.32 umol). The mixture was stirred at 20°C for 1 hr. The reaction mixture was added to the ice water, IM HC1 was added to adjust pH = 5-6. The reaction mixture was extracted with DCM (5 mLx3). The combined organic layers were washed with brine (5 mLx3), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure to give the title compound (153 mg, 98%) as a yellow solid. 1H NMR (400 MHz, CDC13) 8.27 (s, 1 H) 7.00 (s, 1 H) 4.57 (br d, J=0.98 Hz, 2 H) 4.46 (s, 3 H) 4.09 - 4.29 (m, 3 H) 4.01 (s, H) 3.12 (br t, J=5.93 Hz, 2 H) 2.97 (s, 2 H) 2.88 - 2.93 (m, 3 H) 2.81 (s, 6 H) 2.00 - 2.07 (m, WO 2024/184461 PCT/EP2024/056026 H) 1.76 - 1.83 (m, 5 H) 1.21 - 1.29 (m, 4 H) 1.05 (t, J=134 Hz, 3 H) LCMS {Method e. ES+, RT = 0.327 min) 479.2/480.2 (M+H) +

[00872] INTERMEDIATE 142:(R)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carboxamide

[00873]To a solution of Intermediate 140 (130 mg, 352.89 umol) in DMF (1.3 mL) was added Intermediate 124 (63.78 mg, 423.47 umol, HCI), DIEA (182.43 mg, 1.41 mmol) and HATU (147.60 mg, 388.18 umol). The mixture was stirred at 20°C for 1 hr. The reaction mixture was added to the 5 mL ice water, IM HCI was added to adjust pH = 6. The reaction mixture was extracted withEtOAc(5 mLx3), the combined organic phase was washed with brine (5 mLx6), dried by Na2S04, filtered and concentrated under reduced pressure to give the title compound (1mg, crude) as a yellow solid. 1H NMR (400 MHz, CDCI3) 6 8.23 - 8.32 (m, 2 H) 8.03 (s, 1 H) 6.- 7.01 (m, 1 H) 5.36 - 5.42 (m, 1 H) 4.67 - 4.78 (m, 3 H) 4.56 (td, J=10.02, 5.62 Hz, 1 H) 4.46 (s, H) 4.13 (q, J=7.13 Hz, 2 H) 4.00 (s, 3 H) 3.07 - 3.15 (m, 2 H) 2.97 (s, 5 H) 2.83 - 2.92 (m, 8 H) 2.81 (s, 6 H) 2.06 (s, 3 H) 1.90 (s, 3 H) 1.79 - 1.87 (m, 2 H) 1.19 - 1.32 (m, 9 H) 1.05 (t, J=7.Hz, 3 H) 0.81 - 0.91 (m, 3 H) LCMS {Methode. ES+, RT = 0.357 min) 465.1/466.1 (M+H) +

[00874] INTERMEDIATE 143:tert-butyl(S)-( 1 -((4-bromo-3 -methoxyphenethyl) amino)- 4,4,4-trifluoro- 1 -oxobutan-2-yl) carbamate WO 2024/184461 PCT/EP2024/056026

[00875]To a solution of (2S)-2-(tert-butoxycarbonylamino)-4,4,4-trifluoro-butanoic acid (3.g, 14.86 mmol) in DCM (30 mL) was added CDI (3.28 g, 20.26 mmol) at 20°C. The mixture was stirred at 20°C for 1 hr. The mixture was added Intermediate 212 (3.6 g, 13.51 mmol, HC1) and DIEA (3.49 g, 27.01 mmol) at 20°C. The mixture was stirred at 20°C for 2 hr. The reaction was diluted with H20 (100 mL) and extracted with DCM (50 mLx3). The organic layers were concentrated under reduced pressure to give a crude product. The crude product was triturated by MTBE (20 mL) to give the title compound (2.9 g, 46%) as a white solid. 1H NMR (400 MHz, DMSO-de) 6 8.04 (br s, 1 H) 7.43 (d, J=8.00 Hz, 1 H) 7.18 (d, J=8.75 Hz, 1 H) 6.(d, J=1.50 Hz, 1 H) 6.72 (dd,J=8.00, 1.50 Hz, 1 H) 4.18 - 4.27 (m, 1 H) 3.83 (s, 3 H) 3.27 - 3.(m, 2 H) 2.69 (br t, J=7.00 Hz, 2 H) 2.53 - 2.62 (m, 1 H) 2.45 (br s, 1 H) 1.37 (s, 9 H) LCMS (Method e. ES+, RT = 0.528 min) 490.9/492.9 (M+Na) +

[00876] INTERMEDIATE 144:(S)-2-amino-N-(4-bromo-3-methoxyphenethyl)-4,4,4- trifluorobutanamide

[00877]To a solution of Intermediate 143 (4.5 g, 9.59 mmol) in EtOAc (50 mL) was added HCl/EtOAc (4M, 50 mL) at 20°C. The mixture was stirred at 20°C for 2 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (7.7 g, 99%, HC1) as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 8.90 (br t, J = 5.0 Hz, 1H), 8.66 (br s, 3H), 7.(d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.77 (br d, J = 7.9 Hz, 1H), 4.05 (br s, 1H), 3.85 (s, 3H), 3.65 - 3.23 (m, 3H), 2.92 - 2.67 (m, 4H) LCMS (Method g. ES+, RT= 0.337 min) 369.0/371.0 (M+H) + WO 2024/184461 PCT/EP2024/056026

[00878] INTERMEDIATE 145:(S)-N-(4-bromo-3-methoxyphenethyl)-4,4,4-trifluoro-2-formamidobutanamide

[00879]To a solution of Intermediate 144 (J.I g, 20.86 mmol) in ethyl formate (69.78 g, 941.mmol) was added TEA (6.33 g, 62.57 mmol) and MeOH (5 mL) at 20°C. The mixture was stirred at 75 °C for 12 hr. The reaction mixture was concentrated under reduced pressure. The mixture was added with HC1 (0.5 mol) to adjust pH=5, then mixture was diluted with H20 90 mL and extracted with EtOAc (20 mLx3). The combined organic layers were washed with brine 50 mL (25 mLx2), dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (7.5 g, 91%) as a white solid. 1H NMR (400 MHz, DMSO-dg) 6 8.48 - 8.61 (m, 1 H) 8.31 (br t, .7=5.26 Hz, 1 H) 8.03 (s, 1 H) 7.44 (d, J=SMl Hz, 1 H) 6.93 (d, J=1.71 Hz, 1 H) 6.(dd, J=8.01, 1.65 Hz, 1 H) 4.51 - 4.70 (m, 1 H) 3.83 (s, 3 H) 3.24 - 3.32 (m, 2 H) 2.57 - 2.76 (m, H) LCMS (Method g. ES+, RT= 0.413 min) 397.1/399.1 (M+H) +

[00880] INTERMEDIATE 146:9-bromo-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydroimidazo[5, 1 -a] isoquinoline

[00881]A mixture of P205 (10.72 g, 75.53 mmol) in methanesulfonic acid (60 mL) at 20°C was stirred at 75°C for 0.5 hr. Then Intermediate 145 (6 g, 15.11 mmol) was added and stirred at 75°C for 1.5 hr. The mixture was cooled and poured into ice-water, then added with NaOH to adjust pH=8, then was extracted with EtOAc (35 mLx3). The combined organic layers were washed with WO 2024/184461 PCT/EP2024/056026 brine, dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (5.1 g, 93%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 7.75 (s, 1H), 7.71 (s, 1H), 7.18 (s, 1H), 4.13 (t, J = 6.4 Hz, 2H), 3.88 (s, 3H), 3.84 - 3.75 (m, 2H), 3.00 (br t, J = 6.4 Hz, 2H) LCMS (Method h. ES+, RT = 1.847 min) 361.0/363.2 (M+H) +

[00882] INTERMEDIATE 147:ethyl 9-bromo-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydroimidazo[5, 1 -a]isoquinoline-3-carboxylate

[00883]Four batches were earned out in parallel.

[00884]To a solution of Intermediate 146 (0.2 g, 553.78 umol) in THF (3 mL) was added LDA (2 M, 332.27 pL) at -60°C under N2 and stirred at -60°C for 0.5 hr under N2. Then added ethyl chloroformate (0.35 g, 3.23 mmol) at -60°C under N2 and the mixture was stirred at - 60°C for 1 hr. The mixture was poured into sat.NaHCO3 solution (10 mL). The aqueous phase was extracted with ethyl acetate (10 mLx3). The combined organic phase was washed with brine (10 mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/0 to 0/1) to give the title compound (0.2 g, 21%) as a yellow solid. 1H NMR (400 MHz, CDC13) 6 7.73 - 7.78 (m, 1 H) 6.76 - 6.79 (m, 1 H) 4.56 - 4.66 (m, 2 H) 4.34 - 4.45 (m, 2 H) 3.85 - 3.90 (m, 3 H) 3.59 - 3.74 (m, 2 H) 2.91 - 3.00 (m, 2 H) 1.33 - 1.41 (m, 3 H). LCMS (Methoda. ES+, RT = 1.8min) 433.1/435.0 (M+H)+ WO 2024/184461 PCT/EP2024/056026

[00885] INTERMEDIATE 148:potassium 9-bromo-8-methoxy-l-(2, 2,2-trifluoroethyl)-5, 6-dihydroimidazo[5, 1 -a]isoquinoline-3-carboxylate

[00886]To a solution of Intermediate 147 (130 mg, 300.08 pmol) in THF (3 mL) was added TMSOK (76.99 mg, 600.16 umol) at 20°C and stirred at 20°C for 1 hr. The mixture was concentrated under reduced pressure to give the title compound (260 mg, crude) as a brown solid. LCMS {Method h. ES+, RT = 1.448 min) 405.0/407.0 (M+H) +

[00887] INTERMEDIATE 149:(R)-l-(9-bromo-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carboxamide

[00888]To a solution of Intermediate 148 (130 mg, 293.28 umol) in DMF (2 mL) was added HATU (223.03 mg, 586.57 umol), DIEA (227.42 mg, 1.76 mmol) at 20°C and stirred at 20°C for 0.5 hr. Then added (2R)-2-methylpyrrolidine-2-carboxamide (72.43 mg, 439.93 umol HCI) at 25OC for 12 hr. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (5 mLx3). The combined organic phase was washed with brine (mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/0 to 0/1) to give the title compound (120 mg, 79 %) as a brown solid. 1H NMR (400 MHz, CDC13) 8 7.(s, 0.25 H) 7.72 - 7.80 (m, 1 H) 6.78 - 6.89 (m, 1.7 H) 5.33 - 5.48 (m, 1 H) 4.49 - 4.63 (m, 2.7 H) WO 2024/184461 PCT/EP2024/056026 4.07 - 4.35 (m, 4.4 H) 3.91 - 3.96 (m, 4.8 H) 3.60 - 3.74 (m, 2.5 H) 2.93 - 3.05 (m, 3.6 H) 2.39 - 2.52 (m, 1.5 H) 1.86 - 2.03 (m, 4.4 H) 1.77 (br s, 4.8 H) LCMS (Method a . ES+, RT = 1.588 min) 515.1/517.1 (M+H) +

[00889] INTERMEDIATE 150:(R)-l-(9-bromo-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile

[00890]To a solution of Intermediate 149 (90 mg, 174.65 pmol) in THF (1 mL) was added Burgess reagent (83.24 mg, 349.30 umol) in DCM (1 mL) at 20°C and stirred at 20°C for hr. The residue was poured into water (5 mL). The aqueous phase was extracted with DCM (mLx3). The combined organic phase was washed with brine (5 mLx2), dried with anhydrous Na2S04. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l//l) to give the title compound (70 mg, 81%) as a yellow solid. 1HNMR (400 MHz, CDCh) 87.85 (s, 0.2 H) 7.77 (s, 1 H) 6.85 - 6.89 (m, 1 H) 6.81 - 6.84 (m, 0.3 H) 5.38 (d, J=5.3 Hz, 0.3 H) 4.68 (br t, J=6.5 Hz, 2.4 H) 4.10 - 4.30 (m, 3.6 H) 3.91 - 3.98 (m, 4.5 H) 3.66 (qd, J=10.1, 4.6 Hz, 2 H) 3.03 (brt, J=6.4 Hz, 3 H) 2.53 - 2.63 (m, 1.5 H) 2.02 - 2.16 (m, 4.6 H) 1.83 - 1.(m, 4.4 H) 1.23 - 1.32 (m, 3.6 H) LCMS (Methods. ES+, RT = 3.247 min) 496.9/498.9 (M+H) +

[00891] INTERMEDIATE 151:9-bromo-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydroimidazo[5, 1 -a] isoquinoline WO 2024/184461 PCT/EP2024/056026

[00892]To a solution of Intermediate 148 (130 mg, 293.28 pmol) in DMF (2 mL) was added HATU (223.03 mg, 586.57 pmol), DIEA (227.42 mg, 1.76 mmol) at 20°C and stirred at 20°C for 0.5 hr. Then added Intermediate 124 (66.26 mg, 439.93 pmol, HC1) at 25OC for 12 hr. The residue was poured into water (10 mL). The aqueous phase was extracted with EtOAc (mLx3). The combined organic phase was washed with brine (10 mLx2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/O to 0/1) to give the title compound (1mg, 75%) as a brown solid. 1HNMR (400 MHz, CDC13) 8 8.02 - 8.19 (m, 0.8 H) 7.74 - 7.78 (m, 0.3 H) 7.66 - 7.72 (m, 0.8 H) 6.78 (s, 0.7 H) 6.73 - 6.76 (m, 0.5 H) 5.24 - 5.35 (m, 1 H) 4.57 - 4.(m, 3 H) 4.40 - 4.52 (m, 1 H) 4.01 - 4.19 (m, 1 H) 3.83 - 3.92 (m, 4 H) 3.50 - 3.63 (m, 1.8 H) 2.- 2.97 (m, 2.4 H) 2.77 - 2.87 (m, 1 H) 2.71 - 2.74 (m, 0.6 H) 2.04 - 2.14 (m, 0.7 H) 1.82 (s, 3 H) LCMS {Methods. ES+, RT = 2.921 min) 500.9/502.9 (M+H) +

[00893] INTERMEDIATE 152:9-bromo-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydroimidazo[5, 1 -a] isoquinoline

[00894]To a solution of Intermediate 151 (90 mg, 179.53 pmol) in THE (1 mL) was added burgess reagent (85.57 mg, 359.07 pmol) in DCM (1 mL) at 20°C and stirred at 20°C for hr. The residue was poured into water (5 mL). The aqueous phase was extracted with DCM (5mLx3). The combined organic phase was washed with brine (5 mLx2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/O to 0/1) to give the title compound (mg, 69%) as a yellow solid. 1H NMR (400 MHz, CDC13) 8 7.84 (s, 0.4 H) 7.79 (s, 0.2 H) 7.76 (s, H) 6.93 - 7.03 (m, 1.5 H) 6.86 (s, 1.3 H) 6.82 (s, 0.5 H) 5.37 (d, J=5.4 Hz, 0.4 H) 5.02 (s, 0.6 H) 4.63 - 4.88 (m, 6.7 H) 4.14 - 4.23 (m, 1 H) 3.92 - 3.98 (m, 5.53 H) 3.76 (br t, .7=6.4 Hz, 2 H) 3.57 WO 2024/184461 PCT/EP2024/056026 - 3.69 (m, 2.6 H) 2.95 - 3.06 (m, 4 H) 2.86 (ddd, J=11.5, 8.8, 6.3 Hz, 1.6 H) 2.38 - 2.47 (m, 1.7 H) 2.28 (s, 1.9 H) 1.92 - 1.98 (m, 4.6 H) 1.84 - 1.90 (m, 2 H) 1.55 (s, 7 H) LCMS {Methods. ES+, RT = 1.847 min) 361.0/363.2 (M+H) +

[00895] INTERMEDIATE 153:8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydroimidazo[5,l-a]isoquinoline

[00896]To a solution of Intermediate 146 (300 mg, 830.66 umol) l-methyl-3-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrazole (190.11 mg, 913.73 pmol) in dioxane (6 mL) and H2O (1.2 mL) was added XPHOS-Pd-G2 (65.36 mg, 83.07 umol), C82CO3 (1.08 g, 3.32 mmol) at 20°C and stirred at 80°C for 3 hr. The residue was poured into ice-water (10 mL). The aqueous phase was extracted with EtOAc(5 mLx3). The combined organic phase was washed with brine (10 mLx2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/O to 0/1) to give the title compound (260 mg, 86%) as a yellow solid. 1H NMR (400 MHz, CDC13) 6 8.13 - 8.20 (m, 1 H) 7.52 (s, 1 H) 7.41 (d, J=2.13 Hz, 1 H) 6.88 (s, 1 H) 6.72 (d, .7=2.25 Hz, 1 H) 4.11 - 4.19 (m, 2 H) 3.98 (s, 3 H) 3.93 (s, 3 H) 3.75 (q,^=10.51 Hz, 2 H) 3.09 (t, J=6.38 Hz, 2 H) LCMS {Method a. ES+, RT = 1.209 min) 363.3/364.3 (M+H) + WO 2024/184461 PCT/EP2024/056026

[00897] INTERMEDIATE 154:ethyl 8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxylate

[00898]To a solution of Intermediate 153 (170 mg, 469.16 pmol) in THF (2 mL) was added LDA (2 M, 351.87 pL) at -60°C. The mixture was added ethyl formate (173.77 mg, 2.mmol) at -60°C and the mixture was stirred at -60°C for 2 hr. The mixture was added H20 (mL) and extracted with EtOAc (5 mLx3). The organic layers were concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 1/1) to give the title compound (70 mg, 34%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 68.25 (s, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.18 (s, 1H), 6.(d, J = 2.1 Hz, 1H), 4.59 (br t, J = 6.5 Hz, 2H), 4.33 (q, J = 7.0 Hz, 2H), 3.95 - 3.79 (m, 10H), 3.(br t, J = 6.4 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). LCMS {Method e. ES+, RT = 0.461 min) 435.2/436.(M+H) +

[00899] INTERMEDIATE 155:8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-l-(2,2,2- trifluoroethyl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxylic acid

[00900]To a solution of Intermediate 154 (70 mg, 161.14 pm 01) in THF (1 mL) was added TMSOK (41.34 mg, 322.28 pmol). The mixture was stirred at 20°C for 2 hr. The reaction WO 2024/184461 PCT/EP2024/056026 mixture was concentrated under reduced pressure to give the title compound (65 mg, crude) as a yellow solid. LCMS {Method e. ES+, RT = 0.342 min) 407.2/408.2 (M+H) +

[00901] INTERMEDIATE 156:(R)-l-(8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydroimidazo[5,l-a]isoquinohne-3-carbonyl)-2-methylpyrrolidine-2- carboxamide

[00902]To a solution of Intermediate 155 (65 mg, 159.96 umol) and (2R)-2-methylpyrrolidine- 2-carboxamide (31.60 mg, 191.95 umol, HC1) in DMF (1 mL) was added HATU (66.90 mg, 175.95 umol) and DIEA (62.02 mg, 479.87 umol) at 20°C. The mixture was stirred at 20°C for hr. The mixture was diluted with H20 (5 mL) and extracted with EtOAc (2 mLx3). The organic layers were concentrated under reduced pressure to give the title compound (60 mg, crude) as a yellow oil. LCMS {Methode. ES+, RT = 0.396 min) 517.3/518.3 (M+H) +

[00903] INTERMEDIATE 157:tert-butyl (2-((4-bromo-3-methoxyphenethyl)amino)- 1 - (3,3 -difluorocyclobutyl)-2-oxoethyl)carbamate

[00904]To a solution of 2-(tert-butoxycarbonylamino)-2-(3,3-difluorocyclobutyl) acetic acid (7.31 g, 27.57 mmol) in DCM (35 mL) was added CDI (6.39 g, 39.39 mmol) at 20°C for 12 hr, and added Intermediate 212 (7 g, 26.26 mmol, HC1), DIEA (6.79 g, 52.52 mmol). The mixture was stirred at 20°C for 2 hr. The mixture was added with 30 mL H20. The aqueous layer was extracted with DCM (20 mLx3). The combined organic phase was washed with brine (10 mLx2), -357- WO 2024/184461 PCT/EP2024/056026 dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=80/l to 20/1) to give the title compound (7 g, 56%) was obtained as a white solid. 1HNMR (400 MHz, CDC13) 6 7.46 (d, J=8.00 Hz, 1 H) 6.74 (d, J=1.25 Hz, 1 H) 6.67 (dd, J=7.94, 1.44 Hz, 1 H) 6.11 - 6.21 (m, 1 H) 5.(br s, 1 H) 4.04 (br t, .7=8.00 Hz, 1 H) 3.90 (s, 3 H) 3.47 - 3.57 (m, 2 H) 2.78 (t, J=1Ml Hz, 2 H) 2.54 - 2.71 (m, 2 H) 2.30 - 2.52 (m, 3 H) 1.44 (s, 9 H) LCMS {Method I. ES+, RT = 0.521 min) 479.1/477.2 (M+H) +

[00905] INTERMEDIATE 158:2-amino-N-(4-bromo-3-methoxyphenethyl)-2-(3,3- difluorocyclobutyl)acetamide

[00906]To a solution of Intermediate 157 (7 g, 14.66 mmol)inEtOAc (35 mL) was added HCl/EtO Ac (4 M, 75.35 mL). The mixture was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (6 g, 99%, HC1) as a white solid. 1H NMR (400 MHz, DMSO-de) 6 8.70 (br t, .7=5.44 Hz, 1 H) 8.41 (br s, 3 H) 7.46 (d, J=8.00 Hz, 1 H) 7.01 (d, J=1.75 Hz, 1 H) 6.76 (dd, J=8.00, 1.75 Hz, 1 H) 3.84 (s, 3 H) 3.78 (br d, .7=7.63 Hz, 1 H) 3.49 (dq, ^=13.38, 6.88 Hz, 1 H) 3.22 - 3.40 (m, 2 H) 2.72 - 2.76 (m, 1 H) 2.56 - 2.65 (m, 2 H) 2.30 - 2.41 (m, 2 H) LCMS {Method I. ES+, RT = 0.357 min) 379.0/377.0 (M+H) + WO 2024/184461 PCT/EP2024/056026

[00907] INTERMEDIATE 159:N-(4-bromo-3-methoxyphenethyl)-2-(3,3-difluorocyclobutyl)-2-formamidoacetamide

[00908]To a solution of Intermediate 158 (1 g, 2.42 mmol, HC1) in ethyl formate (8.14 g, 109.90 mmol) and MeOH (1 mL) was added Et3N (489.21 mg, 4.83 mmol). The mixture was stirred at 75°C for 24 hr. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with H20 (20 mL) and added with HC1 (0.5 mol) to adjust pH=5, then the mixture was extracted with EtOAc(10 mLx3). The combined organic layers were washed with brine 10 mL (5 mLx2), dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (0.7 g, 71%) as a white solid. 1H NMR (400 MHz, DMSO-d) 6 8.41 (br d, V=8.63 Hz, 1 H) 8.20 (br t, J=5.32 Hz, 1 H) 8.05 (s, 1 H) 7.44 (d, ^=8.13 Hz, 1 H) 6.95 (d, J=L38 Hz, 1 H) 6.73 (dd, J=8.00, 1.50 Hz, 1 H) 4.40 (br t, J=1.15 Hz, 1 H) 3.83 (s, 3 H) 3.34 - 3.41 (m, 1 H) 3.24 - 3.31 (m, 1 H) 2.69 (brt, J=6.94 Hz, 2 H) 2.26 - 2.47 (m, 5 H) LCMS {Method I. ES+, RT= 0.413 min) 407.1/405.1 (M+H) +

[00909] INTERMEDIATE 160:9-bromo-l-(3,3-difluorocyclobutyl)-8-methoxy-5,6- dihydroimidazo[5, 1 -a] isoquinoline

[00910]A mixture of P2O5 (1.23 g, 8.64 mmol) in methanesulfonic acid (7 mL) was stirred at 75°C for 0.5 hr, and was added Intermediate 159 (0.7 g, 1.73 mmol). The mixture was stirred WO 2024/184461 PCT/EP2024/056026 at 75°C for 2 hr. The residue was poured into cooled sat.Na2CO3 to pH=8. The aqueous phase was extracted with EtOAc (10 mLx3). The combined organic phase was washed with brine (mLx2), dried with anhydrous Na2S04, filtered and concentrated to give the title compound (5mg, 91%) as a white solid. ׳H NMR (400 MHz, DMSO-de) 6 7.68 (s, 1 H) 7.59 (s, 1 H) 7.16 (s, H) 4.10 (t, J=6.38 Hz, 2 H) 3.87 (s, 3 H) 3.54 - 3.65 (m, 1 H) 2.78 - 3.03 (m, 6 H) LCMS {Method I. ES+, RT= 0.367 min) 369.0/371.0 (M+H) +

[00911] INTERMEDIATE 161:ethyl 9-bromo-l-(3,3-difluorocyclobutyl)-8-methoxy-5,6- dihydroimidazo[5, 1 -a]isoquinoline-3-carboxylate

[00912]To a solution of Intermediate 160 (0.25 g, 677.13 umol) in THE (2.5 mL) was added EDA (2 M, 406.28 pL) at -60°C under N2 and stirred at -60°C for 0.5 hr under N2. Then added ethyl chloroformate (0.37 g, 3.41 mmol) at -60°C under N2 and the mixture was stirred at - 60°C for 2 hr. The mixture was poured into sat. NaHCO3 solution (5 mL). The aqueous phase was extracted with EtOAc (5 mLx3).The combined organic phase was washed with brine (mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/0 to 0/1) to give the title compound (0.2 g, 67%) as a yellow solid. 1H NMR (400 MHz, CDC13) 6 ppm 7.- 7.64 (m, 1 H) 6.83 - 6.88 (m, 1 H) 4.60 - 4.71 (m, 2 H) 4.46 (q, J=7.1 Hz, 2 H) 3.92 - 3.99 (m, H) 3.53 - 3.66 (m, 1 H) 2.94 - 3.18 (m, 6 H) 1.46 (t, J=1 A Hz, 3 H) LCMS {Method a. ES+, RT = 1.945 min) 444.1/443.0 (M+H) + WO 2024/184461 PCT/EP2024/056026

[00913] INTERMEDIATE 162:9-bromo-l-(3,3-difluorocyclobutyl)-8-methoxy-5,6-dihydroimidazo[5, 1 -a]isoquinoline-3-carboxylic acid

[00914]To a solution of Intermediate 161 (150 mg, 339.93 pmol) in THF (3 mL) was added TMSOK (87.22 mg, 679.86 umol) at 20°C and stirred at 20°C for 1 hr. The mixture was concentrated under reduced pressure to give the title compound (150 mg, crude) as a brown solid. LCMS {Method I. ES+, RT = 0.394 min) 415.0/417.0 (M+H) +

[00915] INTERMEDIATE 163:(R)-l-(9-bromo-l-(3,3-difluorocyclobutyl)-8-methoxy-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carboxamide

[00916]To a solution of Intermediate 162 (150 mg, 332.37 umol), (2R)-2-methylpyrrolidine- 2-carbo xamide (82.08 mg, 498.56 umol, HC1) in DMF (3 mL) was added HATU (139.02 mg, 365.61 umol), DIEA (171.82 mg, 1.33 mmol) at 20°C and stirred at 40°C for 12 hr. Then added (2R)-2-methylpyrrolidine-2-carboxamide (54.72 mg, 332.37 umol, HCI), HATU (88.mg, 232.66 umol), DIEA (85.91 mg, 664.74 umol) at 40°C for 2 hr. The residue was poured into water (10 mL). The aqueous phase was extracted with EtOAc (5 mLx3). The combined organic phase was washed with brine (10 mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/0 to 0/1) to give the title compound (130 mg, 75%) as a yellow solid.

WO 2024/184461 PCT/EP2024/056026 1H NMR (400 MHz, CDC13) 6 7.59 (s, 1 H) 6.84 (s, 1 H) 6.52 (br d, .7=5.9 Hz, 1 H) 5.35 - 5.(m, 1 H) 4.47 - 4.70 (m, 2 H) 4.18 - 4.41 (m, 2 H) 3.90 - 3.97 (m, 3 H) 3.56 - 3.67 (m, 1 H) 2.93 - 3.12 (m, 6 H) 2.48 (dt, J=12.2, 6.2 Hz, 1 H) 2.00 - 2.14 (m, 3 H) 1.72 - 1.82 (m, 3 H) LCMS (Method a . ES+, RT = 1.700 min) 545.1/547.1 (M+H) +

[00917] INTERMEDIATE 164:(R)-l-(9-bromo-l-(3,3-difluorocyclobutyl)-8-methoxy-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile

[00918]To a solution of Intermediate 163 (110 mg, 210.18 pmol) in THF (2 mL) was added burgess reagent (100.17 mg, 420.35 umol) in DCM (2 mL) at 20°C and stirred at 20°C for hr. The residue was poured into water (5 mL). The aqueous phase was extracted with DCM (mLx3). The combined organic phase was washed with brine (5 mLx2), dried with anhydrous Na2S04. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l//l) to give the title compound (100 mg, 94%) as a white solid. 1H NMR (400 MHz, CDCh) 8 7.57 - 7.65 (m, 1 H) 6.87 - 6.88 (m, 1 H) 4.69 - 4.82 (m, 1 H) 4.58 (dt, J=14.0, 7.0 Hz, H) 4.16 - 4.35 (m, 2 H) 3.94 (s, 3 H) 3.61 (td, J=8.6, 2.7 Hz, 1 H) 2.95 - 3.07 (m, 6 H) 2.55 - 2.(m, 1 H) 2.08 - 2.18 (m, 3 H) 1.89 (s, 3 H) 1.55 (s, 4 H). LCMS (Methodi. ES+, RT = 0.595 min) 507.2/505.2(M+H) + WO 2024/184461 PCT/EP2024/056026

[00919] INTERMEDIATE 165:l-(3,3-difluorocyclobutyl)-8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline

[00920]To a solution of Intermediate 160 (300 mg, 812.56 umol), l-methyl-3-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrazole (185.97 mg, 893.82 umol), XPHOS-Pd-G2 (63.mg, 81.26 umol), C82CO3 (1.06 g, 3.25 mmol) in dioxane (2.5 mL) and H20 (0.5 mL) was degassed and purged with N2 for 3 min, and then the mixture was stirred at 80°C for 2 hr under N2 atmosphere. The residue was poured into water (10 mL). The aqueous phase was extracted with DCM (5 mLx3). The combined organic phase was washed with brine (10 mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=5/l to 1/1) to give the title compound (200 mg, 66%) as a white solid. 1H NMR (400 MHz, DMSO-t/6) 5 8.00 (s, 1 H) 7.(d, J=1.75 Hz, 1 H) 7.65 (s, 1 H) 7.10 (s, 1 H) 6.70 (d, J=2.13 Hz, 1 H) 4.13 (brt, J=6.25 Hz, 2 H) 3.86 - 3.96 (m, 6 H) 3.53 - 3.65 (m, 1 H) 2.87 - 3.06 (m, 6 H) LCMS {Method h. ES+, RT = 1.7min) 371.2/372.2 (M+H) +

[00921] INTERMEDIATE 166:ethyl 1-(3,3-difluorocyclobutyl)-8-methoxy-9-(l-methyl- lH-pyrazol-3-yl)-5,6-dihy droimidazo[5,l-a]isoquinoline-3-carboxylate N OEt WO 2024/184461 PCT/EP2024/056026

[00922]To a solution of Intermediate 165 (220 mg, 593.96 pmol) in THF (2 mL) was added LDA (2 M, 326.68 pL) at -60°C. The mixture was added ethyl formate (220.00 mg, 2.mmol) at -60°C and the mixture was stirred at -60°C for 2 hr. The residue was poured into water (5 mL). The aqueous phase was extracted with EtOAc (5mLx3). The combined organic phase was washed with brine (5 mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 1/1) to give the title compound (70 mg, 27%) as a yellow solid. 1H NMR (400 MHz, DMSO-de) 6 8.09 (s, 1 H) 7.72 (d, J=2.03 Hz, 1 H) 7.16 (s, 1 H) 6.72 (d, J=1.Hz, 1 H) 4.58 (br t, J=6.56 Hz, 2 H) 4.30 - 4.39 (m, 2 H) 3.91 (d, J=3.34 Hz, 6 H) 2.94 - 3.11 (m, H) 1.34 (t, .7=7.03 Hz, 3 H) LCMS {Method e. ES+, RT = 0.498 min) 443.2/444.3 (M+H) +

[00923] INTERMEDIATE 167:l-(3,3-difluorocyclobutyl)-8-methoxy-9-(l-methyl-lH- pyrazol-3-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxylic acid

[00924]To a solution of Intermediate 166 (70 mg, 158.21 pmol) in THF (1 mL) was added TMSOK (40.59 mg, 316.41 pmol). The mixture was stirred at 20°C for 2 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (65 mg, crude) as a yellow solid. LCMS {Method e. ES+, RT = 0.358 min) 415.2/416.2 (M+H) + WO 2024/184461 PCT/EP2024/056026

[00925] INTERMEDIATE 168:(R)-l-(l-(3,3-difluorocyclobutyl)-8-methoxy-9-(l-methyl- lH-pyrazol-3-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carboxamide

[00926]To a solution of Intermediate 167 (65 mg, 156.85 umol) and (2R)-2-methylpyrrolidine- 2-carboxamide (30.99 mg, 188.22 umol, HC1) in DMF (1 mL) was added HATU (65.60 mg, 172.54 umol) and DIEA (60.81 mg, 470.55 umol) at 20°C. The mixture was stirred at 20°C for hr. The mixture was added H20 (10 mL) and extracted with EtOAc (5 mLx3). The organic layers were concentrated under reduced pressure to give the title compound (60 mg, 73%) as a yellow solid. LCMS (Methodg. ES+, RT = 0.442 min) 525.2/526.2 (M+H) +

[00927] INTERMEDIATE 169:methyl (S)-2-(9-bromo-l-(3,3-difluorocyclobutyl)-8- methoxy-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxamido)-4,4,4-trifluoro-2- methylbutanoate

[00928]Step A: To a solution of Intermediate 168 (1.5 g, 3.32 mmol) in THE (10 mL) was added HATU (2.53 g, 6.65mmol) at 20°C. The mixture was stirred at 20°C for 30 min.

[00929]Step B: To a solution of Intermediate 115 (957.51 mg, 4.32 mmol) in DMF (10 mL) was added Na2CO3 (1.06 g, 9.97 mmol). The mixture was stirred at 20°C for 30 min.

WO 2024/184461 PCT/EP2024/056026

[00930]Step C: The mixture from step A was added dropwise to the mixture B mixture at 20°C. The mixture was stirred at 20°C for 11 hr. The mixture was added with 10 mL H2O, then it was extracted with EtOAc (15 mLx3), the combined organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EtOAc =100/0 to 50/50) to give the title compound (1.35 g, 70%) as a yellow solid. 1H NMR (400 MHz, CDCI3) 6 = 8.- 8.14 (m, 1H), 7.59 (s, 1H), 6.84 (s, 1H), 4.68 (t, J = 6.6 Hz, 2H),3.94 (s, 3H), 3.86 (s, 3H), 3.(s, 2H), 3.63 - 3.55 (m, 1H), 3.39 - 3.26 (m, 2H), 3.01 - 2.97 (m, 2H), 1.79 (s, 3H),1.62 (s, 2H) LCMS {Methodi. ES+, RT = 0.623 min) 580.2/582.2 (M+H) +

[00931] INTERMEDIATE 170:(S)-2-(9-bromo-l-(3,3-difluorocyclobutyl)-8-methoxy-5,6- dihydroimidazo[5, 1 -a]isoquinoline-3-carboxamido)-4,4,4-trifluoro-2-methylbutanoic acid F

[00932]To a solution of Intermediate 169 (0.5 g, 861.56 umol) in THE (5 mL) was added TMSOK (221.05 mg, 1.72 mmol). The mixture was added with HC1 (0.5 mol) to adjust pH=5, then mixture was diluted with H20 (20 mL) and extracted with EtOAc( 10 mLx3). The combined organic layers were washed with brinelO mL (5 mLx2), dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (900 mg, crude) as a yellow foam. LCMS {Method g. ES+, RT = 0.564 min) 566.1/568.1 (M+H) +

[00933] INTERMEDIATE 171:(S)-N-(l-amino-4,4,4-trifluoro-2-methyl-l-oxobutan-2-yl)- 9-bromo- 1 -(3,3-difluorocyclobutyl)-8-methoxy-5,6-dihydroimidazo[5, 1 -a]isoquinoline-3- carboxamide WO 2024/184461 PCT/EP2024/056026

[00934]To a solution of Intermediate 170 (0.8 g, 1.41 mmol) in THF (I mL) was added CDI (343.59 mg, 2.12 mmol) and NHJ.H2O (247.54 mg, 4.24 mmol, 60%). The mixture was stirred at 25OC for 2 h. The mixture was diluted with H20 (20 mL) and extracted with EtOAc(10 mLx3). The combined organic layers were washed with brine (5 mLx2), dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (700 mg, crude) as a yellow solid. LCMS (Method g. ES+, RT = 0.559 min) 565.1/567.1 (M+H) +

[00935] INTERMEDIATE 172:(S)-9-bromo-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-l-(3,3- difluorocyclobutyl)-8-methoxy-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxamide

[00936]To a solution of Intermediate 171 (0.6 g, 1.06 mmol) in THF (3 mL) and DCM (3 mL) was added Burgess reagent (505.84 mg, 2.12 mmol). The mixture was stirred at 30°C for 2 hr. The mixture was diluted with H20 (10 mL) and extracted with DCM (10 mLx3). The combined organic layers were washed with brine (5 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EtOAc =10/1 to 1/1) to give the title compound (450 mg, 78%) as a white solid.

[00937] INTERMEDIATE 173:(S)-9-bromo-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-l-(3,3- difluorocyclobutyl)-8-methoxy-N-methyl-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxamide o °،nh 2 WO 2024/184461 PCT/EP2024/056026

[00938]DMF (3 mL) was charged to the three-necked round bottom flask, then starting Intermediate 172 (0.3 g, 548.13 pmol) was added to the mixture at 0°C for 10 min. At 0°C inner temperature NaH (32.88 mg, 822.20 pmol, 60% purity) was added to the reaction mixture at 0°C within 10 min. Then CH3I (155.60 mg, 1.10 mmol) was added. After the addition, the mixture was stirred at 70°C for 2 hr. The reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA =1/0 to 2/1) to give the title compound (2mg, 65%) as a white solid. 1H NMR (400 MHz, CDCI3) 6 ppm 2.04 -2.10 (m, 3 H) 2.94 - 3.(m, 6 H) 3.11 - 3.23 (m, 1 H) 3.25 -3.36 (m, 1 H) 3.58 - 3.64 (m, 4 H) 3.95 (s, 3 H) 4.37 - 4.55 (m, H) 6.85 (s, 1 H) 7.58 - 7.62 (m, 1 H) LCMS (Methodi. ES+, RT = 0.600 min) 561.2/563.2 (M+H) +

[00939] INTERMEDIATE 174:(2R,4S)-l-(9-bromo-l-(3,3-difluorocyclobutyl)-8-methoxy- 5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-4-hydroxy-2-methylpyrrolidine-2- carboxamide

[00940]To a solution of Intermediate 162 (1 g, 2.22 mmol) in DMF (10 mL) was added HATU (1.69 g, 4.43 mmo) at 20°C. The mixture was stirred at 20°C for 30 min (mixture A).

■Is) OH WO 2024/184461 PCT/EP2024/056026

[00941]To a solution of Intermediate 256 (520.32 mg, 2.88 mmol, HC1) in DMF (10 mL) was added Na2CO3 (469.70 mg, 4.43 mmol). The mixture was stirred at 20°C for 30 min (mixture B). The mixture A was added dropwise to the mixture B mixture at 20°C. The mixture was stirred at 20°C for 1 hr. The mixture was diluted with H20 20 mL and extracted with EtOAc (20 mLx3). The combined organic layers were washed with brine (15 mLx2), dried over Na2S04, filtered and concentrated under reduced pressure. The crude product was triturated with MTBE at 20°C for min to give the title compound (700 mg, 59%) as a yellow solid. 1H NMR (400 MHz, DMSO- d6) 6 7.63 (s, 1 H), 7.19 (s, 1 H), 7.11 (br s, 1 H), 6.83 (br s, 1 H), 5.13 (d, J=3.70 Hz, 1 H), 4.27 - 4.45 (m, 3 H), 4.13 - 4.23 (m, 1 H), 4.02 - 4.12 (m, 1 H), 3.88 (s, 3 H), 3.69 (m, 1 H), 2.84 - 3.(m, 6 H), 2.19 (m, 1 H), 1.82 (m, 1 H), 1.65 (s, 3 H) LCMS {Method I. ES+, RT = 0.426 min) 539.1/541.1 (M+H) +

[00942] INTERMEDIATE 175:(2R,4S)-l-(9-bromo-l-(3,3-difluorocyclobutyl)-8-methoxy- 5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-4-hydroxy-2-methylpyrrolidine-2- carbonitrile

[00943]To a solution of Intermediate 174 (250 mg, 463.50 umol) in pyridine (2.5 mL) was added TFAA (778.80 mg, 3.71 mmol) at 20°C. The mixture was stirred at 20°C for 1 hr. The reaction mixture was poured into water, then the mixture was added with IM HC1 to adjust pH=and extracted with MTBE (20 mLx3). The combined organic layers were washed with brine (mLx3), dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (200 mg, 83%) as a yellow solid. 1H NMR (400 MHz, CDCI3) 6 7.60 (s, 1 H), 6.88 (s, H), 4.65 - 4.70 (m, 1 H), 4.54 - 4.64 (m, 2 H), 4.42 (br d, 1=13.35 Hz, 1 H), 4.17 (m, 1 H), 3.- 3.99 (m, 3 H), 3.68 (m, 1 H), 3.06 (br t, J=6.32 Hz, 4 H), 2.76 (m, 1 H), 2.35 (m, 1 H), 2.01 (s, H), 1.25 (s, 3 H) LCMS {Methodi. ES+, RT = 0.519 min) 521.2/523.2 (M+H) +-369- /S) OH WO 2024/184461 PCT/EP2024/056026

[00944] INTERMEDIATE 176:ethyl 9-bromo-l-isobutyl-8-methoxy-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylate

[00945]To a solution of Intermediate 39 (11.97 g, 30.99 mmol) in AczO (70 mL) was added 4- methylpent- 1-yne (3.31 g, 40.29 mmol, 4.74 mL) at 20°C. The mixture was stirred at 140°C for hr. The reaction mixture was concentrated under reduced pressure. The residue was added with Na2CO3 to adjust pH=8, then mixture was extracted with EtOAc 100 mL (50 mLx2). The combined organic layers were washed with brine 80 mL (40 mLx2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 0/1). The crude product was triturated with PE at 20 °C for 30 min. Then it was filtered to give the title compound (17 g, 67.49%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 ppm 0.94 (d, J=6.Hz, 6 H), 1.28 (t, J=7.07 Hz, 3 H), 1.82 (dt, 1=13.26, 6.63 Hz, 1 H), 2.53 (br s, 2 H), 2.99 (br t, J=6.44 Hz, 2 H), 3.88 (s, 3 H), 4.22 (q, J=7.13 Hz, 2 H), 4.37 - 4.59 (m, 2 H), 6.75 (s, 1 H), 7.(s, 1 H), 7.69 (s, 1 H). LCMS {Method I. ES+, RT = 0.74 min) 406.1/408.1 (M+H)+

[00946] INTERMEDIATE 177:9-bromo-l-isobutyl-8-methoxy-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxylic acid

[00947]To a solution of Intermediate 176 (2.5 g, 6.15 mmol) in EtOH (10 mL) and THE (10mL) was added KOH (1.04 g, 18.46 mmol) in H20 (10 mL). The mixture was stirred at WO 2024/184461 PCT/EP2024/056026 °C for 5hr. The reaction mixture was adjust pH=3 with IM HC1. The reaction mixture was filtered. The filtrate was extracted with EtOAc (10 mLx 3). The combined organic layers were washed with brine (10 mL), dried 0verNa2S04, filtered and concentrated under reduced pressure to give a residue. The filter cake was washed three times with toluene and concentrated under reduced pressure to give the title compound (2.06 g, crude) was obtained as a pink solid. 1H NMR (400 MHz, DMSO-6) 6 ppm 12.25 (br s, 1 H), 7.67 (s, 1 H), 7.15 (s, H), 6.67 - 6.74 (m, 1 H), 4.40 - 4.58 (m, 2 H), 3.82 - 3.93 (m, 4 H), 2.93 - 3.06 (m, 2 H), 2.55 - 2.62 (m, 1 H), 2.52 (br s, 1 H), 1.72-1.91 (m, 1 H), 0.92 - 1.00 (m, 6 H), 0.87 - 0.91 (m, 1 H). LCMS {Methode. ES+, RT = 0.57 min) 378.0/380.0 (M+H) +

[00948] INTERMEDIATE 178:(R)-l-(9-bromo-l-isobutyl-8-methoxy-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carboxamide

[00949]To a solution of Intermediate 177 (1.65 g, 4.36 mmol) and Intermediate 124 (597.mg, 5.23 mmol) in DMF (15 mL) was added HATU (1.99 g, 5.23 mmol) and DfEA (2.26 g, 17.mmol, 3.04 mL). The mixture was stirred at 20°C for 2 hr. The combined reaction mixture was poured into ice-water (20 mL) and added 1 M HC1 to pH=5-6. The reaction mixture was extracted with EtOAc 60 mL (20 mLx3). The combined organic layers were washed with brine 40 mL (mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with PE at 20°C for 10 min. Then filtered, the filter cake was dried under reduced pressure to give the title compound (1.8 g, 86.98%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 = 7.73 - 7.55 (m, 2H), 7.27 - 7.09 (m, 2H), 6.51 (br s, 1H), 4.56 - 4.(m, 4H), 3.90 - 3.83 (m, 3H), 2.99 - 2.87 (m, 2H), 2.55 - 2.52 (m, 2H), 2.48 - 2.39 (m, 1H), 2.10 - 1.98 (m, 1H), 1.88 - 1.76 (m, 1H), 1.67 (br s, 3H), 1.40 (s, 1H), 0.99 - 0.92 (m, 7H). LCMS {Method I. ES+ RT = 0.563 min) 474.2/476.2 (M+H) +.

WO 2024/184461 PCT/EP2024/056026

[00950] INTERMEDIATE 179:(R)-l-(9-bromo-l-isobutyl-8-methoxy-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile

[00951]To a solution of Intermediate 178 (1.8 g, 3.79 mmol) in pyridine (17 mL) was added TFAA (6.38 g, 30.35 mmol, 4.22 mL). The mixture was stirred at 20°C for 2 hr. The combined reaction mixture was poured into ice-water (20 mL) and added 1 M HC1 to pH=2-3. The reaction mixture was extracted with EtOAc 60 mL (20 mLx3). The combined organic layers were washed with brine 40 mL (20 mLx2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with PE at 20°C for 10 min. Then filtered, the filter cake was concentrated under reduced pressure to give the title compound (1.6 g, 92%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 = 7.72 - 7.64 (m, 1H), 7.19 - 7.11 (m, 1H), 6.57 - 6.47 (m, 1H), 4.57 - 4.34 (m, 4H), 3.88 (s, 3H), 2.96 (t, J = 6.4 Hz, 2H), 2.73 (ddd, J = 6.0, 9.0, 11.5 Hz, 1H), 2.56 - 2.53 (m, 1H), 2.52 (br d, J = 2.0 Hz, 2H), 2.46 - 2.38 (m, 1H), 1.87 - 1.78 (m, 4H), 0.98 - 0.90 (m, 6H). LCMS (Method I. ES+ RT = 0.643 min) 456.2/458.1 (M+H) +.

[00952] INTERMEDIATE 180:phenyl (R)-3-(2-cyano-2-methylazetidine-l-carbonyl)- 1- isobutyl-8-methoxy-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxylate

[00953]To a solution of Intermediate 179 (500 mg, 1.10 mmol), 2-phenylacetaldehyde (789.mg, 6.57 mmol, 512.86 uL), TEA (665.17 mg, 6.57 mmol, 914.95 uL), Pd(dppf)C12.CH2C12 (89.mg, 109.56 umol) in DMF (5 mL) was degassed and purged with N2 for 3 times at 20°C, and then -372- WO 2024/184461 PCT/EP2024/056026 the mixture was stirred at 120°C for 12 h. The combined reaction mixture was poured into ice- water (20 mL) and added 1 M HCI to pH = 5-6. The reaction mixture was extracted with EtOAc mL (20 mL x 3). The combined organic layers were washed with brine 40 mL (20 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/ EtOAc =3/1 to 0/1) to give the title compound (1.2 g, 73%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 = 8.21 (s, 1H), 7.55 - 7.42 (m, 2H), 7.35 - 7.22 (m, 4H), 6.62 - 6.52 (m, 1H), 5.81 - 5.71 (m, 1H), 4.61 - 4.47 (m, 2H), 4.46 - 4.35 (m, 2H), 3.92 (s, 3H), 3.15 - 3.04 (m, 2H), 2.80 - 2.69 (m, 1H), 2.57 (br d, J = 6.Hz, 2H), 2.47 - 2.38 (m, 1H), 1.92 - 1.79 (m, 4H), 0.98 - 0.89 (m, 6H). LCMS {Methodg. ES+ RT = 0.609 min) 498.2/499.3 (M+H) +.

INTERMEDIATE 181:(R)-3-(2-cyano-2-methylazetidine- 1 -carbonyl)- 1 -isobutyl-8-methoxy- 5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxylic acid

[00954]To a solution of Intermediate 180 (600 mg, 1.21 mmol) in THE (10 mL) was added TMSOK (309.38 mg, 2.41 mmol). The mixture was stirred at 20°C for 2hr. The combined reaction mixture was poured into ice-water (10 mL) and added 1 M HC1 to pH = 5-6. The reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine mL (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (450 mg, 88%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) 6 ppm 0.99 (br d, J=6.38 Hz, 6 H), 1.81 (s, 3 H), 1.84 - 1.94 (m, 1 H), 2.39 - 2.47 (m, 1 H), 2.60 (br d, J=6.75 Hz, H), 2.68 - 2.74 (m, 1 H), 3.07 (br t, J=6.25 Hz, 2 H), 4.08 (s, 3 H), 4.37 - 4.60 (m, 4 H), 6.27 (t, J=6.88 Hz, 1 H), 6.56 (s, 1 H), 7.13 (dd, J=6.50, 1.38 Hz, 1 H), 7.29 (s, 1 H), 8.31 - 8.55 (m, 2 H), 10.88 (s, 1 H), 11.99 (br s, 1 H). LCMS {Methodg. RT = 0.493 min) 422.2/423.2 (M+H) +.

WO 2024/184461 PCT/EP2024/056026

[00955] INTERMEDIATE 182:ethyl l-isobutyl-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate

[00956]A mixture of Intermediate 176 (2 g, 4.92 mmol), Intermediate 26 (3.67 g, 9.84 mmol) and XPHOS-Pd-G2 (387.29 mg, 492.23 umol) in DMF (5 mL) was degassed and purged with Ar for 3 times, and then the mixture was stirred at 120°C for 12 hr under Ar atmosphere. The reaction mixture was poured into H20 (20 mL) and added 10% KF (20 mL). The mixture was stirred 5 min and filtered. Then it was extracted with EtOAc (30 mLx3). The combined organic layers were washed with brine 20 mL, dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/0 to 61/39). Then organic layers was concentrated under reduced pressure to give the title compound (1.06 g, 53%) was obtained as an orange solid. 1H NMR (400 MHz, DMSO-<76) ppm 8.15 (s, 1 H), 7.21 - 7.29 (m, 1 H), 6.73 - 6.80 (m, 1 H), 4.49 - 4.59 (m, 2 H), 4.38 - 4.(m, 3 H), 4.17 - 4.28 (m, 2 H), 3.84 - 3.98 (m, 3 H), 3.07 - 3.15 (m, 2 H), 2.52 - 2.62 (m, 2 H), 1.- 1.92 (m, 1 H), 1.22 - 1.36 (m, 3 H), 0.91 - 1.00 (m, 6 H). LCMS {Method a. RT = 2.144 min) 409.2/410.2 (M+H) + WO 2024/184461 PCT/EP2024/056026

[00957] INTERMEDIATE 183:l-isobutyl-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylic acid

[00958]To a solution of Intermediate 182 (0.8 g, 1.95 mmol) in EtOH (3 mL), THE (3 mL) and H20 (3 mL) was added KOH (328.84 mg, 5.86 mmol). The mixture was stirred at 90°C for 2 hr. The reaction mixture was poured into H20 5 mL and adjust pH=3 with 1M HCI. The reaction mixture was filtered. The filtrate was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The filter cake was dried under reduced pressure to give the title compound (0.7 g, 94%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d) 6 ppm 12.23 (br s, 1 H), 7.99 - 8.33 (m, 1 H), 7.24 (s, 1 H), 6.63 - 6.85 (m, 1 H), 4.49 - 4.60 (m, 2 H), 4.37 - 4.45 (m, 3 H), 3.85 - 3.94 (m, 3 H), 3.01 - 3.13 (m, 2 H), 2.52 - 2.62 (m, 2 H), 1.78 - 1.(m, 1 H), 0.88 - 1.02 (m, 6 H). LCMS (Method a. RT =1.161 min) 381.2/382.2 (M+H) +.

[00959] INTERMEDIATE 184:(2R,4S)-4-hydroxy-l-(l-isobutyl-8-methoxy-9-(2-methyl- 2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carboxamide

[00960]To a solution of Intermediate 183 (350 mg, 917.61 umol) in DMF (5 mL) was added HATU (418.68 mg, 1.10 mmol) and TEA (278.55 mg, 2.75 mmol, 383.16 uL). The mixture was -375- WO 2024/184461 PCT/EP2024/056026 stirred at 25°C for 0.5 hr. Then the mixture was added Intermediate 256 (215.47 mg, 1.19 mmol, HCI salt). The mixture was stirred at 45OC for 12 hr. The reaction mixture was poured into H5 mL and adjust pH=7 with IM HC1. The reaction mixture was extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/ EtOAc =100/0 to 5/95). The title compound (200 mg, 43%) was obtained as a brown solid. 1H NMR (400 MHz, DMSO-do) 6 ppm 8.11 (s, 1 H), 7.(s, 1 H), 7.09 (br s, 1 H), 6.76 - 6.86 (m, 1 H), 6.46 (s, 1 H), 4.38 - 4.44 (m, 3 H), 4.29 - 4.33 (m, H), 4.25 (br t, J=5.15 Hz, 2 H), 4.04 - 4.14 (m, 1 H), 3.88 (s, 3 H), 3.59 (dd, J=10.51, 4.77 Hz, H), 2.97 - 3.07 (m, 2 H), 2.56 (br d, J=6.12 Hz, 2 H), 2.19 (dd, J=12.78, 5.68 Hz, 1 H), 1.75 - 1.92 (m, 2 H), 1.63 (s, 3 H), 0.98 (dd, J=6.36, 1.59 Hz, 6 H). LCMS {Method a. RT = 1.306 min.) 507.2/508.2 (M+H) +.

[00961] INTERMEDIATE 185:Ethyl 8-methoxy-9-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate /0,/x /X

[00962]To a solution of ethyl 9-bromo-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate (12 g, 27.76 mmol) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (35.25 g, 138.mmol) in heptane (100 mL) and dioxane (20 mL) was added KOAc (20.44 g, 208.mmol) and Pd(dppf)C12.CH2C12 (453.44 mg, 555.26 umol) at 20°C. The mixture was stirred at 95OC for 12 hr. The reaction mixture was filtered and then diluted with H20 50 mL and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a crude product. The crude product was triturated with PE (100 ml) at 20 °C for 1 hr. Then was filtered, the filter cake was WO 2024/184461 PCT/EP2024/056026 concentrated under reduced pressure to give the title compound (8 g, 60%) was obtained as a light brown soild. 1H NMR (400 MHz, CDCh) 5 = 7.95 (s, 1H), 7.01 (s, 1H), 6.78 (s, 1H), 4.59 (t, J = 6.5 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 3.59 (q, J = 10.6 Hz, 2H), 3.01 (t, J = 6.5 Hz, 2H), 1.40 - 1.34 (m, 15H), 1.27 (s, 3H). LCMS {Method I. RT = 0.67 min) 480.2(M+H) +׳

[00963] INTERMEDIATE 186:ethyl 8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l -(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate

[00964]To a solution of Intermediate 185 (8 g, 16.69 mmol) and 5-bromo-2-methyl-tetrazole (2.99 g, 18.36 mmol) in dioxane (80 mL) andH2O (40 mL) was added XPHOS-Pd-G2 (656.mg, 834.56 umol) and C82CO3 (16.31 g, 50.07 mmol) at 20°C. The mixture was stirred at 70°C for 3 hr. The reaction mixture was filtered, and then diluted with H2O 30 mL and extracted with DCM (50 mLx2). The combined organic layers were washed with brine (30 mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was triturated with PE (50 ml) at 20 °C for 15 min. Then was filtered, the filter cake was concentrated under reduced pressure to give the title compound (6.3 g, 86%) was obtained as a brown solid. 1H NMR (400 MHz, DMSO-d6) 6 = 8.11 (s, 1H), 7.29 (s, 1H), 6.94 (s, 1H), 4.61 - 4.47 (m, 2H), 4.43 (s, 3H), 4.25 (q, J = 7.0 Hz, 2H), 3.90 (s, 3H), 3.84 - 3.68 (m, 2H), 3.10 (br t, J = 6.1 Hz, 2H), 1.29 (t, J = 7.0 Hz, 3H). LCMS {Method I. RT = 0.54 min) 436.2/437.2 (M+H) +.

WO 2024/184461 PCT/EP2024/056026

[00965] INTERMEDIATE 187:8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l -(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylic acid

[00966]To a solution of Intermediate 186 (6.3 g, 14.47 mmol) inTHF (25 mL), EtOH (mL) and H20 (13 mL) was added KOH (1.62 g, 28.94 mmol) at 20°C. The mixture was stirred at 80°C for 2 hr. The reaction mixture was concentrated under reduced pressure to remove THE and EtOH, diluted with H2O 50 mL and adjusted pH to 3-4, which was filtered and dried under reduced pressure to give a crude product. The title compound (5.7 g, 96%) was obtained as a brown solid. 1H NMR (400 MHz, DMSO-d6) 6 = 12.49 (br s, 1H), 8.10 (s, 1H), 7.29 (s, 1H), 6.93 - 6.86 (m, 1H), 4.56 (br t, J = 6.4 Hz, 2H), 4.43 (s, 3H), 3.89 (s, 3H), 3.81 - 3.67 (m, 2H), 3.08 (br t, J = 6.Hz, 2H), 1.29 - 1.08 (m, 1H). LCMS (Methodi. RT = 0.41 min) 408.2/409.2(M+H) +.

[00967] INTERMEDIATE 188:methyl (S)-4,4,4-trifluoro-2-(8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamido)-2- methylbutanoate

[00968]To a solution of Intermediate 187 (1 g, 2.45 mmol) in DMF (10 mL) was added HATU (1.12 g, 2.95 mmol) and DIEA (1.27 g, 9.82 mmol, 1.71 mL) at 25OC for 3h, then it was added Intermediate 115 (785.81 mg, 3.19 mmol, HC1 salt). The mixture was stirred at 80°C for 9 h. Poured into ice water, added with HC1 to adjust pH=6 and filtered under reduced pressure. The WO 2024/184461 PCT/EP2024/056026 filter cake was dissolved with EtOAc and the organic phase was washed with brine, concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/ EtOAc =1/1). The title compound (920 mg, 65%) was obtained as a brown solid. 1HNMR (400 MHz, DMSO-d6) ppm 8.59 (s, 1 H) 8.07 (s, 1 H) 7.27 (s, 1 H) 7.05 (s, 1 H) 4.49 (br t, J=6.38 Hz, 2 H) 4.43 (s, 3 H) 3.89 (s, 3 H) 3.72 (q, 1=11.17 Hz, 2 H) 3.65 (s, 3 H) 3.15 - 3.29 (m, 1 H) 3.04 (br t, J=6.25 Hz, H) 2.77 - 2.88 (m, 1 H) 2.65 - 2.71 (m, 5 H) 1.57 (s, 3 H). LCMS {Method a. RT = 1.81 min) 575.2/576.2 (M+H) +.

[00969] INTERMEDIATE 189:(S)-4,4,4-trifluoro-2-(8-methoxy-9-(2-methyl-2H-tetrazol- 5-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamido)-2- methylbutanoic acid

[00970]To a solution of Intermediate 188 (100 mg, 174.07 umol) in THE (1 mL) was added TMSOK (44.66 mg, 348.14 umol). The mixture was stirred at 50 °C for 12 hr. The reaction mixture was adjusted to pH=3 with 1M HC1. The aqueous layer was extracted with EtOAc (mLx3). The combined organic phase was washed with brine (5 mLx2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The title compound (60 mg, 61%) was obtained as a white solid. 1HNMR (400 MHz, CDC13) 8 ppm 8.21 (s, 1 H) 6.99 (s, 1 H) 6.70 (d, J=7.46 Hz, 1 H) 4.55 - 4.66 (m, 2 H) 4.46 (s, 3 H) 4.00 (s, 3 H) 3.75 - 3.80 (m, 1 H) 3.57 - 3.(m, 2 H) 3.03 - 3.09 (m, 3 H) 1.78 - 1.85 (m, 3 H) 1.23 - 1.32 (m, 2 H). LCMS {Method I. RT = 0.459 min) 561.3/562.3 (M+H) +.

WO 2024/184461 PCT/EP2024/056026

[00971] INTERMEDIATE 190:(S)-N-(l-amino-4,4,4-trifluoro-2-methyl-l-oxobutan-2-yl)- 8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxamide

[00972]To a solution of Intermediate 189 (60 mg, 107.06 umol) in THF (1 mL) was added CDI (26.04 mg, 160.59 umol) and NHJ.H2O (45.02 mg, 321.17 umol, 49.48 pL, 25% purity). The mixture was stirred at 25°C for 2 hr. The residue was poured into water (10 mL). The aqueous phase was extracted with DCM (5 mLx3). The combined organic phase was washed with brine (10 mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column to give the title compound (42.69 mg, 71%) as a white solid. IHNMR (400 MHz, DMSO-d6) 6 ppm 8.12 (s, 1 H) 8.07 (s, 1 H) 7.48 (br s, 1 H) 7.27 (s, 1 H) 7.14 (br s, 1 H) 6.96 (s, 1 H) 4.46 - 4.54 (m, 2 H) 4.43 (s, 3 H) 3.89 (s, 3 H) 3.72 (q, 1=11.34 Hz, H) 3.18 - 3.29 (m, 1 H) 2.93 - 3.07 (m, 3 H) 1.55 (s, 3 H). LCMS (Methodr. RT = 2.785 min) 560.0/561.0 (M+H) +.

[00973] INTERMEDIATE 191:(S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8-methoxy-9-(2- methyl-2H-tetrazol-5-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carboxamide WO 2024/184461 PCT/EP2024/056026

[00974]To a solution of Intermediate 190 (490 mg, 875.84 pmol) in THE (5 mL) was added burgess reagent (417.43 mg, 1.75 mmol) in DCM (5 mL). The mixture was stirred at 25OC for 12hr. The reaction mixture was partitioned between H20 5 mL and DCM 10 mL. The organic phase was separated, washed with brine 10 mL (5 mL x 2), dried 0verNa2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc=l/l). The title compound (300 mg, 63%) was obtained as a yellow solid. 1HNMR (400 MHz, DMSO-d6) 6 ppm 8.60 - 8.68 (m, 1 H) 8.09 (s, H) 7.29 (s, 1 H) 7.05 (s, 1 H) 4.56 (br t, J=6.25 Hz, 2 H) 4.43 (s, 3 H) 3.89 (s, 3 H) 3.73 (q, 1=11.Hz, 2 H) 3.17 - 3.29 (m, 2 H) 2.99 - 3.13 (m, 3 H) 1.83 (s, 3 H). LCMS (Methodi. RT = 0.51 min) 542.2/543.3 (M+H) +.

[00975] INTERMEDIATE 192:Rel-(R)-3-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l- (2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4- carboxamide

[00976]To a solution of Intermediate 187 (300 mg, 736.47 umol) in DMF (1 mL) was added DIEA (285.55 mg, 2.21 mmol, 384.83 pL) and HATH (308.03 mg, 810.12 umol) at 20°C for 30 min under N2. Then was added Intermediate 10 8 (115.02 mg, 883.77 umol) at 20°C.The mixture was stirred at 40°C for 2 h. The solvent was evaporated and the pH was adjusted to 5-6 with 1M HC1. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (3 mLx3). The combined organic phase was washed with brine (5 mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EtOAc =10/1to EtOAc/MeOH=50/l) to give the title compound (250 mg, 65%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.13 - 8.(m, 1H), 7.35 - 7.23 (m, 2H), 7.07 - 6.97 (m, 1H), 6.60 - 6.54 (m, 1H), 5.38 - 5.32 (m, 1H), 5.21 - -381- WO 2024/184461 PCT/EP2024/056026 .14 (m, 1H), 4.42 (s, 3H), 4.38 - 4.20 (m, 2H), 4.09 (d, J= 8.9 Hz, 1H), 4.06 - 3.99 (m, 1H), 3.(s, 3H), 3.82 (d, J= 8.9 Hz, 1H), 3.79 - 3.66 (m, 3H), 3.10 - 2.97 (m, 2H), 1.99 (s, 1H), 1.91 (s, 1H), 1.52 (s, 2H), 1.43 (s, 1H), 1.17 (t, J= 1A Hz, 1H). LCMS {Method a. RT = 1.3min)5 19.2/520.1 (M+H) +.

[00977] INTERMEDIATE 193:methyl (S)-2-(9-bromo-8-methoxy-l -(2,2,2-trifluoroethyl)- 5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamido)-4,4,4-trifluoro-2-methylbutanoate

[00978]To a solution of 9-bromo-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxylic acid (800 mg, 1.98 mmol) in DMF (8 mL) was added DIEA (1.02 g, 7.92 mmol, 1.38 mL) and HATU (903.12 mg, 2.38 mmol). The mixture was stirred at 25 °C for 3hr . Then was added Intermediate 115 (526.35 mg, 2.38 mmol, HC1 salt) and stirred at 80°C for 9hr. Poured the mixture into ice water, filtered and the solid was collected, dissolved the cake with EtOAc. The combined organic phase was washed with brine (10 mLx2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc=5/l). The title compound (750 mg, 66%) was obtained as a brown solid. 1H NMR (400 MHz, CDCI3) 6 ppm 7.72 (s, 1 H) 6.83 (s, H) 6.65 (s, 1 H) 4.52 - 4.58 (m, 2 H) 3.94 (s, 3 H) 3.86 (s, 3 H) 3.41 - 3.60 (m, 3 H) 2.88 - 3.(m, 3 H) 1.77 (s, 3 H). LCMS {Method a. RT = 2.10 min) 571.1/572.9 (M+H) +

[00979] INTERMEDIATE 194:(S)-2-(9-bromo-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxamido)-4,4,4-trifluoro-2-methylbutanoic acid 9 °VOMe WO 2024/184461 PCT/EP2024/056026

[00980]To a solution of Intermediate 193 (650 mg, 1.14 mmol) in THF (7 mL) was added TMSOK (291.92 mg, 2.28 mmol). The mixture was stirred at 50 °C for 12hr. The reaction mixture was adjusted to pH 5-6 with 1M HC1. The aqueous layer was extracted with EtOAc (mLx3). The combined organic phase was washed with brine (10mLx2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The title compound (550 mg, 86%) was obtained as a white solid. IHNMR (400 MHz, CDC13) 8 ppm 7.72 (s, 1 H) 6.83 (s, 1 H) 6.61 - 6.68 (m, 2 H) 4.55 (br t, J=6.38 Hz, 2 H) 3.92 - 3.95 (m, 3 H) 3.53 (q, 1=10.55 Hz, 2 H) 3.21 - 3.(m, 1 H) 3.06 - 3.19 (m, 1 H) 2.96 (br t, J=6.44 Hz, 2 H) 1.78 - 1.85 (m, 3 H). LCMS (Method a. RT = 1.905 min) 557.2/558.7 (M+H) +.

[00981] INTERMEDIATE 195:(S)-N-(l-amino-4,4,4-trifluoro-2-methyl-l-oxobutan-2-yl)- 9-bromo-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamide

[00982]To a solution of Intermediate 194 (550 mg, 986.94 umol) in THF (6 mL) was added CDI (240.05 mg, 1.48 mmol) at 25OC for 5 min. The mixture was stirred at 25OC for ih. Then it was added NHJ.HO (415.06 mg, 2.96 mmol, 456.11 pL, 25% purity). The mixture was stirred at 25°C for ih. The residue was poured into water (10 mL). The aqueous phase was extracted with EtOAc (5 mLx3). The combined organic phase was washed with brine (10 mLx2), WO 2024/184461 PCT/EP2024/056026 dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The title compound (545 mg, 99%) was obtained as a white solid. IHNMR (400 MHz, DMSO-d6) 6 ppm 8.11 (s, 1 H) 7.74 (s, 1 H) 7.47 (hr s, 1 H) 7.11 - 7.18 (m, 2 H) 6.92 (s, 1 H) 4.43 (hr t, J=6.02 Hz, H) 3.88 (s, 3 H) 3.75 (q, 1=11.25 Hz, 3 H) 3.17 - 3.28 (m, 2 H) 2.88 - 3.02 (m, 4 H) 1.55 (s, H). LCMS (Method a. RT = 1.819 min) 568.1/570.1 (M+H) +

[00983] INTERMEDIATE 196:(S)-9-bromo-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8- methoxy-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamide

[00984]To a solution of Intermediate 195 (450 mg, 808.92 umol) in THF (1 mL) was added burgess reagent (385.54 mg, 1.62 mmol) in DCM (1 mL). The mixture was stirred at °C for ihr. The residue was poured into water (10 mL). The aqueous phase was extracted with DCM (10 mLx3). The combined organic phase was washed with brine (10 mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column to give the title compound (180 mg, 41%) was obtained as a white solid. IHNMR (4MHz, CDCh) 8 ppm 7.71 (s, 1 H) 6.85 (s, 1 H) 6.62 (s, 1 H) 5.98 (s, 1 H) 4.54 - 4.68 (m, 2 H) 3.(s, 3 H) 3.54 (q, 1=10.42 Hz, 2 H) 3.13 - 3.24 (m, 1 H) 3.02 - 3.13 (m, 1 H) 2.98 (t, J=6.44 Hz, H) 1.96 (s, 3 H). LCMS (Method a. RT = 2.032 min) 538.1/540.1 (M+H) +.

[00985] INTERMEDIATE 197:(S)-9-bromo-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8- methoxy-N-methyl-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carboxamide WO 2024/184461 PCT/EP2024/056026

[00986]DMF (10 mL) was charged to the three-necked round bottom flask, then Intermediate 196 (280 mg, 520.18 pmol) was added to the mixture at 25OC for 5min. At 0°C, NaH (31.21 mg, 780.26 pmol, 60% purity) was added to the reaction mixture at 0°C under Ar. Then CH3I (147.mg, 1.04 mmol, 64.77 pL) was added at 0°C under Ar. After the addition, the mixture was stirred at 70°C for 2hr under Ar. The reaction was quenched with NH4C1 (10 mL) under Ar and extracted with EtOAc (15 mL). The organic layer was washed with water (10 mL) and brine (15 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/ EtOAc=l/l). The title compound (230 mg, 80%) was obtained as a white solid. IHNMR (400 MHz, CDCI3) 6 ppm 7.72 (s, 1 H) 6.84 (s, 1 H) 6.53 (s, 1 H) 4.31 (qt, 1=12.62, 6.25 Hz, 2 H) 3.94 (s, 3 H) 3.53 (q, 1=10.47 Hz, 2 H) 3.39 (s, 3 H) 3.22 - 3.33 (m, 1 H) 3.14 - 3.22 (m, 1 H) 2.99 (br t, J=6.48 Hz, 2 H) 2.05 (s, 3 H). LCMS (Method a. RT = 2.10 min) 552.1/554.0 (M+H) +.

[00987] INTERMEDIATE 198:3-ethyl 9-phenyl 8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3,9-dicarboxylate

[00988]To a solution of ethyl 9-bromo-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate (8 g, 18.51 mmol) and phenyl formate (15.57 g, 129.56 mmol, 10.11mL) in DMF (40 mL) was added TEA (13.11 g, 129.56 mmol, 18.

WO 2024/184461 PCT/EP2024/056026 mL) and Pd(dppf)C12. CH2C12 (3.02 g, 3.70 mmol) at 20°C. The mixture was stirred at 120°C for 12 hr. The reaction mixture was extracted with EtOAc (30 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=5/l to 4/1). The title compound (6 g, 68.47%) was obtained as a white solid. 1H NMR (400 MHz, CDCh) 5 = 8.25 (s, 1H), 7.40 - 7.31 (m, 2H), 7.17 (s, 3H), 6.96 - 6.92 (m, 1H), 6.91 - 6.87 (m, 1H), 4.65 - 4.53 (m, 2H), 4.33 - 4.18 (m, 2H), 3.91 (s, 3H), 3.61 - 3.42 (m, 2H), 3.09 - 2.95 (m, 2H), 1.38 - 1.21 (m, 3H). LCMS (Method I. RT = 0.63 min) 474.3/475.2 (M+H) +.

[00989] INTERMEDIATE 199:3-(ethoxycarbonyl)-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxylic acid

[00990]To a solution of Intermediate 198 (5.5 g, 11.62 mmol) in THE (100 mL) was added TMSOK (2.98 g, 23.23 mmol). The mixture was stirred at 20 °C for 2hr. The combined reaction mixture was poured into ice-water (20 mL) and added 1 M HC1 to pH=5-6. The reaction mixture was extracted with EtOAc 60 mL (20mL x3). The combined organic layers were washed with brine 60mL (30mL x2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The title compound (4 g, 86%) was obtained as a white solid. 1H NMR (4MHz, CDCh) 8 = 10.57 - 10.42 (m, 1H), 8.32 (s, 1H), 7.19 (s, 1H), 7.02 - 6.83 (m, 2H), 4.66 - 4.50 (m, 2H), 4.31 - 4.19 (m, 2H), 4.05 (s, 3H), 3.62 - 3.48 (m, 2H), 2.99 (s, 2H), 1.35 - 1.24 (m, 3H). LCMS (Method g. RT = 0.505 min) 398.1/399.1 (M+H) +.

[00991] INTERMEDIATE 200:ethyl 9-(2-(tert-butoxycarbonyl)hydrazine-l-carbonyl)-8- methoxy-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate WO 2024/184461 PCT/EP2024/056026 BocHN

[00992]To a solution of Intermediate 199 (1 g, 2.52 mmol) in DMF (10 mL) was added HATU (1.15 g, 3.02 mmol), DIEA (1.30 g, 10.07 mmol, 1.75 mL) and tert-butyl N-aminocarbamate (432.39 mg, 3.27 mmol). The mixture was stirred at 20 °C for 1b. The reaction mixture was added to the ice water, white solid appeared, then filtered. The filter cake was dissolved with 30 mL EtOAc and washed with brine (30 mL x 3), the organic phase was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The title compound (1.2 g, 93%) was obtained as a white solid. 1H NMR (400 MHz, CDCI3) 6 ppm 9.51 (br s, 1H), 8.47 (s, 1H), 7.02 (s, 1H), 6.92 (s, 2H), 4.62 (t, J= 6.50 Hz, 2H), 4.31 (q, J= 7.13 Hz, 2H), 4.05 (s, 3H), 3.63 (q,J= 10.59 Hz, 2H), 3.05 (t,J= 6.44 Hz, 2H), 1.52 (s,9H), 1.38 (t,J= 7.07 Hz, 3H). LCMS (Method I. RT = 0.550 min) 456.2 (M-t-Bu) +.

[00993] INTERMEDIATE 201:ethyl 9-(hydrazinecarbonyl)-8-methoxy-l -(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate

[00994]To a solution of Intermediate 200 (1.26 g, 2.46 mmol) in DCM (15 mL) was added HCl/EtOAc (4M, 15 mL) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude was dissolved in mL EtOAc and 10 mL THE, the solution was washed with sat. NaHCO3 to pH = 9. The organic phase was washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The title compound (950 mg, 93%) was obtained as a -387- WO 2024/184461 PCT/EP2024/056026 yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 9.26 (br s, 1H), 8.00 (s, 1H), 7.18 (s, 1H), 6.92 (s, 1H), 4.46 - 4.63 (m, 4H), 4.24 (q, J = 7.05 Hz, 2H), 3.91 (s, 3H), 3.74 (q, J = 11.09 Hz, 2H), 3.05 (br t, J = 6.31 Hz, 2H), 1.29 (t, J = 7.05 Hz, 3H). LCMS (Method I. RT = 0.424 min) 412.2 (M+H) +.

[00995] INTERMEDIATE 202:ethyl 8-methoxy-9-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2- yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate

[00996]To a solution of Intermediate 201 (700 mg, 1.70 mmol) in DCM (7 mL) was added CDI (358.69 mg, 2.21 mmol). The mixture was stirred at 20°C for 2hr. The reaction mixture was washed with H20 (20 mL x 2), washed with brine (30 mL), the combined organic phase was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The title compound (720 mg, 96%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 12.51 (br s, 1H), 7.90 (s, 1H), 7.29 (s, 1H), 6.93 (s, 1H), 4.46 - 4.63 (m, 2H), 4.24 (q, J= 7.09 Hz, 2H), 3.92 (s, 3H), 3.77 (q, J= 11.09 Hz, 2H), 2.98 -3.18 (m, 2H), 1.19-1.(m, 3H). LCMS (Method I. RT = 0.511 min) 438.2 (M+H) +.

[00997] INTERMEDIATE 203:8-methoxy-9-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-l- (2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylic acid WO 2024/184461 PCT/EP2024/056026

[00998]To a solution of Intermediate 202 (2.2 g, 4.64 mmol, HC1 salt) in THF (20 mL) and EtOH (20 mL) was added LiOH.H2O (584.51 mg, 13.93 mmol) and H20 (20 mL) at 20°C. The mixture was stirred at 50°C for 8 hr. The reaction mixture was added to 10 mL ice water and 0.2N HCI was added to adjust pH=3-4, then suspension was filtered to give a residue. The title compound (1.85 g, crude) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 12.27 - 12.72 (m, 2H), 7.84 - 7.93 (m, 1H), 7.28 (s, 1H), 6.88 (s, 1H), 4.55 (hr t, J = 6.32 Hz, 2H), 3.92 (s, 3H), 3.75 (q, J = 11.17 Hz, 2H), 3.07 (hr t, J = 6.26 Hz, 2H). LCMS {Method I. RT = 0.385 min) 410.1 (M+H) +.

[00999] INTERMEDIATE 204:methyl (S)-4,4,4-trifluoro-2-(8-methoxy-9-(5-oxo-4,5- dihydro-l,3,4-oxadiazol-2-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carboxamido)-2-methylbutanoate

[001000]To a solution of Intermediate 203 (230 mg, 561.91 umol) in DMF (2.3 mL) was added HATU (256.39 mg, 674.30 umol) and DIEA (290.49 mg, 2.25 mmol, 391.50 pL) at 20 °C for 2h. Intermediate 115 (161.88 mg, 730.49 umol, HCI salt) was added to the reaction mixture at 20 °C and the mixture was stirred at 80 °C for 6 hr. The reaction mixture was added to ice water and adjust pH = 3-4 by IM HCI, then the suspension was extracted with EtOAc (15 mLx3), the combined organic phase was washed with brine (10 mLx5), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/ EtOAc = 100/1 to 1/1). The title compound (133 mg, 41%) was obtained as a brown solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 12.50 (br s, 1H), 8.60 (s, 1H), 7.86 (s, 1H), 7.27 (s, 1H), 7.04 (s, 1H), 4.47 (brt, J = 6.32 Hz, 2H),3.91 (s,3H),3.74 (q,J= 11.Hz, 2H), 3.64 (s, 3H), 3.18 - 3.26 (m, 1H), 3.03 (brt, J = 6.19 Hz, 2H), 2.79 - 2.90 (m, 1H), 1.(s, 3H). LCMS {Method o. RT =1.561 min) 577.2 (M+H) +.

WO 2024/184461 PCT/EP2024/056026

[001001] INTERMEDIATE 205:(S)-4,4,4-trifluoro-2-(8-methoxy-9-(5-oxo-4,5-dihydro- l,3,4-oxadiazol-2-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamido)-2-methylbutanoic acid

[001002]To a solution of Intermediate 204 (350 mg, 607.17 pmoljinTHF (3.5 mL) was added TMSOK (155.78 mg, 1.21 mmol) at 20°C. The mixture was stirred at 50°C for 2 hr. Then TMSOK (38.95 mg, 303.59 umol) was added and stirred at 50°C for 0.5 hr. The reaction mixture was added to the ice water, IM HC1 was added to adjust pH = 3-4. The reaction mixture was extracted with EtOAc (5 mLx3). The combined organic layers were washed with brine (mLx3), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The title compound (300 mg, 87%) was obtained as a brown solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 12.61 - 13.06 (m, 1H), 12.50 (s, 1H), 8.31 - 8.48 (m, 1H), 7.86 (s, 1H), 7.26 (s, 1H), 7.02 (s, 1H), 4.50 (quin, J = 7.21 Hz, 2H), 3.91 (s, 3H), 3.73 (q, J = 11.25 Hz, 2H), 3.19 - 3.26 (m, 1H), 2.99 - 3.07 (m, 2H), 2.77 - 2.88 (m, 1H), 1.56 (s, 3H). LCMS (Methode. RT = 0.4min) 563.1 (M+H) +.

[001003] INTERMEDIATE 206:(S)-N-(l-amino-4,4,4-trifluoro-2-methyl-l-oxobutan-2-yl)- 8-methoxy-9-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxamide /0. /X WO 2024/184461 PCT/EP2024/056026

[001004]To a solution of Intermediate 205 (280 mg, 497.85 pmoljinTHF (2.9 mL) was added CDI (121.09 mg, 746.78 pmol) at 20 °C and stirred for 2 hr. Then NHJ.HO (209.37 mg, 1.49 mmol, 230.08 pL, 25% purity) was added and stirred at 20 °C for 30 min. The reaction mixture was poured into 5 mL water and 0.2 M HCI was added to the reaction mixture to adjust pH= 6-7. The aqueous phase was extracted with DCM (10 mLx3). The combined organic phase was washed with brine 20 mL, dried with anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The title compound (230 mg, 82%) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 12.29 - 12.65 (m, 1H), 8.07 - 8.20 (m, 1H), 7.87 (s, 1H), 7.47 (br s, 1H), 7.26 (s, 1H), 7.11 - 7.18 (m, 1H), 6.95 (s, 1H), 4.41 - 4.54 (m, 2H), 3.89 - 3.94 (m, 3H), 3.64 - 3.78 (m, 2H), 3.25 (br dd, J = 15.56, 12.34 Hz, 1H), 3.02 (br d, J = 3.58 Hz, 2H), 2.92 - 2.99 (m, 1H), 1.55 (s, 3H). LCMS (Method e. RT = 0.417 min) 562.0 (M+H) +.

[001005] INTERMEDIATE 207:(S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8-methoxy-9-(5- oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamide

[001006]To a solution of Intermediate 206 (95 mg, 169.21 pmol in pyridine (1.9 mL) was added TFAA (284.32 mg, 1.35 mmol, 188.16 pL). The mixture was stirred at 20°C for 8 hr. The reaction mixture was added to ice water and I M HCI was added to adjust pH = 2-3. The suspension was extracted with EtOAc (15 mL x 3) and washed with 20 mL brine, then the organic phase was concentrated under reduced pressure to give a residue. The residue was dissolved in MeOH (2 mL) and K2CO3 (28.06 mg, 203.05 pmol) was added to the reaction mixture, the suspension was stirred at 20°C for 6 hr. The suspension was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/ EtOAc =1/0 to 0/1). The title compound (110 mg, 59%) was obtained as a white WO 2024/184461 PCT/EP2024/056026 solid (2 batches in total). 1H NMR (400 MHz, DMSO-d6) 8 ppm 12.51 (br s, 1H), 8.65 (s, 1H), 7.88 (s, 1H), 7.29 (s, 1H), 7.05 (s, 1H), 4.54 (br t, J = 6.32 Hz, 2H), 3.92 (s, 3H), 3.75 (q, J = 11.Hz, 2H), 3.16 - 3.29 (m, 2H), 3.06 (br t, J = 6.19 Hz, 2H), 1.82 (s, 3H). LCMS {Method g. RT = 0.489 min) 544.2 (M+H) +.

[001007] INTERMEDIATE 208:(R)-l-(9-bromo-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carboxamide

[001008]To a solution of 9-bromo-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxylic acid (1.6 g, 3.96 mmol) and Intermediate 124 (715.44 mg, 4.75 mmol, HC1 salt) in DMF (16 mL) was added with HATU (1.66 g, 4.35 mmol) and DIEA (2.05 g, 15.mmol, 2.76 mL, 4 eq). The mixture was stirred at 25OC for 1 hr under N2 atmosphere. The mixture was poured into ice-water (50 mL). Filtered and filter cake was dissolved with EtOAc (50 mL), the organic phase was washed with brine (20 mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The title compound (1.88 g, 94%) was obtained as a white solid. 1HNMR (400 MHz, DMSO-d6) 8 = 7.76 (s, 1H), 7.55 (br s, 1H), 7.19 (br s, 1H), 7.16 (s, 1H), 6.67 (br s, 1H), 4.53 - 4.34 (m, 2H), 4.29 (br s, 2H), 3.88 (s, 3H), 3.75 (q, J = 11.2 Hz, 2H), 2.94 (br t, J = 6.4 Hz, 2H), 2.48 - 2.38 (m, 1H), 2.12 - 2.00 (m, 1H), 1.67 (br s, 3H). LCMS {Method a. ES+, RT = 1.74 min) 500.3/502.0 (M+H) +

[001009] INTERMEDIATE 209:(R)-l-(9-bromo-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile WO 2024/184461 PCT/EP2024/056026

[001010]To a solution of Intermediate 208 (1.6 g, 3.20 mmol) in THF (16 mL) was added with Burgess reagent (1.52 g, 6.40 mmol) in DCM (16 mL). The mixture was stirred at 25°C for 2 hr under N2 atmosphere. The mixture was added with 10 mL H2O. The organic layer was washed with brine 5 mL and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/ EtOAc =100/1 to 5/1). The title compound (1.5 g, 97.25%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 = 7.79 (s, 1H), 7.18 (s, 1H), 6.70 (s, 1H), 4.54 - 4.42 (m, 2H), 4.39 (br t, J = 7.5 Hz, 2H), 3.89 (s, 3H), 3.83 - 3.71 (m, 2H), 2.97 (br t, J = 6.4 Hz, 2H), 2.78 - 2.69 (m, 1H), 2.47 - 2.38 (m, 1H),1.81 (s, 3H). LCMS (Method a. ES+, RT =1.99 min) 482.2/484.1 (M+H) +

[001011] INTERMEDIATE 210:phenyl (R)-3-(2-cyano-2-methylazetidine-l-carbonyl)-8- methoxy-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxylate

[001012]To a solution of Intermediate 209 (500 mg, 1.04 mmol) and phenyl formate (1.14 g, 9.33 mmol,) in DMF (5 mL) was added with TEA (944.15 mg, 9.33 mmol) and Pd(dppf)C12.CH2C12 (253.99 mg, 311.01 umol). The mixture was stirred at 120°C for 12 hr under N2 atmosphere. The mixture was poured into water (10 mL). The aqueous phase was extracted with EtOAc (10 mLx3). The combined organic phase was washed with brine (10 mLx2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/ EtOAc =10/1 to 1/1). The title compound (450 mg, 82%) was obtained as a brown solid. 1H NMR (400 MHz, DMSO-d6) 6 = 8.22 (s, 1H), 7.51 - 7.44 (m, 2H), 7.34 - 7.28 (m, 2H), 7.25 (d, J = 7.6 Hz, 2H), 6.73 (s, 1H), 4.(brt, J = 6.1 Hz, 2H), 4.41 (brt, J = 7.2 Hz, 2H), 3.93 (s, 3H), 3.78 (q, J = 11.1 Hz, 2H), 3.09 (br t, J = 6.3 Hz, 2H), 2.80 - 2.70 (m, 1H), 2.48 - 2.39 (m, 1H), 1.82 (s, 3H). LCMS (Method a. ES+, RT = 1.99 min) 524.4 (M+H) + WO 2024/184461 PCT/EP2024/056026

[001013] INTERMEDIATE 211:(R)-3-(2-cyano-2-methylazetidine-l-carbonyl)-8-methoxy- l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxylic acid

[001014]To a solution of Intermediate 210 (200 mg, 382.04 umol) in THF (4 mL) was added with TMSOK (98.02 mg, 764.08 umol). The mixture was stirred at 15°C for 3 hr under Natmosphere. The reaction mixture was added with H20 (5 mL) and extracted with MTBE (5 mL). The aqueous phase was acidified with 1 N HC1 to pH = 2 and extracted with EtOAc (5 mLx3). The organic layers were washed with 5 mL brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The title compound (150 mg, 87.76%) was obtained as a white solid. 1HNMR (400 MHz, DMSO-d6) 6 = 12.61 (br s, 1H), 9.31 (s, 1H), 7.97 (s, 1H), 7.- 7.12 (m, 3H), 6.78 - 6.69 (m, 4H), 5.75 (s, 1H), 4.50 (brt, J = 6.6 Hz, 2H), 4.39 (brt, J = 8.1 Hz, 2H), 3.86 (s, 3H), 3.72 (q, J = 11.0 Hz, 2H), 3.03 (br t, J = 6.4 Hz, 2H), 2.79 - 2.68 (m, 1H), 2.- 2.39 (m, 1H), 1.81 (s, 3H). LCMS {Method a. ES+, RT = 1.49 min) 448.3 (M+H) +

[001015] INTERMEDIATE 212:2-(4-bromo-3-methoxyphenyl)ethan-l-amine (HC1 salt)

[001016]A solution of Intermediate 2 (225 g, 977.83 mmol, 1 eq) in HCl/EtOAc (2 M, 2.25 L) was stirred at 20 °C for 1 h. The mixture was filtered, the filter cake was dried under reduced pressure to give the title compound (220 g, 825.32 mmol, 84.40% yield, 100% purity, HC1)) as a white solid. 1H NMR (400 MHz, DMSO-do) 6 = 8.06 (br s, 3H), 7.50 (d, J= 8.0 Hz, 1H), 7.04 (d, J= 1.7 Hz, 1H), 6.79 (dd, J= 1.8, 8.0 Hz, 1H), 3.85 (s, 3H), 3.04 (br s, 2H), 2.93 - 2.84 (m, 2H).

WO 2024/184461 PCT/EP2024/056026

[001017] INTERMEDIATE 213:N-(4-bromo-3-methoxyphenethyl)-2-(4-fluorophenyl)-2- formamidoacetamide

[001018]To a solution of Intermediate 4 (24 g, 99.96 mmol)inMeOH (240 mL) was added HCOONH4 (12.61 g, 199.92 mmol) and 4-fluorobenzaldehyde (13.03 g, 104.96 mmol, 11.04 mL) at 20°C. The mixture was stirred at 80°C for 4 hr. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H20 (1mL) and extracted with EtOAc (200 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The crude product was triturated by MTBE (100 mL) and filtered to give the title compound (51 g, 124.62 mmol, 62.33% yield) as a pink solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.84 (br d, J = 7.7 Hz, 1H), 8.40 (br t, J = 5.3 Hz, 1H), 8.03 (s, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.33 (dd, 5.6, 8.6 Hz, 2H), 7.13 (t, J= 8.9 Hz, 2H), 6.89 (d,J= 1.7 Hz, 1H), 6.(dd, J= 1.7, 8.0 Hz, 1H), 5.46 (d, J = 8.2 Hz, 1H), 3.77 (s, 3H), 3.40 - 3.34 (m, 1H), 3.32 - 3.(m, 1H), 2.67 (t, J= 6.8 Hz, 2H). LCMS {Methodi. ES+, RT = 0.629 min) 431.1/433.1 (M+H) +

[001019] INTERMEDIATE 214:9-bromo-l-(4-fluorophenyl)-8-methoxy-5,6- dihydroimidazo[5, 1 -a] isoquinoline

[001020]A solution of P205 (44.22 g, 311.55 mmol, 19.23 mL) in methanesulfonic Acid (2mL) was stirred at 75°C for 0.5 hour. The mixture was added Intermediate 213 (25.5 g, 62.

WO 2024/184461 PCT/EP2024/056026 mmol) at 75°C and the mixture was stirred at 75°C for 1.5 hour. The reaction was cooled and poured into cold Na2CO3 solution (500 mL) slowly to adjust pH = 8 and extracted with EtOAc (300 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The crude product was triturated with MTBE (150 mL) at 20 °C to give the title compound (42 g, 90.30%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 = 7.79 (s, 1H), 7.- 7.56 (m, 2H), 7.49 (s, 1H), 7.30 - 7.22 (m, 2H), 7.18 (s, 1H), 4.15 (t, J = 6.4 Hz, 2H), 3.87 (s, 3H), 3.07 (t, J= 6.4 Hz, 2H). LCMS (Method d. ES+, RT = 0.553 min) 373.1/375.1 (M+H) +

[001021] INTERMEDIATE 215:l-(4-fluorophenyl)-8-methoxy-9-(l-methyl-lH-pyrazol-3- yl)-5,6-dihydroimidazo[5,l-a]isoquinoline

[001022]To a solution of Intermediate 214 (500 mg, 1.34 mmol) and l-methyl-3-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrazole (334.49 mg, 1.61 mmol) in dioxane (mL) and H20 (1 mL) was added XPHOS-Pd-G2 (105.41 mg, 133.97 umol) and C82CO3 (1.75 g, 5.36 mmol) at 20°C. The mixture was stirred at 100°C for 2 hr. The reaction mixture was diluted with H20 (8 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (4 mL) at 20°C for 15 min to give the title compound (1.5 g, 74.76%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.09 (s, 1H), 7.76 (s, 1H), 7.70 - 7.60 (m, 3H), 7.27 - 7.17 (m, 2H), 7.10 (s, 1H), 6.59 (d,J=2.1 Hz, 1H), 4.(t, J= 6.4 Hz, 2H), 3.92 - 3.84 (m, 3H), 3.76 (s, 3H), 3.09 (t, J= 6.3 Hz, 2H). LCMS (Method a. ES+, RT =1.146 min) 375.3/376.3 (M+H) + WO 2024/184461 PCT/EP2024/056026

[001023] INTERMEDIATE 216:ethyl l-(4-fluorophenyl)-8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxylate

[001024]To a solution of Intermediate 215 (400mg, 1.07 mmol) in THF (5 mL) was added n- BuLi (2.5 M, 512.81 pL) at -60°C. The mixture was added ethyl formate (395.71 mg, 5.34 mmol, 429.65 pL) at -60°C and the mixture was stirred at -60°C for 2 hrs. The mixture was added H(3 mL) and extracted with EtOAc (5 mL x 3). The organic layers were concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 1/1) to give the title compound (310 mg, 32%) as a yellow solid. 1H NMR (400 MHz, CDC13) 8 = 8.00 (s, 1H), 7.76 - 7.67 (m, 2H), 7.32 (d, J= 2.1 Hz, 1H), 7.10 (t, J = 8.8 Hz, 2H), 6.88 (s, 1H), 6.54 (d, J= 2.1 Hz, 1H), 4.73 (t, J= 6.6 Hz, 2H), 4.48 (q, J = 7.0 Hz, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.15 (t, J = 6.6 Hz, 2H), 1.46 (t, J= 1A Hz, 3H). LCMS (Method g. ES+, RT = 0.480 min) 447.1/448.1 (M+H)

[001025] INTERMEDIATE 217:l-(4-fluorophenyl)-8-methoxy-9-(l-methyl-lH-pyrazol-3- yl)-5,6-dihydroimidazo[5,l-a]isoquino line-3-carboxylic acid

[001026]To a solution of Intermediate 216 (150 mg, 335.97 pmol) in THF (1 mL) was addedTMSOK (86.20 mg, 671.93 pmol) at 20°C. The mixture was stirred at 20 °C for 2 hr. The reaction WO 2024/184461 PCT/EP2024/056026 mixture was concentrated under reduced pressure to give the title compound (281 mg, crude) as a yellow solid. LCMS (Method g. ES+, RT = 0.347 min) 419.3/420.1 (M+H)

[001027] INTERMEDIATE 218:(R)-l-(l-(4-fluorophenyl)-8-methoxy-9-(l-methyl- 1H-pyrazol-3-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carboxamide

[001028]To a solution of Intermediate 217 (140 mg, 334.59 umol) and (2R)-2- methylpyrrolidine-2-carboxamide (66.10 mg, 401.51 umol, HC1) in DMF (1 mL) was added HATU (139.94 mg, 368.05 umol) and DIEA (129.73 mg, 1.00 mmol, 174.84 pL) at 20°C. The mixture was stirred at 20°C for 1 hr. The mixture was diluted with H20 (5 mL) and extracted with EtOAc (2 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The crude product was washed by MTBE (5 mL) to give the the title compound (110 mg, 62.20%) as a white solid. 1H NMR (400 MHz, CDCh) 5 = 8.07 (s, 1H), 7.75 (br dd, J = 5.8, 7.Hz, 2H), 7.33 (d, J= 2.3 Hz, 1H), 7.15 (br t, J= 8.7 Hz, 3H), 6.91 - 6.87 (m, 1H), 6.58 (d, J= 2.Hz, 1H), 4.66 - 4.50 (m, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.22 (s, 2H), 3.15 (br t, J= 5.8 Hz, 3H), 2.56 - 2.41 (m, 1H), 2.21 - 1.90 (m, 4H). LCMS (Method g. ES+, RT = 0.435 min) 529.2/530.(M+H)

[001029] INTERMEDIATE 219:(R)-l-(l-(4-fluorophenyl)-8-methoxy-9-(l-methyl- 1H- pyrazol-3-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carboxamide N، NH2 WO 2024/184461 PCT/EP2024/056026

[001030]To a solution of Intermediate 217 (140 mg, 334.59 pmol) and Intermediate 124 (60.mg, 401.51 pmol, HCI) in DMF (I mL) was added HATU (139.94 mg, 368.05 pmol) and DIEA (129.73 mg, 1.00 mmol, 174.84 pL) at 20°C. The mixture was stirred at 20°C for 1 hr. The mixture was diluted with H20 (5 mL) and extracted with EtOAc (2 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The crude product was washed by MTBE (5 mL) to give the title compound (70 mg, 40.66%) as a white solid. 1H NMR (400 MHz, CDCh) 8 = 8.28 (hr s, 1H), 8.08 (s, 1H), 7.72 (dd, J= 5.6, 8.6 Hz, 2H), 7.34 (d, J = 2.1 Hz, 1H), 7.15 - 7.06 (m, 2H), 6.92 - 6.86 (m, 1H), 6.60 - 6.53 (m, 1H), 5.40 (hr s, 1H), 4.81 - 4.70 (m, 2H), 4.62 (dt, J= 5.8, 10.2 Hz, 1H), 3.98 - 3.91 (m, 3H), 3.91 - 3.83 (m, 3H), 3.22 (s, 1H), 3.20 - 3.(m, 3H), 2.22 -2.13 (m, 1H), 1.20 (s, 3H). LCMS (Method g. ES+, RT = 0.458 min) 515.2/516.(M+H)

[001031] INTERMEDIATE 220:(l-(4-fluorophenyl)-8-methoxy-5,6-dihydroimidazo[5,l- a]isoquinolin-9-yl)boronic acid

[001032]To a solution of Intermediate 214 (2.5 g, 6.70 mmol) in EtOH (25 mL) was added hypoboric acid (1.80 g, 20.10 mmol) DIEA (4.33 g, 33.49 mmol, 5.83 mL) and Pd(dtbpf)C(218.29 mg, 334.92 pmol). The mixture was stirred at 60 °C for 6 hr. The reaction solution was used directly in next step. LCMS (Method a. ES+, RT = 0.959 min) 339.3 (M+H) WO 2024/184461 PCT/EP2024/056026

[001033] INTERMEDIATE 221:l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline

[001034]To a solution of Intermediate 220 (a solution from the previous step), 5-bromo-2- methyl-tetrazole (697.90 mg, 4.28 mmol) in H20 (0.3 mL) was added XPHOS-Pd-G2 (126.35 mg, 160.58 umol) and C82CO3 (5.23 g, 16.06 mmol). The mixture was stirred at 70 °C for 3 hr. The residue was poured into water (10 mL). The aqueous phase was extracted with DCM (5 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, EA: MeOH =20/1 to 5/1) to give the title compound (850 mg, 42.19%) as a white solid. 1H NMR (400 MHz, CDCh) 8 = 8.16 (s, 1H), 7.74 - 7.63 (m, 3H), 7.09 (t, J= 8.Hz, 2H), 6.97 (s, 1H), 4.38 (s, 3H), 4.21 (br t, J= 5.9 Hz, 2H), 3.97 (s, 3H), 3.19 (br t, J= 5.6 Hz, 2H). LCMS (Method e. ES+, RT = 0.305 min) 377.1/378.1 (M+H)

[001035] INTERMEDIATE 222:ethyl l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxylate

[001036]THF (75 mL) was charged to the 100 mL three-necked round bottom flask, then Intermediate 221 (1.3 g, 3.45 mmol) was added at 20°C n. At -65 °C inner temperature, n-BuLi (2.5 M, 2.76 mL) was added dropwise to the reaction mixture at -65°C. After the addition, the WO 2024/184461 PCT/EP2024/056026 mixture was stirred at -65°C for 1 hr. At -65 °C inner temperature, ethyl chloroformate (1.93 g, 17.78 mmol, 1.70 mL) was added dropwise to the reaction mixture at -65°C. After the addition, the mixture was stirred at -65°C for 0.5 hr, then the mixture was stirred at 0°C for 3.5 hr. The residue was poured into ice water (30 mL) at 0°C. The aqueous phase was extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate= 100/1 to 10/1) to give title compound (310 mg, 32.50%) was obtained as a yellow solid. 1H NMR (400 MHz, CDC13) 8 = 8.06 (s, 1H), 7.72 - 7.64 (m, 2H), 7.14 - 7.05 (m, 2H), 6.99 (s, 1H), 4.75 (t, J = 6.6 Hz, 2H), 4.(q, J= 7.1 Hz, 2H), 4.37 (s, 3H), 3.98 (s, 3H), 3.20 (t, J = 6.6 Hz, 2H), 1.46 (t, J = 1A Hz, 3H). LCMS (Method a. ES+, RT = 1.543 min) 449.3/450.3 (M+H)

[001037] INTERMEDIATE 223:l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5- yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxylic acid

[001038]To a solution of Intermediate 222 (110 mg, 245.29 umol) in THE (2 mL) was added TMSOK (62.94 mg, 490.58 umol) at 20°C. The mixture was stirred at 20°C for l h. The mixture was concentrated in vacuo to give title compound (100 mg, crude) as a brown solid. LCMS (Methode. ES+, RT = 0.494 min) 421.1/422.1 (M+H)

[001039] INTERMEDIATE 224:(R)-l-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carboxamide WO 2024/184461 PCT/EP2024/056026

[001040]To a solution of Intermediate 223 (180 mg, 428.17 pmol) in DMF (2 mL) was added HATU (211.64 mg, 556.62 pmol), (2R)-2-methylpyrrolidine-2-carboxamide(98.69 mg, 599.44 pmol, HC1) and DIEA (221.35 mg, 1.71 mmol, 298.32 pL) at 20°C. The mixture was stirred at 20 °C for 2 hr. The reaction mixture was diluted with H20 (20 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (180 mg, crude) as a white solid. LCMS (Method e. ES+, RT = 0.387 min) 531.1/532.1 (M+H)+.

[001041] INTERMEDIATE 225:(R)-l-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carboxamide

[001042]To a solution of Intermediate 223 (185 mg, 440.06 pmol) in DMF (3 mL) was added Intermediate 124 (79.53 mg, 528.07 pmol, HC1), HATU (184.06 mg, 484.07 pmol) DIEA (227.mg, 1.76 mmol, 306.60 pL) at 20°C. The mixture was stirred at 20°C for 4 h. Then another batch Intermediate 124 (19.88 mg, 132.02 pmol, HC1), HATU (50.20 mg, 132.02 pmol), DIEA (56.mg, 440.06 pmol, 76.65 pL) at 20°C and stirred at 80°C for 12 h. The residue was poured into water (5 mL), adjusted to pH 5-6 with 1M HC1, filtered, the solid was dissolved in EtOAc (10 mL) and washed with brine (10 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under WO 2024/184461 PCT/EP2024/056026 reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/O to 0/1) to give the title compound (140 mg, 61.59%) as a white solid. 1H NMR (400 MHz, CDCh) 8 = 8.28 - 8.22 (m, 1H), 8.18 - 8.13 (m, 1H), 7.76 - 7.65 (m, 2H), 7.14 - 7.06 (m, 2H), 7.01 - 6.98 (m, 1H), 5.42 - 5.34 (m, 1H), 4.84 - 4.73 (m, 3H), 4.70 - 4.59 (m, 1H), 4.40 - 4.35 (m, 3H), 4.02 - 3.96 (m, 3H), 3.23 - 3.15 (m, 2H), 2.99 - 2.86 (m, 1H), 2.25 - 2.13 (m, 1H), 1.96 - 1.89 (m, 3H). LCMS (Method a. ES+, RT = 1.464 min) 517.4/518.4 (M+H)

[001043] INTERMEDIATE 226:(R)-l-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carboxamide

[001044]To a solution of Intermediate 220 (a solution from previous step), 3-bromopyridine-2- carbonitrile (1.35 g, 7.38 mmol, 1.1 eq) in H20 (10 mL) was added XPHOS-Pd-G2 (158.46 mg, 201.40 umol, 0.03 eq) and C82C03 (6.56 g, 20.14 mmol, 3 eq). The mixture was stirred at 70 °C for 3 hr .The residue was poured into water (10 mL). The aqueous phase was extracted with DCM (5 mL x 3).The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM/MeOH=l/0 to 0/1) to give the title compound (1.9 g, 71.40%) as a white solid. 1H NMR (400 MHz, CDCh) 8 = 8.64 (dd, J= 1.6, 4.6 Hz, 1H), 7.72 (dd, J= 5.4, 8.Hz, 2H), 7.64 - 7.60 (m, 1H), 7.58 (s, 1H), 7.53 - 7.47 (m, 1H), 7.44 (s, 1H), 7.09 (t, J = 8.8 Hz, 3H), 6.97 - 6.93 (m, 1H), 4.20 (t, J = 6.4 Hz, 2H), 3.87 (s, 3H), 3.20 (t, J = 6.3 Hz, 2H). LCMS (Method h. ES+, RT = 1.831 min) 397.2/398.2 (M+H) WO 2024/184461 PCT/EP2024/056026

[001045] INTERMEDIATE 227:ethyl 9-(2-cyanopyridin-3-yl)-l-(4-fluorophenyl)-8-methoxy-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carboxylate

[001046]THF (40 mL) was charged to the 100 mL three-necked round bottom flask, then Intermediate 226 (1.2 g, 3.03 mmol) was added at 25°C. Then LDA (2 M, 4.54 mL) was added dropwise to the reaction mixture at -60°C. The mixture was stirred at -60°C for 30 min. At -60°C, ethyl chloroformate (1.64 g, 15.14 mmol, 1.45 mL) was added dropwise to the reaction mixture at -60°C. After the addition, the mixture was stirred at -60°C for 30 min. After 1 hr, the reaction mixture was added to ice-water. The mixture was extracted by DCM (20 mL x 2). Then organic phase was washed by H20 (20 mL x 3), brine (20 mL). The organic layers were dried over Na2S04, filtered. The organic phase was concentrated under reduced pressure at 40°C to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/0 to 0/1) to give the title compound (600 mg, 42.31%) as a white solid. 1H NMR (400 MHz, CDCI3) = 8.64 (d, J= 4.5 Hz, 1H), 7.70 (dd, J= 5.7, 7.8 Hz, 2H), 7.60 - 7.55 (m, 1H), 7.52 - 7.47 (m, 1H), 7.35 (s, 1H), 7.09 (t, J = 8.6 Hz, 2H), 6.98 (s, 1H), 4.76 (t, J = 6.5 Hz, 2H), 4.49 (q, J = 7.0 Hz, 2H), 3.89 (s, 3H), 3.21 (brt, J= 6.5 Hz, 2H), 1.46 (t, J= 1A Hz, 3H). LCMS (Methodh. ES+, RT = 2.077 min) 469.2/470.2 (M+H) WO 2024/184461 PCT/EP2024/056026

[001047] INTERMEDIATE 228:9-(2-cyanopyridin-3-yl)-l-(4-fluorophenyl)-8-methoxy-5,6- dihydroimidazo[5, 1 -a]isoquinoline-3-carboxylic acid

[001048]To a solution of Intermediate 227 (150 mg, 320.19 umol) in THF (1.5 mL) was added TMSOK(82.15 mg, 640.37 umol). The mixture was stirred at 25 °C for 2 hr. The reaction solution was concentrated under reduced pressure to give the title compound (141 mg, crude) as a brown solid. LCMS (Method h. ES+, RT =1.431 min) 441.1/442.1 (M+H)

[001049] INTERMEDIATE 229:(R)-l-(9-(2-cyanopyridin-3-yl)-l-(4-fluorophenyl)-8- methoxy-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carboxamide

[001050]To a solution of Intermediate 228 (235 mg, 533.58 umol) and (2R)-2- methylpyrrolidine-2-carboxamide (105.41 mg, 640.29 umol, HC1) in DMF (2.5 mL) was added HATU (223.17 mg, 586.93 umol) and DIEA (275.84 mg, 2.13 mmol, 371.76 uL). The mixture was stirred at 25 °C for 1 hr. Pour the mixture into ice water, filtered and the solid was dissolved with EA. The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (250 mg, 85.10%) as a white solid. 1H NMR (400 MHz, CDCI3) 6 = 8.64 (dd, J = 1.6, 4.8 Hz, 1H), 7.74 - WO 2024/184461 PCT/EP2024/056026 7.67 (m, 2H), 7.61 (dd, J= 1.6, 8.0 Hz, 1H), 7.49 (dd, J= 4.8, 8.0 Hz, 1H), 7.39 (s, 1H), 7.10 (t, J = 8.7 Hz, 2H), 6.97 (s, 1H), 4.75 - 4.55 (m, 2H), 4.40 -4.18 (m, 2H), 3.87 (s, 3H), 3.16 (brt, J = 6.4 Hz, 2H), 2.81 (s, 3H), 2.47 (td, J= 5.8, 11.9 Hz, 1H),2.O2- 1.88 (m, 2H), 1.77 (s, 3H). LCMS (Methodh. ES+, RT = 1.869 min) 551.2/552.2 (M+H)

[001051] INTERMEDIATE 230:(R)-l-(9-(2-cyanopyridin-3-yl)-l-(4-fluorophenyl)-8- methoxy-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carboxamide F

[001052]To a solution of Intermediate 227 (235 mg, 533.58 umol) and Intermediate 124 (96.mg, 640.29 umol, HC1) in DMF (2 mL) was added HATU (223.17 mg, 586.93 umol) and DIEA (275.84 mg, 2.13 mmol, 371.76 uL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was partitioned between H20 (3 mL) andEtOAc(3 mL). The organic phase was separated, washed with brine (3 mL x 2), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the title compound (180 mg, 62.87%) as a brown solid. 1H NMR (4MHz, CDCI) 6 = 8.64 (dd, J = 1.6, 4.8 Hz, 1H), 8.23 (br s, 1H), 7.70 (dd, J = 5.5, 8.6 Hz, 2H), 7.61 (dd, J = 1.6, 7.9 Hz, 1H), 7.50 (dd, J = 4.8, 7.9 Hz, 1H), 7.42 (s, 1H), 7.14 - 7.07 (m, 2H), 6.98 (s, 1H), 4.85 - 4.70 (m, 3H), 4.60 (dt, J = 5.8, 10.3 Hz, 1H), 3.88 (s, 3H), 3.18 (br t, J = 6.Hz, 2H), 2.22 - 2.11 (m, 1H), 1.91 (s, 3H), 1.52 - 1.41 (m, 1H). LCMS (Method h. ES+, RT = 1.928 min) 537.2/538.2 (M+H) WO 2024/184461 PCT/EP2024/056026

[001053] INTERMEDIATE 231:ethyl 9-bromo-l-(4-fluorophenyl)-8-methoxy-5,6- dihydroimidazo[5, 1 -a]isoquinoline-3-carboxylate N OEt

[001054]To a solution of Intermediate 214 (1.00 g, 2.68 mmol) in THF (10 mL) was added LDA (2 M, 1.61 mL) at -70°C. The mixture was stirred at -70°C for 30 min. Then ethyl chloroformate (1.45 g, 13.40 mmol, 1.28 mL) was added the reaction mixture at -70°C. The mixture was stirred at -70°C for 30 min. The reaction mixture was diluted with H20 (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 1/1) give the title compound (500.00 mg, 42.00%) as a yellow solid. 1H NMR (400 MHz, CDCI3) 6 ppm 1.(t, J=7.15 Hz, 3 H), 3.10 (t, J=6.54 Hz, 2 H), 3.94 (s, 3 H), 4.47 (q, J=7.09 Hz, 2 H), 4.70 (t, J=6.Hz, 2 H), 6.83 (s, 1 H), 7.12 (t, J=8.68 Hz, 2 H), 7.59 - 7.72 (m, 3 H). LCMS {Method g. ES+, RT = 0.338 min) 445.1/447.1 (M+H)

[001055] INTERMEDIATE 232:9-bromo-l-(4-fluorophenyl)-8-methoxy-5,6- dihydroimidazo[5, 1 -a]isoquinoline-3-carboxylic acid

[001056]To a solution of Intermediate 231 (530.00 mg, 1.19 mmol) in THF (6 mL) was addedTMSOK (305.40 mg, 2.38 mmol) at 20°C. The mixture was stirred at 20°C for 2 h. The reaction N ,9 WO 2024/184461 PCT/EP2024/056026 solution was concentrated under reduced pressure to give the title compound (541.00 mg, 99.83%) as a white solid. LCMS (Method 1. ES+, RT = 0.40 min) 417.1/419.0 (M+H)

[001057] INTERMEDIATE 233:(R)-l-(9-bromo-l-(4-fluorophenyl)-8-methoxy-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carboxamide

[001058]To a solution of Intermediate 232 (540.00 mg, 1.19 mmol) in DMF (10 mL) was added (2R)-2-methylpyrrolidine-2-carboxamide (234.30 mg, 1.42 mmol, HCI), HATU (496.04 mg, 1.mmol) and DIEA (613.11 mg, 4.74 mmol, 826.29 pL) at 20°C. The mixture was stirred at 20°C for 2 h. The reaction mixture was poured into H20 (15 mL) and extracted with EtOAc(4 mL x 3). The combined organic layers were washed with brine (4 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (520.00 mg, 83.14%) as a white solid. 1H NMR (400 MHz, CDCh) 5 ppm 1.78 (s, 3 H), 1.86 - 2.04 (m, 3 H), 2.48 (dt, J=11.37, 5.81 Hz, 1 H), 3.01 - 3.12 (m, 2 H), 3.93 (s, 3 H), 4.19 - 4.28 (m, 1 H), 4.29 - 4.42 (m, 1 H), 4.- 4.60 (m, 1 H), 4.60 - 4.71 (m, 1 H), 5.19 - 5.41 (m, 1 H), 6.46 - 6.63 (m, 1 H), 6.83 (s, 1 H), 7.(t, J=8.68 Hz, 2 H), 7.58 - 7.72 (m, 3 H). LCMS (Method I. ES+, RT = 0.49 min) 527.2/529.(M+H)

[001059] INTERMEDIATE 234:(R)-l-(9-bromo-l-(4-fluorophenyl)-8-methoxy-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile /Ox N ,0 N ,9 WO 2024/184461 PCT/EP2024/056026

[001060]To a solution of Intermediate 233 (300 mg, 568.84 pmol) in THF (3 mL) was added Burgess reagent (271.12 mg, 1.14 mmol) and DCM (3 mL) at 20°C. The mixture was stirred at 20°C for 2 h. The reaction mixture was diluted with H20 (10 mL) and extracted with DCM (3 mL x 3). The combined organic layers were washed with brine (3 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate=10/l to 0/1) to give the title compound (220.00 mg, 75.93%) as a white solid. 1H NMR (400 MHz, CDCI3) 6 ppm 1.89 (s, 3 H), 2.02 - 2.17 (m, 3 H), 2.53 - 2.62 (m, 1 H), 3.02 - 3.16 (m, 2 H), 3.94 (s, 3 H), 4.17 - 4.33 (m, 2 H), 4.- 4.62 (m, 1 H), 4.81 (ddd, 1=13.23, 7.49, 5.56 Hz, 1 H), 6.84 (s, 1 H), 7.13 (t, J=8.68 Hz, 2 H), 7.58 - 7.70 (m, 3 H). LCMS (Method I. ES+, RT = 0.58 min) 509.1/511.1 (M+H)

[001061] INTERMEDIATE 235:phenyl (R)-3-(2-cyano-2-methylpyrrolidine-l-carbonyl)- 1- (4-fluorophenyl)-8-methoxy-5,6-dihydroimidazo[5,l-a]isoquinoline-9-carboxylate

[001062]To a solution of Intermediate 234 (220.00 mg, 215.95 pmol) in DMF (1.5 mL) was added phenyl formate (158.23 mg, 1.30 mmol, 141.28 uL), TEA (131.11 mg, 1.30 mmol, 180.uL), Pd(dppf)C12.CH2C12 (44.09 mg, 53.99 pmol) at 20°C. The mixture was stirred at 120°C for h. The reaction mixture was diluted with H20 (8 mL) and extracted with DCM (2 mL x 3). The combined organic layers were washed with brine (2 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 0/1) to give the title compound (1mg, 58.87%) as a white solid. 1H NMR (400 MHz, CDCI3) 6 ppm 1.90 (s, 3 H), 2.05 -2.18 (m, H), 2.54 - 2.67 (m, 1 H), 3.12 - 3.29 (m, 2 H), 3.94 - 4.06 (m, 3 H), 4.20 - 4.38 (m, 2 H), 4.61 - 4.72 (m, 1 H), 4.81 - 4.95 (m, 1 H), 6.98 (s, 1 H), 7.05 - 7.14 (m, 4 H), 7.21 - 7.26 (m, 1 H), 7.36 WO 2024/184461 PCT/EP2024/056026 - 7.44 (m, 2 H), 7.67 (br dd, J=8.51, 5.63 Hz, 2 H), 8.20 (s, 1 H). LCMS (Method I. ES+, RT = 0.58 min) 551.3/552.3 (M+H)

[001063] INTERMEDIATE 236:(R)-3-(2-cyano-2-methylpyrrolidine-l-carbonyl)- 1-(4- fluorophenyl)-8-methoxy-5,6-dihydroimidazo[5,l-a]isoquinoline-9-carboxylic acid

[001064]To a solution of Intermediate 235 (120.00 mg, 217.95 umol) in THF (2 mL) was added TMSOK (55.92 mg, 435.91 umol) at 20°C. The mixture was stirred at 20°C for 2 h. The reaction mixture was added with HC1 (0.5 mol) to adjust pH=3, then mixture was diluted with H20 (5 mL) and extracted with EtOAc(2 mL x 3). The combined organic layers were washed with brine (mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (103.00 mg, 99.60%) as a white solid. LCMS (Method I. ES+, RT = 0.46 min) 475.3/476.3 (M+H)

[001065] INTERMEDIATE 237:(R)-3-(2-cyano-2-methylpyrrolidine-l-carbonyl)- 1-(4- fluorophenyl)-8-methoxy-5,6-dihydroimidazo[5,l-a]isoquinoline-9-carboxylic acid /0 Br'

[001066]To a solution of Intermediate 232 (93 mg, 222.90 umol) and (lS)-2,2,2-trifluoro-l- [(2 S)-2-methylpyrrolidin-2-yl] ethanol (58.75 mg, 267.48 umol, HCljinDMF (1 mL) was added HATU (93.23 mg, 245.19 umol) and DIEA (115.23 mg, 891.60 umol, 155.30 pL) at 20°C.

WO 2024/184461 PCT/EP2024/056026 The mixture was stirred at 20 °C for 2hr. The reaction mixture was added H20 (5mL) at 0°C, and then extracted with EtOAc (2 mL x 3). The combined organic layers were washed with brine (mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 2/1) to give the title compound (23.6 mg, 49.54%) as a white solid. 1HNMR (4MHz, DMSO-d6) 8 = 7.65 - 7.56 (m, 2H), 7.46 (s, 1H), 7.29 (t, J = 8.9 Hz, 2H), 7.21 (s, 1H), 6.(d, J = 6.8 Hz, 1H), 5.22 - 5.10 (m, 1H), 4.53 - 4.42 (m, 1H), 4.38 - 4.21 (m, 2H), 3.88 (s, 3H), 3.67 (dt, J = 6.6, 10.8 Hz, 1H),3.11 - 3.04 (m, 2H), 2.40 (br dd, J = 4.1, 11.1 Hz, 1H), 1.93 - 1.(m, 2H), 1.67 - 1.59 (m, 1H), 1.57 (s, 3H). LCMS {Method I. ES+, RT = 0.611 min)582. 1/584.(M+H)

[001067] INTERMEDIATE 238:(2R,4S)-l-(9-bromo-l-(4-fluorophenyl)-8-methoxy-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-4-hydroxy-2-methylpyrrolidine-2-carboxamide ■!S) OH

[001068]To a solution of Intermediate 232 (350.00 mg, 419.44 umol) in DMF (5 mL) was added Intermediate 256 (90.92 mg, 503.32 umol, HCI), HATU (175.43 mg, 461.38 umol) and DfEA (216.83 mg, 1.68 mmol, 292.23 pL) at 20°C. The mixture was stirred at 20°C for 2 h. The reaction mixture was added with HCI (0.5 mol) to adjust pH=3, then mixture was diluted with H20 (8 mL) and extracted with EtOAc(3 mL x 2). The combined organic layers were washed with brine (mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Ethyl acetate: Methanol= 10/1 to 0/1) to give the title compund (270.00 mg, 59.23% yield) was obtained as a white solid. 1H NMR (4MHz, CDCh) 8 ppm 1.26 (s, 3 H), 1.93 (s, 3 H), 1.97 - 2.09 (m, 1 H), 2.07 - 2.13 (m, 1 H), 2.(dd, 1=13.26, 5.25 Hz, 1 H), 3.06 (t, J=6.38 Hz, 2 H), 3.93 (s, 3 H), 4.32 - 4.41 (m, 1 H), 4.42 - WO 2024/184461 PCT/EP2024/056026 4.51 (m, 1 H), 4.53 - 4.67 (m, 3 H), 6.83 (s, 1 H), 7.13 (t, J=8.63 Hz, 2 H), 7.59 - 7.70 (m, 3 H). LCMS (Method I. ES+, RT = 0.43 min) 443.2/445.2 (M+H)

[001069] INTERMEDIATE 239:(2R,4S)-l-(9-bromo-l-(4-fluorophenyl)-8-methoxy-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-4-hydroxy-2-methylpyrrolidine-2-carbonitrile

[001070]To a solution of Intermediate 238 (210.00 mg, 386.47 umol) in pyridine (2 mL) was added TFAA (811.70 mg, 3.86 mmol, 537.20 pL) at 20°C. The mixture was stirred at 30°C for h. The reaction mixture was poured into water, then mixture was added with HC1 (0.5 mol) to adjust pH=3 and extracted with MTBE (2mL x 3). The combined organic layers were washed with brine (2mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with K2CO3 (30.00 mg) and MeOH (2 mL) at 20°C for min. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 0/1) to give the title compound (100.00 mg, 49.25% yield) was obtained as a white solid. 1HNMR (400 MHz, DMSO-d6) 8 ppm 1.88 (s, 3 H), 2.19 (dd, 1=12.87, 3.58 Hz, 1 H), 2.- 2.65 (m, 1 H), 3.11 (br s, 2 H), 3.89 (s, 3 H), 4.07 - 4.13 (m, 1 H), 4.16 - 4.26 (m, 1 H), 4.33 - 4.40 (m, 1 H), 4.52 (br d, J=4.65 Hz, 2 H), 5.36 (d, J=3.10 Hz, 1 H), 7.22 (s, 1 H), 7.31 (t, J=8.Hz, 2 H), 7.47 (s, 1 H), 7.63 (dd, J=8.64, 5.66 Hz, 2 H). LCMS (Method I. ES+, RT = 0.53 min) 525.2/527.2 (M+H) •!S) OH WO 2024/184461 PCT/EP2024/056026

[001071] INTERMEDIATE 240:(R)-l-(l-(2-(benzyloxy)-2-methylpropyl)-8-methoxy-9-(2- methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine- 2-carboxamide

[001072]To a solution of Intermediate 52 (500 mg, 1.03 mmol) and Intermediate 124 (185.mg, 1.23 mmol, HCI) in DMF (5 mL) was added HATU (428.93 mg, 1.13 mmol) and DIEA (530.17 mg, 4.10 mmol, 714.52 pL) at 20°C. The mixture was stirred at 20°C for 2hr. The reaction mixture was added H20 (30 mL) at 0°C, and then extracted with EtOAc (lOmLx 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a crude product. The title compound (500 mg, 83.53%) was obtained as a brown solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.44 (s, 1H), 7.58 (br s, 1H), 7.(br d, J = 3.7 Hz, 7H), 6.59 (br s, 1H), 4.51 (br s, 1H), 4.47 (s, 2H), 4.41 (s, 3H), 4.14 - 3.99 (m, 2H), 3.88 (s, 3H), 3.07 - 2.92 (m, 4H), 2.69 (d, J = 0.7 Hz, 1H), 2.43 - 2.33 (m, 1H), 2.04 - 1.(m, 1H), 1.65 (br s, 3H), 1.28 (s, 6H) LCMS (Method I. ES+, RT = 0.50 min) 584.3/585.4 (M+H) +

[001073] INTERMEDIATE 241:ethyl 9-bromo-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylate N ,9 WO 2024/184461 PCT/EP2024/056026

[001074]To a solution of Intermediate 240 (480 mg, 822.37 umol, 1 eq) in THF (2.5 mL) was added burgess reagent (391.95 mg, 1.64 mmol, 2 eq) in DCM (2.5 mL) at 0°C. The mixture was stirred at 20°C for 2hr. The reaction mixture was diluted with H20 10 mL and extracted with DCM (3 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/ EtOAc =9/1 to 0/1). The title compound (400 mg, 85.99%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.45 (s, 1H), 7.21 (s, 5H), 6.60 (s, 1H), 4.56 - 4.44 (m, 4H), 4.41 (s, 3H), 4.20 - 4.08 (m, 2H), 3.(s, 3H), 3.06 - 2.98 (m, 4H), 2.71 - 2.62 (m, 2H), 2.39 - 2.32 (m, 1H), 1.79 (s, 3H), 1.27 (s, 6H) LCMS {Method I. ES+, RT = 0.56 min) 458.3/459.2 (M+H) +

[001075] INTERMEDIATE 242:methyl (S)-4,4,4-trifluoro-2-(l-(5-fluoropyridin-2-yl)-8- methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamido)- 2-methylbutanoate

[001076]To a solution of l-(5-fluoropyridin-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylic acid (1 g, 2.38 mmol) in DMF (10 mL) was added HATU (1.36 g, 3.57 mmol), DIEA (1.23 g, 9.51 mmol, 1.66 mL) and Intermediate 1(790.70 mg, 3.57 mmol, HC1) at 20°C. The mixture was stirred at 80°C for 12 hr. The reaction mixture poured into H20 (20 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 0/1) to give title compound (900 mg, 64.40%) as a white solid. 1H NMR (400 MHz, CDCh) 8 = 2.05 (s, 1 H), 2.81 (s, 2 H), 2.94 - 3.06 (m, 1 H), 3.13 (br t, J = 6.38 Hz, 2 H), 3.33 - 3.46 (m, 1 H), 3.85 (s, 3 H), 3.98 (s, 3 H), 4.37 (s, 3 H), 4.58 - 4.70 (m, WO 2024/184461 PCT/EP2024/056026 2 H), 6.87 - 6.99 (m, 3 H), 7.45 (td, J = 8.38, 2.88 Hz, 1 H), 7.59 (dd, J = 8.69, 4.32 Hz, 1 H), 8.(s, 1 H), 8.49 (d, J = 2.88 Hz, 1 H) LCMS {Method I. ES+, RT =0.48 min) 588.4/589.3 (M+H) +

[001077] INTERMEDIATE 243:(S)-4,4,4-trifluoro-2-(l-(5-fluoropyridin-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxamido)-2-methylbutanoic acid

[001078]To a solution of Intermediate 242 (800 mg, 1.36 mmol) in THF (8 mL) was added TMSOK (349.36 mg, 2.72 mmol) at 20°C. The mixture was stirred at 50°C for 2 hr. The reaction mixture was diluted with 5 ml H2O, adjusted to pH = 5 with 1M HC1. The aqueous layer was extracted with EtOAc (6 mL x 3), The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure to give title compound (750 mg, 96.04%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 6 = 1.56 (s, 3 H), 1.99 (s, 1 H), 2.79 - 2.89 (m, 1 H), 3.11 (br t, J = 6.23 Hz, 2 H), 3.26 (br dd, J = 15.28, 12.59 Hz, H), 3.88 (s, 3 H), 4.36 (s, 3 H), 4.47 - 4.63 (m, 2 H), 7.19 - 7.32 (m, 2 H), 7.59 (dd, J = 8.80, 4.Hz, 1 H), 7.68 - 7.78 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 8.53 (d, J = 2.93 Hz, 1 H). LCMS {Method I. ES+, RT = 0.43 min) 574.3/575.3 (M+H) + HN—(S) WO 2024/184461 PCT/EP2024/056026

[001079] INTERMEDIATE 244:(S)-N-(l-amino-4,4,4-trifluoro-2-methyl-l-oxobutan-2-yl)- l-(5-fluoropyridin-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxamide HN—(S)

[001080]To a solution of Intermediate 243 (730.0 mg, 636.45 umol) in THF (8 mL) was added CD1 (154.80 mg, 954.67 umol) at 20°C for l b. The mixture was added NHJ.HO (267.66 mg, 1.91 mmol, 25% purity) at 20°C for 2 hr. The residue was poured into water (20 mL). The aqueous phase was extracted with DCM (5 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure to give title compound (600 mg, 82.33%) as a white solid. 1H NMR (400 MHz, CDCI3) 6 = 1.73 (s, H), 3.02 - 3.19 (m, 3 H), 3.31 (br dd, J = 16.01, 11.51 Hz, 1 H), 3.98 (s, 3 H), 4.37 (s, 3 H), 4.(ddd, J = 13.35, 8.29, 5.00 Hz, 1 H), 4.53 - 4.63 (m, 1 H), 4.68 - 4.79 (m, 1 H), 6.54 (s, 1 H), 6.(d, J = 8.50 Hz, 2 H), 7.13 (s, 1 H), 7.39 (td, J = 8.38, 2.88 Hz, 1 H), 7.55 (dd, J = 8.69, 4.32 Hz, H), 7.75 (s, 1 H), 8.08 (s, 1 H), 8.49 (d, J = 2.75 Hz, 1 H) LCMS {Method I. ES+, RT = 0.min) 573.3/574.3 (M+H) +

[001081] INTERMEDIATE 245:(S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-l-(5-fluoropyridin-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxamide N ,0 O, WO 2024/184461 PCT/EP2024/056026

[001082]To a solution of Intermediate 244 (600 mg, 524.01 pmol) in THF (6 mL) was added Burgess reagent (249.75 mg, 1.05 mmol) and DCM (6 mL) at 20°C. The mixture was stirred at 20°C for 2 hr. The reaction mixture was diluted with H20 20 mL and extracted with DCM 15 mL. The combined organic layers were washed with brine (10 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/l to 0/1) to give title compound (5mg, 86.04%) as a white solid. 1H NMR (400 MHz, CDCh) 8 = 1.92 (s, 3 H), 2.05 (s, 1 H), 3.- 3.25 (m, 3 H), 3.99 (s, 3 H), 4.38 (s, 3 H), 4.62 - 4.74 (m, 2 H), 6.40 (s, 1 H), 6.98 (d, J = 3.Hz, 2 H), 7.40 - 7.50 (m, 1 H), 7.58 (dd, J = 8.76, 4.38 Hz, 1 H), 8.05 (s, 1 H), 8.49 (d, J = 2.Hz, 1 H) LCMS {Method I. ES+, RT = 0.47 min) 555.3/556.4 (M+H) +

[001083] INTERMEDIATE 246:ethyl 9-bromo-l-(tert-butyl)-8-methoxy-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylate

[001084]To a solution of Intermediate 39 (3.3 g, 8.54 mmol) in Ac2O (50 mL) was added 3,3- dimethylbut- 1-yne (1.40 g, 17.09 mmol) at 20°C. The mixture was stirred at 140°C for Ihr. The reaction mixture was concentrated under reduced pressure to remove Ac20. The residue was diluted with H20 100 mL and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc=10/l to 0/1). The title compound (8 g, 76.81%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 = 1.28 (t, J=7.07 Hz, 3 H), 1.37 (s, 9 H), 2.90 (br t, J=6.25 Hz, H), 3.89 (s, 3 H), 4.22 (q, J=7.09 Hz, 2 H), 4.43 (t, J=6.25 Hz, 2 H), 6.88 (s, 1 H), 7.15 (s, 1 H), 7.89 (s, 1 H). LCMS {Method h. ES+, RT = 2.90 min) 406.1/408.2 (M+H) +

[001085] INTERMEDIATE 247:ethyl l-(tert-butyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5- yl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylate WO 2024/184461 PCT/EP2024/056026

[001086]To a solution of Intermediate 246 (1 g, 2.46 mmol) in DMF (10 mL) was added Intermediate 26 (1.84 g, 4.92 mmol) and XPHOS-Pd-G2 (387.29 mg, 492.23 pmol) at 20°C. The mixture was stirred at 120°C for 12hr. The reaction mixture was filtered. The residue was diluted with H20 (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc=10/0 to 0/1). The crude product was triturated with MTBE at 20°C for 30 min. The title compound (800 mg, 79.38%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) = 1.29 (t, J=7.07 Hz, 3 H), 1.40 (s, 9 H), 3.00 (br t, J=6.07 Hz, 2 H), 3.91 (s, 3 H), 4.23 (q, J=7.Hz, 2 H), 4.42 (s, 3 H), 4.48 (br t, J=6.19 Hz, 2 H), 6.90 (s, 1 H), 7.25 (s, 1 H), 8.35 - 8.45 (m, H). LCMS (Method I. ES+, RT = 0.60 min) 410.2/411.2 (M+H) +.

[001087] INTERMEDIATE 248:l-(tert-butyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylic acid

[001088]To a solution of Intermediate 247 (340 mg, 830.32 pmol) in EtOH (0.5 mL) and THE (0.5 mL) was added KOH (139.76 mg, 2.49 mmol) in H20 (0.5 mL) at 20°C. The mixture was stirred at 80°C for 2hr. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H20 10 mL and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The title compound (300 mg, 94.72%) was obtained as WO 2024/184461 PCT/EP2024/056026 a blue solid. 1H NMR (400 MHz, DMSO-d6) 8 = 1.40 (s, 9 H), 2.99 (br t, J=5.94 Hz, 2 H), 3.(s, 3 H), 4.42 (s, 2 H), 4.47 - 4.52 (m, 2 H), 6.88 (s, 1 H), 7.24 (s, 1 H), 8.39 (s, 1 H), 12.23 (br s, H). LCMS (Method I. ES+, RT = 0.46 min) 382.1/383.2 (M+H) +.

[001089] INTERMEDIATE 249:ethyl 9-bromo-l-(3,5-difluorophenyl)-8-methoxy-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxylate

[001090]To a solution of Intermediate 39 (6 g, 15.54 mmol) in Ac2O (50 mL) was added 1- ethynyl-3,5-difluoro-benzene (3.22 g, 23.30 mmol, 1.5 eq) at 20°C. The mixture was stirred at 140°C for Ihr. The reaction mixture was concentrated under reduced pressure to remove solvent. The combined reaction mixture was poured into ice-water (100 mL) and added Na2CO3 to pH= 8- 9. The reaction mixture was extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE at 20 °C for 10 min. The title compound (5.2 g, 72.40%) was obtained as a white solid. 1H NMR (400 MHz, CDC13) 8 = 7.42 - 7.37 (m, 1H), 7.21 - 7.18 (m, 1H), 6.93 - 6.85 (m, 3H), 6.74 - 6.66 (m, 2H), 4.61 - 4.49 (m, 2H), 4.29 -4.16 (m, 2H), 3.91 - 3.78 (m, 3H), 2.97 (t, J = 6.5 Hz, 2H), 1.37 - 1.23 (m, 3H). LCMS (Method g. ES+, RT = 0.70 min) 462.2/464.2 (M+H) +.

WO 2024/184461 PCT/EP2024/056026

[001091] INTERMEDIATE 250:ethyl l-(3,5-difluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylate

[001092]To a solution of Intermediate 249 (2 g, 4.33 mmol) Intermediate 26 (3.23 g, 8.65 mmol) in DMF (20 mL) was added XPHOS-Pd-G2 (680.80 mg, 865.27 umol) at 20°C. The mixture was stirred at 120°C for 12hr under Ar. The reaction mixture was diluted in H20 (50 mL) and added KF (20 mL). The reaction mixture was extracted with DCM (50 mL x 3). The combined organic layers were washed with (50 mL x 4), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE at 20 °C for 5 min to give title compound (1.3 g, 64.56%) as a white solid. 1H NMR (400 MHz, CDCI3) 6 = 7.91 (s, 1H), 6.98 - 6.84 (m, 4H), 6.72 - 6.58 (m, 1H), 4.66 - 4.52 (m, 2H), 4.30 - 4.21 (m, 5H), 3.93 - 3.88 (m, 3H), 3.14 - 2.99 (m, 2H), 1.34 - 1.27 (m, 5H), 0.90 - 0.81 (m, 3H). LCMS (Method I. ES+, RT = 0.61 min) 466.2/467.2 (M+H) +.

[001093] INTERMEDIATE 251:l-(3,5-difluorophenyl)-8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carboxylic acid

[001094]To a solution of Intermediate 250 (1.2 g, 2.58 mmol, 1 eq) in THF (30 mL) was added TMSOK (992.23 mg, 7.73 mmol, 3 eq). The mixture was stirred at 20 °C for 2hr. The reaction WO 2024/184461 PCT/EP2024/056026 mixture was poured into ice-water (50 mL) and added 1 M HC1 to pH=5-6. The reaction mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (mL x 3), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with PE at 20 °C for 5 min to give title compound (8mg, 70.94%) as a white solid. 1H NMR (400 MHz, CDCh) 5 = 7.88 - 7.72 (m, 1H), 7.35 - 7.(m, 1H), 7.20 - 7.07 (m, 3H), 6.99 (s, 1H), 4.64 - 4.51 (m, 2H), 4.40 - 4.29 (m, 3H), 3.97 - 3.(m, 3H), 3.17 (br t, J = 6.3 Hz, 2H). LCMS {Method a. ES+, RT = 1.63 min) 438.2/439.2 (M+H)

[001095] INTERMEDIATE 252:1-(tert-butyl) 2-methyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-pyrrolidine- 1,2-dicarboxylate {R) O N-V; s ؟ TBSO

[001096]Under argon atmosphere, imidazole (42.47 g, 623.8 mmol) was added portions to a solution of 01-tert-butyl O2-methyl (2R,4S)-4-hydroxypyrrolidine- 1,2-dicarboxylate (90 g, 366.94 mmol) and tert-butyl-chloro-dimethyl-silane (82.96 g, 550.41 mmol, 67.72 mL) in DCM (540 mL) at 0°C. Then reaction was stirred at 15°C for 16 hr. The residue was poured into water (500 mL). The aqueous phase was extracted with DCM (500 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/l to 25/1). The title compound (112 g, 84.90% yield) was obtained as a white solid. 1HNMR (400 MHz, DMSO-d6) 8 4.43 (br s, 1H), 4.25-4.15 (m, 1H), 3.68 - 3.61 (m, 3H), 3.51 - 3.38 (m, 1H), 3.25 (br t, J= 10.9 Hz, 1H), 2.16-2.05 (m, 1H), 2.04-1.89 (m, 1H), 1.- 1.30 (m, 9H), 0.86 - 0.79 (m, 10H), 0.06 (d, J = 2.1 Hz, 6H)

[001097] INTERMEDIATE 253:1 -(tert-butyl) 2-methyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-methylpyrrolidine- 1,2-dicarboxylate WO 2024/184461 PCT/EP2024/056026 0 TBSOW^ 0

[001098]Three batches were earned out in parallel. Intermediate 252 (30 g, 83.44 mmol) was dissolved in dry THF (300 mL). The mixture was cooled to -78°C and LiHMDS (IM, 208.mL) was added dropwise. Reaction was stirred at that temperature for 30 min. Then Mel (47.g, 333.77 mmol, 20.78 mL) was added dropwise. The mixture was stirred at -78°C to 15°C for hr. The residue was poured into water (1000 mL). The aqueous phase was extracted with EtOAc (1000 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=50/l to 20/1). The title compound (33 g, 70.58% yield) was a colorless oil. 1H NMR (400 MHz, DMSO-d6) 8 4.43 (qd, J = 2.3, 4.Hz, 1H), 3.69-3.61 (m, 2H), 3.61-3.54 (m, 2H), 3.31 - 3.25 (m, 1H), 2.33-2.18 (m, 1H), 1.91-1.(m, 1H), 1.60-1.52 (m, 3H), 1.40-1.30 (m, 9H), 0.88-0.76 (m, 9H), 0.09-0.02 (m, 6H)

[001099] INTERMEDIATE 254:(2R,4S)-l-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)-2-methylpyrrolidine-2-carboxylic acid r-AW OTBSO^sr^ o

[001100]To a solution of Intermediate 253 (17.5 g, 46.85 mmol) in THF (170 mL) was added TMSOK (12.02 g, 93.69 mmol) at 20°C. The mixture was stirred at 50°C for 12 hours. The reaction was added H20 (500 mL) and the mixture was added IN HC1 solution to make the pH = and the extracted with EtOAc (300 mL x 3). The organic layers were concentrated under reduced pressure to give a product. The title compound (33 g, 97.96% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 4.41 (br s, 1H), 3.54 (br dd, J=4.5, 11.3 Hz, 1H), 3.30-3.20 (m, WO 2024/184461 PCT/EP2024/056026 1H), 2.31-2.18 (m, 1H), 1.88-1.73 (m, 1H), 1.52 (s, 3H), 1.40-1.31 (m, 9H), 0.89-0.81 (m, 9H), 0.06 (s, 6H)

[001101] INTERMEDIATE 255:tert-butyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-carbamoyl-2-methylpyrrolidine-1 -carboxylate S1 ؟ TBSO

[001102]To a solution of Intermediate 254 (15 g, 41.72 mmol) in THF (150 mL) was added CDI (10.15 g, 62.58 mmol) at 20°C. The mixture was stirred at 20°C for 0.5 hour. The mixture was added NH3 H20 (26.11 g, 208.60 mmol, 28.70 mL, 28% purity) at 20°C. The mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with H20 (500 mL) and the reaction was added IN HC1 solution to adjust the pH =7, the reaction was extracted with MTBE (200 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The crude product was washed by NaHCO3 solution (300 mL) and the mixture was filtered to give the product as a white solid. The white solid was dissolved by MTBE (500 mL) and the organic layers was washed by H20 and brine (100 mL). The organic layers was dried over Na2S04 and the mixture was filtered. The organic layers were concentrated under reduced pressure to give a product. The title compound (25 g, 83.56% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO- d6) 5 7.11 - 7.00 (m, 1H), 6.98-6.81 (m, 1H), 4.37 (br d, J= 2.4 Hz, 1H), 3.68 (br dd, J= 4.9, 11.Hz, 1H), 3.25-3.16 (m, 1H), 2.20 (br dd, J= 5.5, 12.9 Hz, 1H), 1.84-1.70 (m, 1H), 1.56-1.49 (m, 3H), 1.39-1.32 (m, 9H), 0.89-0.82 (m, 9H), 0.08-0.03 (m, 6H)

[001103] INTERMEDIATE 256:(2R,4S)-4-hydroxy-2-methylpyrrolidine-2-carboxamide O.—NH2(R)NH WO 2024/184461 PCT/EP2024/056026

[001104]To a solution of Intermediate 255 (2 g, 5.58 mmol) in MeOH (4 mL) was added HCl/MeOH (40 mL). The mixture was stirred at 20 °C for ihr. The reaction mixture was concentrated under reduced pressure to remove solvent. The reaction mixture was concentrated under reduced pressure to remove solvent. The title compound (1 g, 99.25% yield, HCI) was obtained as a white oil. 1H NMR (400 MHz, DMSO-d6) 8 9.97-9.79 (m, 1H), 8.86-8.70 (m, 1H), 8.15-8.03 (m, 1H), 7.83-7.74 (m, 1H), 4.46-4.34 (m, 1H), 3.44-3.30 (m, 1H), 3.17-3.04 (m, 1H), 2.64-2.54 (m, 1H), 2.45-2.33 (m, 1H), 2.17-2.05 (m, 1H), 1.74 (s, 3H)

[001105] INTERMEDIATE 257:tert-butyl (S)-2-methyl-2-((S)-3,3,3-trifluoro-l-hydroxypropyl)-pyrrolidine- 1 -carboxylate

[001106]To a solution of Intermediate 103 (20 g, 67.73 mmol) in MeOH (100 mL) was added Tetrabutylammonium borohydride (34.85 g, 135.46 mmol) at 0°C. The mixture was stirred at 30°C for 1 hour. The two reactions was combined to work up. The mixture was diluted with H(300 mL) and extracted with EtOAc (100 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=20/l to 1/1) to give the title compound (10.5 g, 52% yield) as a yellow oil. 1H NMR (400 MHz, CDCI3) 8 6.37-6.10 (m, 1H), 4.15 (br d, J= 7.5 Hz, 1H), 3.- 3.56 (m, 1H), 3.37-3.25 (m, 1H), 2.32-2.11 (m, 2H), 1.89-1.62 (m, 4H), 1.50-1.35 (m, 12H)

[001107] INTERMEDIATE 258:tert-butyl (S)-2-methyl-2-((S)-3,3,3-trifluoro-l- hydroxypropyl)-pyrrolidine- 1 -carboxylate /CF3 HCI HN-T 'OHt s A WO 2024/184461 PCT/EP2024/056026

[001108]To a solution of Intermediate 257 (200 mg, 672.69 pmol) in MeOH (0.5 mL) was added HCl/MeOH (4 M, 5.00 mL, 29.73 eq) at 20°C. The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove MeOH. The title compound (150 mg, 641.96 pmol, 95.43% yield, HC1) was obtained as a white solid. 1H NMR (400 MHz, MeOD-d) 6 = 3.98-4.01 (d, J = 9.2 Hz, 1H), 3.37-3.37(m, 2H), 2.39-2.44(m, 2H), 2.10-2.14(m, 2H), 1.89-1.93((m, 2H), 1.35(s, 3H).

[001109] EXAMPLE 1 (METHOD A)t (2R,4S)-4-hydroxy-l-(8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2- methylpyrrolidine-2-carbonitrile

[001110]To a solution of Intermediate 28 (80 mg, 155.82 pmol) in DMF (0.8 mL) was added Intermediate 2 (116.28 mg, 311.64 pmol) and XPHOS-Pd-G2 (12.26 mg, 15.58 pmol) at 20 °C. The mixture was stirred at 120 °C for 12 h. The reaction mixture was added to the ice water and extracted with EtOAc (2 mL x 3), combined organic phase was washed with 3 mL brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Method 15). EXAMPLE 1 (41.38 mg, 51.41% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 8.32 (s, 1H), 7.56 (dd, J= 5.13, 1.Hz, 1H), 7.37 (dd, J=3.56, 0.94 Hz, 1H), 7.33 (s, 1H), 7.11 (dd, J=5.13, 3.63 Hz, 1H), 5.39 (d, J = 3.38 Hz, 1H), 4.55 (brt, J = 6.38 Hz, 2H), 4.33-4.43 (m, 4H), 4.17 - 4.28 (m, 1H), 4.08 (dd, J= 11.69, 3.06 Hz, 1H), 3.91 (s, 3H), 3.19 (br t, J=6.38 Hz, 2H), 2.62 (dd, J= 13.13, 5.13 Hz, 1H), 2.20 (dd, J= 13.07, 3.94 Hz, 1H), 1.89 (s, 3H) LCMS (Methodr. ES+, RT = 2.655 min) 517.0/518.(M+H) + WO 2024/184461 PCT/EP2024/056026 Example No. Precursor Structure/Name LCMSInt. 17| X 1 ° י (R)-1 -(8-methoxy-9-(2-methyl-2H- tetrazol-5 -yl)- 1 -(thiophen-2-yl)-5 ,6- dihydroimidazo[5 ,1 -a] isoquinoline-3 - carbonyl)-2-methylpyrrolidine-2- carbonitrile LCMS (Method s. ES+, RT=2.9min) 501.(M+H) + 3 Int. 29T 1 0 HO F (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l- a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-3, 3,3-trifluoro- 1 -hydroxypropyl)pyrrolidin- -yl)methanone LCMS (Method f. ES+,RT = 3.0min) 588.2/589.(M+H) + WO 2024/184461 PCT/EP2024/056026 4 Int. 30T II 0 ו HO F (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l- a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,,3-trifluoro- 1 -hydroxypropyl)pyrrolidin- 1 - yl)methanone LCMS (Method f. ES+, RT = 3.1min) 588.2/589.(M+H) + Int. 35I |j 1 0J IJ-XW' 0 X (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)- 8-methoxy-N-methyl-9-(2-methyl-2H- tetrazol-5 -yl)- 1 -(thiophen-2-yl)-5 ,6- dihydroimidazo[5 ,1 -a] isoquinoline-3 - carboxamide LCMS (Method f. ES+,RT = 3.0min) 557.0/558.(M+H) + 6 Int. 175T Y 1 Vn F / OHF(2R,4S)-l-(l-(3,3-difluorocyclobutyl)-8- methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 5,6-dihydroimidazo[5 ,1 -a]isoquinoline-3 - carbonyl)-4-hydroxy-2-methylpyrrolidine- 2-carbonitrile LCMS (Method f. ES+,RT= 2.7min) 525.2/526.(M+H) + WO 2024/184461 PCT/EP2024/056026

[001111] EXAMPLE 1 (METHOD B): (R)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile

[001112]To a solution of Intermediate 150 (55 mg, 110.60 umol). Intermediate 26 (82.53 mg, 221.19p.mol) in DMF (1 mL) was added XPHOS-Pd-G2 (8.70 mg, 11.06 umol) at 20 °C. The mixture was stirred at 110 °C for 60 min. The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Method 16). EXAMPLE 7 (13.12 mg, 23.7% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 8.08 - 8.14 (m, 1 H) 7.- 7.36 (m, 1 H) 4.53 (br t, J=6.6 Hz, 2 H) 4.43 (s, 3H) 3.99 - 4.09 (m, 2 H) 3.90 (s, 3 H) 3.83 (q, J=11.0 Hz, 2 H) 3.14 (br t, J=6.4 Hz, 2 H) 2.43 - 2.47 (m, 1 H) 2.13 -2.25 (m, 1 H) 2.07 - 2.08 (m, H) 2.07 - 2.08 (m, 1 H) 1.87 - 2.06 (m, 2 H) 1.76 (s, 3 H) LCMS (Method r. ES+, RT = 2.8min) 501.1/502.1 (M+H) +

[001113] EXAMPLE 8 (METHOD Q:(8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-l- (thiophen-2-yl)-5,6-dihydroimidazo[5, l-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2, 2,2-tri fluoro- -hydroxyethyl)pyrro lidin- 1 -yl)methanone

[001114]To a solution of Intermediate 9 (90 mg, 221.43 umol) and (lR)-2,2,2-trifluoro-l- [(2 S)-2-methylpyrrolidin-2-yl] ethanol (53.50 mg, 243.57 umol, HC1) in DMF (0.5 mL) was WO 2024/184461 PCT/EP2024/056026 added HATU (92.61 mg, 243.57 pmol) and DIEA (85.85 mg, 664.28 pmol) at 20 °C. The mixture was stirred at 20 °C for 2 hr. The organic layers was concentrated under reduced pressure to give a crude product. The residue was purified by prep-HPLC (Method 15) to give EXAMPLE 8 (46.mg, 36% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.44 (s, 1H), 7.65 (d, J= Hz, 1H), 7.52 (d,J=5.2 Hz, 1H), 7.40 (d, J=2.8Hz, 1H), 7.13-7.10 (m, 2H), 6.71 (d,J=7.2Hz, 1H), 6.63 (s, 1H), 5.04 (t, J = 6.6 Hz, 1H), 4.36 (q, J = 1A Hz, 2H), 4.20 (m, 1H), 3.89 (s, 3H), 3.84-3.81 (m, 4H), 3.07 (t, J = 6.6 Hz, 2H), 2.39-2.36 (m, 1H), 1.84-1.80 (m, 2H), 1.74-1.69 (m, 1H), 1.61 (s, 3H). LCMS (Methods. ES+, RT = 3.22 min) 572.3 (M+H) + Example No. Precursor Structure/Name LCMSInt. 9A AL׳׳״:׳ y« sa (8-methoxy-9-( 1 -methyl- 1 H-pyrazol-3-yl)- l-(thiophen-2-yl)-5,6-dihydroimidazo[5,la]isoquinolin-3- yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-l- hydroxyethyl)pyrrolidin- 1 -yl) methanone LCMS (Method s.ES+, RT =3.224 min)572.2 (M+H) + Int. 14T 1 1 ° oh MXPk n-n s An (+> !L F (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l- a]isoquinolin-3-yl)((S)-2-methyl-2-((R)- 2,2,2-trifluoro- 1 -hydroxyethyl)pyrrolidin- -yl)methanone LCMS (Method s. ES+, RT = 3.07 min) 574.3 (M+H) + WO 2024/184461 PCT/EP2024/056026 11 Int. 14J T Ji ,° 0HNx/AA J = 7Y ؛ NA //؟ n" Hn-־n eJ־־N f fz v M (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l- a]isoquinolin-3-yl)((R)-2-methyl-2-((S)- 2,2,2-trifluoro- 1 -hydroxyethyl)pyrrolidin- -yl)methanone LCMS (Method s.ES+, RT =3.098 min)574.3 (M+H) + 12 Int. 24 W ° An ,n7^ (R)-3 -(2-cyano-2-methylpyrrolidine- 1 - carbonyl)-8-methoxy-N-( 1 -methyl-2-oxo- 1,2-dihydropyri din- 3 -yl)- 1 -(thiophen-2- yl)-5,6-dihydroimidazo[5,l-a]isoquinoline- 9-carboxamide LCMS (Method s.ES+, RT = 2.984 min)569.0 (M+H) + 13 Int. 24O Xw1^־* (R)-3 -(2-cyano-2-methylpyrrolidine- 1 - carbonyl)-8-methoxy-N-(2-oxo- 1,2- dihydropyridin-3 -yl)- 1 -(thiophen-2-yl)- 5,6-dihydroimidazo[5,l-a]isoquinoline-9- carboxamide LCMS (Method s. ES+,RT =2.864 min) 555.0 (M+H) + WO 2024/184461 PCT/EP2024/056026 14 Int. HOBץ (I I 0 HO Fj<+ Y Y® ״n״n / L >! ( (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)--propyl-5,6-dihydropyrrolo[2, 1 - a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3 -trifluoro- 1 -hydroxypropyl)lyrrolidine-1 -yl)methanone LCMS (Methodf. ES+,RT = 3.313 min) 547.2 (M+H) +.

Int. 109Bf if 1 0 HOYT ' w ((S)-2-((R)-1,2-dihydroxy-2-methylpropyl)-2-methylpyrro lidin- 1 -yl)( 1 - (4-fluorophenyl)-8-methoxy-9-(2-methyl- 2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinolin-3-yl)methanone LCMS (Method r.ES+, RT = 2.975 min)575.1 (M+H) + WO 2024/184461 PCT/EP2024/056026 16 hit. 109Br if ו o ho n ? ץ (/NzX®) n-n O (l-(4-fluorophenyl)-8-methoxy-9-(2- methyl-2H-tetrazol-5 -yl)-5 ,6- dihydropyrrolo[2, 1 -a]isoquinolin-3- yl)((S)-2-methyl-2-((R)-3 ,3,3 -trifluoro- 1 - hydroxypropyl)pyrrolidin- 1 -yl)methanone LCMS (MethodfES+ RT=3.209 min) 599.(M+H)+. 17 Int. 109Bץ |f 1 0 HON.AA/yJ 1 I CFNf T V/NX) M'n O M (l-(4-fluorophenyl)-8-methoxy-9-(2- methyl-2H-tetrazol-5 -yl)-5 ,6- dihydropyrrolo[2, 1 -a]isoquinolin-3- yl)((S)-2-methyl-2-((S)-3 ,3,3 -trifluoro- 1 - hydroxypropyl)pyrrolidin- 1 -yl)methanone LCMS (Method b ES+ RT= 2.965 min) 599.2 (M+H)+. 18 Int. 128 ° 1__ (R)-3 -(2-cyano-2-methylazetidine- 1 - carbonyl)-8-methoxy-N-( 1 -methyl-2-oxo- 1,2-dihydropyridin-3-yl)-l -propyl-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-9- carboxamide LCMS (Method h. ES+,RT = 2.084 min) 514.2 (M+H) +.

WO 2024/184461 PCT/EP2024/056026 19 Int. 128O"xo (R)-3 -(2-cyano-2-methylazetidine- 1 - carbonyl)-8-methoxy-N-(2-oxo- 1,2- dihydropyridin-3 -yl)- 1 -propyl-5 ,6- dihydropyrrolo[2, 1 -a]isoquinoline-9- carboxamide LCMS (Method r. ES+,RT=2.913 min) 500.1 (M+H)+ Int. 140T T 0 י oh MXP N'N Z~N ،L F (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- -propyl-5,6-dihydroimidazo[5, 1 -a]isoquinolin-3-yl)((S)-2-methyl-2-((R)- 2,2,2-trifluoro- 1 -hydroxyethyl)pyrrolidin- -yl)methanone LCMS (Method r.ES+,RT = 2.980 min)534.1/535.1 (M+H) + 21 Int. 140ill 9 °h n" H //nXXtCn-־n T^f (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- -propyl-5,6-dihydroimidazo[5, 1 - a]isoquinolin-3-yl) ((R)-2-methyl-2-((S)- 2,2,2-trifluoro- 1 -hydroxyethyl)pyrrolidin- -yl) methanone LCMS (Method k. ES+,RT=2.495min) 534.4 (M+H) + WO 2024/184461 PCT/EP2024/056026 22 Int. 181JI jL I 0Hn Vy'+/A // (R)-3 -(2-cyano-2-methylazetidine- 1 -carbonyl)- 1 -isobutyl-8-methoxy-N-(2-oxo- 1,2-dihydropyridin-3-yl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9- carboxamide LCMS (Methodr. RT = 3.02 min) 514.2/515.2 (M+H)+. 23 Int. 181 (R)-3 -(2-cyano-2-methylazetidine- 1 - carbonyl)- 1 -isobutyl-8-methoxy-N-( 1 - methyl-2-oxo-1 ,2-dihydropyri din-3-yl)- 5,6-dihydropyrrolo[2,l-a]isoquinoline-9- carboxamide LCMS (Method q. RT = 2.82 min) 528.3/529.3 (M+H) +. 24 Int. 187V ؟ Lll! /? .H F ؛ N? X X_77sn״n x yyX~FF F(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2, 1 -a]isoquinolin-3- yl)((S)-2-methyl-2-((S)-3 ,3,3 -trifluoro- 1 - hydroxypropyl)pyrrolidin- 1 -yl)methanone LCMS (Method f, RT = 3.06 min) 587.3/588.3 (M+H) +.

WO 2024/184461 PCT/EP2024/056026 WO 2024/184461 PCT/EP2024/056026 27 Int. 223T T J. O OH J(^b F c(l-(4-fluorophenyl)-8-methoxy-9-(2- methyl-2H-tetrazol-5 -yl)-5 ,6- dihydroimidazo[5,l-a]isoquinolin-3- yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-l- hydroxyethyl)pyrro lidin- 1 -yl)methanone LCMS (Method s.ES+,RT=3.107min)586.2/587.2 (M+H) + 28 Int. 236 W FZ (R)-3 -(2-cyano-2-methylpyrrolidine- 1 - carbonyl)- 1 -(4-fluorophenyl)-8-methoxy- N-(l-methyl-2-oxo-l,2-dihydropyri din-3- yl)-5,6-dihydroimidazo[5,l-a]isoquinoline- 9-carboxamide LCMS (Method s.ES+,RT = 3.051 min) 581.1/582.1 (M+H) + WO 2024/184461 PCT/EP2024/056026 *** = 8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(thiophen-2-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxylic acid, prepared in accordance with a method analogous to that of method 19 (steps 1 to 3) using ethyl 9-bromo-8-methoxy-l-(2-thienyl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxylate (as described herein) as the starting material. 29 Int. 251Y Y । 0 HO FnvVvnJ 1JL Jk< 1 /־־^ n ״ n F(l-(3,5-difluorophenyl)-8-methoxy-9-(2- methyl-2H-tetrazol-5 -yl)-5 ,6- dihydropyrrolo[2, 1 -a]isoquinolin-3- yl)((S)-2-methyl-2-((S)-3 ,3,3 -trifluoro- 1 - hydroxypropyl)pyrrolidin- 1 -yl)methanone LCMS (method f.ES+,RT=3.25 min) 617.2/618.2 (M+H) + ***Y T I 0 HO F {(S)-2-[(S)-3,3,3-trifluoro-l-hydroxypropyl] -2-methyl- 1 - pyrrolidinyl} {11-methoxy-12-(2-methyl- 2H-tetraazol-5-yl)-3-(2-thienyl)-6- azatricyclo[7.4.0.0 2,6]trideca- 1(13),2,4,9,1 l-pentaen-5-yl) methanone LCMS (method M9. ES+,RT= 3.87 min) 587.3 (M+H) +

[001115] EXAMPLE 31 (METHOD D): (R)-l-(8-methoxy-9-(l -methyl-lH-pyrazol-3-yl)-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile WO 2024/184461 PCT/EP2024/056026

[001116]To a solution of Intermediate 11 (550 mg, 1.06 mmol) in THF (5 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (634.26 mg, 2.66 mmol) in DCM (5 mL) at °C. The mixture was stirred at 20 °C for 2 hr. The residue was diluted with H20 (30 mL) and extracted with DCM (15 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 10/1 to 0/1) to give EXAMPLE 31 (385 mg, 36% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.48 (s, 1H), 7.65 (d, J = 2 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.42 (d,J=2.8Hz, 1H), 7.16(s, 1H), 7.13-7.11 (m, 1H), 6.64 (d,J=7.2 Hz, 1H), 4.50 (t, J= 6.Hz, 2H), 4.12-4.07 (m, 2H), 3.91 (s, 3H), 3.81 (s, 3H), 3.11 (t, J= 6.6 Hz, 2H), 2.21-2.18 (m, 1H), 2.05-1.94 (m, 2H), 1.78 (s, 3H). LCMS (Methods. ES+, RT = 3.08 min) 499.2 (M+H) + Example No. Precursor Structure/Name LCMS 32 Int. 58 /0. t 0/N־N 1H ' (R)-1 -(8-methoxy-9-(2-methyl-2H-tetrazol- -yl)- 1 -(2-methylprop- 1 -en- 1 -yl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-3- carbonyl)-2-methylazetidine-2-carbonitrile LCMS (Methodf. ES+, RT=3.08 min) 458.2 (M+H) +.

WO 2024/184461 PCT/EP2024/056026 33 Int. 109 0 / לN 0M-N XM 1N->CNp + (S)-3-(l-(4-fluorophenyl)-8-methoxy-9-(2- methyl-2H-tetrazol-5 -yl)-5,6-dihydropyrrol o[2,l-a]isoquinoline-3-carbonyl)-4-methyl oxazolidine-4-carbonitrile LCMS (Method r. ES+,RT = 3.038 min) 514.0 (M+H) +. 34 Int. 110/°x_ N/ 0׳N־N JOdn , CN 9(S)-3-(8-methoxy-9-(2-methyl-2H-tetrazol- -yl)- 1 -propyl-5,6-dihydropyrrolo[2, 1 - a] isoquinoline-3-carbonyl)-4- methyloxazolidine-4-carbonitrile LCMS (Method s.ES+,RT =2.991 min)462.1 (M+H)+ Int. 141T T 1 0 V ״ ״ Nn-n /-n / ץ (R)-1 -(8-methoxy-9-(2-methyl-2H-tetrazol- -yl)- 1 -propyl-5,6-dihydroimidazo[5, 1 - a]isoquinoline-3-carbonyl)-2- methylpyrrolidine-2-carbonitrile LCMS (Method r.ES+,RT= 2.846 min)461.1/462.1 (M+H) + WO 2024/184461 PCT/EP2024/056026 36 Int. 156 / 7 ) n Xn ־ n ؛ (R)-1 -(8 -methoxy-9-( 1 -methyl- 1 H-pyrazol- 3-yl)-l-(2,2,2-trifluoroethyl)-5,6- dihydroimidazo[5, 1 -a] isoquinoline-3- carbonyl)-2-methylpyrrolidine-2- carbonitrile LCMS (Methodf.ES+,RT= 2.996 min)499.2/500.2 (M+H) + 37 Int. 168 CT Xn K F^/ F(R)-1-(1 -(3,3-difluorocyclobutyl)-8- methoxy-9-( 1 -methyl- 1 H-pyrazol-3 -yl)- 5,6-dihydroimidazo[5,l-a]isoquinoline-3- carbonyl)-2-methylpyrrolidine-2- carbonitrile LCMS (Methodf.ES+,RT= 3.221 min)507.2/508.2 (M+H) + 38 Int. 192 /0x N> ---- X^N 0N-N XH. 1 F ff 0 (S)-3-(8-methoxy-9-(2-methyl-2H-tetrazol- 5-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropy rrolo[2,l-a]isoquinoline-3-carbonyl)-4-met hyloxazolidine-4-carbonitrile LCMS (Methodr. RT =2.895 min) 501.2/502.0 (M+H) +.

WO 2024/184461 PCT/EP2024/056026 39 Int. 218 FZ (R)-1 -(1 -(4-fluorophenyl)-8-methoxy-9-( 1 - methyl- 1 H-pyrazol-3 -yl)-5 ,6- dihydroimidazo[5, 1 -a] isoquinoline-3- carbonyl)-2-methylpyrrolidine-2- carbonitrile LCMS (Method s. ES+,RT = 3.1min) 511.2/512.(M+H) + 40 Int. 219|| T 1 0v // ) •*N-N FZ (R)-1 -(1 -(4-fluorophenyl)-8-methoxy-9-( 1 - methyl- 1 H-pyrazol-3 -yl)-5 ,6- dihydroimidazo[5, 1 -a] isoquinoline-3- carbonyl)-2-methylazetidine-2-carbonitrile LCMS (Method s. ES+,RT =3.208 min) 497.2/498.2 (M+H) + 41 Int. 224Il T 1 0N <؛؛- ב zN^/X^X/Nx JI-N FZ (R)-1-(1 -(4-fluorophenyl)-8-methoxy-9-(2- methyl-2H-tetrazol-5 -yl)-5 ,6- dihydroimidazo[5, 1 -a] isoquinoline-3- LCMS (Method s. ES+,RT =2.995 min) 513.2/514.2 (M+H) + WO 2024/184461 PCT/EP2024/056026 carbonyl)-2-methylpyrrolidine-2- carbonitrile 42 Int. 225 /Oxxx/xx n'Tn -־n y —n । T/ F(R)-1-(1 -(4-fluorophenyl)-8-methoxy-9-(2- methyl-2H-tetrazol-5 -yl)-5 ,6- dihydroimidazo[5, 1 -a] isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile LCMS (Method s.ES+,RT=3.019min)499.2/500.2 (M+H) + 43 Int. 229 N 1 FZ (R)-3-(3-(2-cyano-2-methylpyrrolidine-l- carbonyl)- 1 -(4-fluorophenyl)-8-methoxy- 5,6-dihydroimidazo[5,l-a]isoquinolin-9- yl)picolinonitrile LCMS (Methodf, ES+,RT=3.218min) 533.2/534.2 (M+H) +.

WO 2024/184461 PCT/EP2024/056026 44 fnt. 230n-UCQn^° f'(R)-3-(3 -(2-cyano-2-methylazetidine- 1 - carbonyl)- 1 -(4-fluorophenyl)-8-methoxy- 5,6-dihydroimidazo[5,l-a]isoquinolin-9- yl)picolinonitrile LCMS (Method s, ES+, RT=3.209 min) 519.0/520.0 (M+H)+.

[001117] EXAMPLE 45 (METHOD E): (R)-l-(9-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-8-methoxy-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile

[001118]To a solution of Intermediate 17 (100 mg, 201.04 umol) in dioxane (1 mL) was added 4,4-dimethyl-5H-oxazole (39.86 mg, 402.09 umol) and DPPE (4.81 mg, 12.06 umol), t-BuOLi (80.47 mg, 1.01 mmol, 90.62 uL), Pd(OAc)2 (9.03 mg, 40.21 umol) at 20 °C. The mixture was stirred at 110 °C for 12 hr. The reaction mixture was filtered to give the residue. The residue was purified by prep-HPLC (Method 15) to give EXAMPLE 45 (8.06 mg, 7.78% yield) as a white solid. 1HNMR(400 MHz, CDCh) 5 = 1.89 (s, 3 H), 2.06 - 2.18 (m, 3 H), 2.55 - 2.65 (m, 1 H), 3.17 (t, J= 6.50 Hz, 2 H), 3.99 (s, 3 H), 4.30 (br s, 2 H), 4.66 - 4.87 (m, 2 H), 6.98 (s, 1 H), 7.07 (dd, J = 5.13, 3.63 Hz, 1 H), 7.16 (d, J = 7.63 Hz, 2 H), 7.23 - 7.26 (m, 1 H), 7.32 - 7.35 (m, 1 H), 7.38 - 7.44 (m, 3 H), 8.51 - 8.60 (m, 1 H). LCMS (Methods. ES+, RT = 3.082 min) 516.1 (M+H) + WO 2024/184461 PCT/EP2024/056026

[001119] EXAMPLE 46 {METHODF): (R)-8-methoxy-5-methyl-3-((R)-2-methyl-2-((S)- 2,2,2-trifluoro- 1 -hydroxyethyl)pyrrolidine- 1 -carbonyl)-N-( 1 -methyl-2-oxo-1 ,2-dihydropyridin- 3-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide

[001120]A mixture of Intermediate 55B (93 mg, 190.01 umol) , (lS)-2,2,2-trifluoro-l-[(2R)-2- methylpyrrolidin-2-yl] ethanol (70.95 mg, 323.02 umol, HC1) and GDI (33.89 mg, 209.umol) inNMP (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 12 hr under N2 atmosphere. The residue was purified by prep-HPLC (Method 15) to give EXAMPLE 46. (19.42 mg, 15.61% yield) as white solid. 1H NMR (400 MHz, DMSO- d6) 8= 10.96 (s, 1H), 8.46 (br d, J= 6.6 Hz, 1H), 8.37 (s, 1H), 7.44 (br d, J= 6.3 Hz, 1H), 7.32 (s, 1H), 6.69 (br d, 5.4 Hz, 1H), 6.48 (s, 1H), 6.30 (brt, J= 7.1 Hz, 1H), 5.10 - 4.96 (m, 2H), 4.(s, 3H), 3.84 - 3.60 (m, 3H), 3.56 (s, 4H), 3.27 - 3.18 (m, 1H), 2.98 (br d, J= 15.9 Hz, 1H), 2.43 - 2.32 (m, 1H), 1.86 - 1.84 (m, 1H), 1.85 - 1.66 (m, 2H), 1.61 (s, 3H), 1.08 (br d, J= 6.4 Hz, 3H). LCMS (Method q. ES+, RT = 2.773 min) 655.3/656.3 (M+H) +.

[001121] EXAMPLE 47 (METHOD G): 3-((R)-3-((2R,4S)-2-cyano-4-hydroxy-2- methylpyrrolidine-l-carbonyl)-8-methoxy-5-methyl-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2, 1 -a]isoquinolin-9-yl)picolinonitrile WO 2024/184461 PCT/EP2024/056026

[001122]To a solution of Intermediate 37 (100 mg, 174.40 pmol) and 3-bromopyridine-2- carbonitrile (38.30 mg, 209.27 pmol) in dioxane (1 mL) H20 (0.2 mL) was added C82CO3 (227.mg, 697.58 pmol) and degassed and purged with N2 for 3 time. And then the mixture was added XPHOS-Pd-G2 (13.72 mg, 17.44 pmol) and stirred at 80 °C for 2 hr. The residue was diluted with H2O 10 mL and then extracted with EtOAc 30 mL (10 mL x 3). The combined organic layers were washed with brine 30 mL (10 mL x 3), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Method 15) to give the EXAMPLE 47 (45 mg, 46.95% yield) as a white solid. 1H NMR (4MHz, DMSO-d6) 8 = 8.81 - 8.70 (m, 1H), 8.14 - 8.08 (m, 1H), 7.87 - 7.79 (m, 1H), 7.67 - 7.61 (m, 1H), 7.33 - 7.27 (m, 1H), 6.71 - 6.66 (m, 1H), 5.45 - 5.39 (m, 1H), 5.26 (quin, J = 6.0 Hz, 1H), 4.39 - 4.32 (m, 1H), 4.04 - 3.97 (m, 1H), 3.92 - 3.76 (m, 5H), 3.68 - 3.61 (m, 1H), 3.31 - 3.24 (m, 1H), 3.05 - 2.94 (m, 1H), 2.66 - 2.60 (m, 1H), 2.55 - 2.46 (m, 14H), 2.23 - 2.15 (m, 1H), 1.91 - 1.85 (m, 3H), 1.21 - 1.14 (m, 3H). LCMS (Method h. ES+, RT = 1.930 min) 550.2/551.2 (M+H)+ EXAMPLE 48 (METHOD H): (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2-methylprop-l- en-l-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3, 3,3-tri fluoro- 1- hydroxypropyl)pyrrolidin- 1 -yl)methanone

[001123]To a solution of Intermediate 57 (48 mg, 126.51 pmol) and Intermediate 258 (35.mg, 151.81 pmol, HC1) in DMF (I mL) was added HATU (62.53 mg, 164.47 pmol) and D1EA (65.40 mg, 506.05 pmol, 88.14 pL) at 20 °C. The mixture was stirred at 80 °C for 2 hr. The reaction mixture was added H20 (5 mL) at 0 °C, and then extracted with EtOAc (2 mL x 3). The combined organic layers were washed with brine (3 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by prep- HPLC (Method 15). EXAMPLE 48 (24.09 mg, 34.09% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.12 (s, 1H), 7.20 (s, 1H), 6.50 (s, 1H), 6.21 (s, 1H), 5.47 (d, J= WO 2024/184461 PCT/EP2024/056026 6.5 Hz, 1H), 4.81-4.71 (m, 1H), 4.45 - 4.32 (m, 4H), 4.09 (td,J=6.5, 13.2 Hz, 1H), 3.88 (s, 3H), 3.85 - 3.68 (m, 2H), 3.11 - 3.02 (m, 2H), 2.40 - 2.15 (m, 2H), 2.12 - 2.01 (m, 1H), 1.87 (s, 3H), 1.83 - 1.67 (m, 5H), 1.64 - 1.56 (m, 1H), 1.54 (s, 3H). LCMS (Methods. ES+, RT = 3.238 min) 559.2/560.2 (M+H) +

[001124] EXAMPLE 49 (METHOD 1): (2R,4S)-4-hydroxy-l-(l-isobutyl-8-methoxy-9-(2- methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile

[001125]To a solution of Intermediate 184 (70 mg, 137.91 umol) in pyridine (1 mL) was added TFAA (231.72 mg, 1.10 mmol, 153.36 pL) at 20 °C. The mixture was stirred at 25 °C for hr. The reaction mixture was diluted with H20 (5 mL), adjusted pH=3-4with 1M HC1 and extracted with EtOAc (3 mL x 3). The combined organic layers were washed with brine (1 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Method 15). EXAMPLE 49 (23.11 mg, 34.23% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.12 - 8.16 (m, 1 H), 7.22 - 7.(m, 1 H), 6.53 - 6.57 (m, 1 H), 5.38 - 5.45 (m,l H), 4.41 - 4.44 (m, 3 H), 4.28 - 4.40 (m, 3 H), 3.- 4.05 (m, 1 H), 3.87 - 3.93 (m, 3 H), 3.60 - 3.67 (m, 1 H), 3.03 -3.11 (m, 2 H), 2.54 - 2.64 (m, H), 2.09 - 2.17 (m, 1 H), 1.81-1.90 (m, 4H), 0.95 - 1.00 (m, 6 H). LCMS (Methodr). ES+, RT = 2.833 min) 490.1/491.1 (M+H) +.

[001126] EXAMPLE 50 (METHOD J): (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8- methoxy-N-methyl-9-(2-methyl-2H-tetrazol-5-yl)- 1 -(2-methylprop- 1 -en- 1 -yl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-3-carboxamide WO 2024/184461 PCT/EP2024/056026

[001127]Equip a 25 mL three-necked round bottom flask, addition funnel and thermometer, Ar balloon etc. DMF (1 mL) was charged to the three-necked round bottom flask, then starting Intermediate 48 (100 mg, 194.74 umol) was added to the mixture at 20 °C under Ar. At 0 °C inner temperature NaH (11.68 mg, 292.11 umol, 60% purity) was added in portions to the reaction mixture for 15 min. Then, CHI (55.28 mg, 389.47 umol, 24.25 pL) was added at 0 °C. After the addition, the mixture was stirred at 70 °C for 2 h under Ar. When the starting material was consumed the reaction was quenched with water (5 mL) and diluted with ethyl acetate (2 mL x 3). The organic layer was washed with water (3 mL x 2) and brine (5 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. When the starting material was consumed the reaction was quenched with water (5 mL) and diluted with ethyl acetate (2 mL x 3). The organic layer was washed with water (3 mL x 2) and brine (5 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Method 15). The EXAMPLE 50 (40.92 mg, 39.83% yield) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.16 (s, 1H), 7.24 (s, 1H), 6.53 (s, 1H), 6.21 (s, 1H), 4.42 (s, 3H), 4.34 - 4.16 (m, 2H), 3.89 (s, 3H), 3.47 - 3.35 (m, 1H), 3.29 - 3.20 (m, 4H), 3.10 (brt, J = 6.8 Hz, 2H), 1.93 (s, 3H), 1.89 (s, 3H), 1.77 (s, 3H). LCMS (Methodr). ES+, RT= 3.267 min) 528.1/529.(M+H) +.

Example No. Precursor Structure/Name LCMSInt. 87° זזו n-n )—y .n 7s / < ' ^CF3 F F LCMS (Method s, ES+RT=3.min) 552.0/553.(M+H)+.

WO 2024/184461 PCT/EP2024/056026 (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-l-(2,2- diflu oropropyl)-8-methoxy-N-methyl-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carboxamideInt. 93 N' 0 N/N-N V /// (11 /N V_CF>N cf3 (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8- methoxy-N-methyl-9-(2-methyl-2H-tetrazol-5- yl)-l-(l,3,4-thiadiazol-2-yl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-3- carboxamide LCMS (Method g. ES+, RT = 2.80 min) 558.1/559.(M+H) + 53 Int. 244 /0.,N.N' //N/־N JT ///N-s)11 /CFF(S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-l-(5- fluoropyridin-2-yl)-8-methoxy-N-methyl-9-(2- methyl-2H-l,2,3-triazol-4-yl)-5,6- dihydropyrrolo[2, 1 -a]isoquinoline-3- carboxamide LCMS (method h. ES+,RT = 2.min) 569.3/570.(M+H) +

[001128] EXAMPLE 54 (METHOD K): ((R)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2-methylprop- 1 -en- 1 -yl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile WO 2024/184461 PCT/EP2024/056026

[001129]To a solution of Intermediate 54 (40 mg, 78.80 pmol) in THF (0.2 mL) was added Burgess reagent (18.78 mg, 78.80 pmol) in DCM (0.2 mL). The mixture was stirred at 0 °C for hr. The reaction mixture was extracted with DCM (5 mL x 3). The combined organic layers were washed with brine 10 mL (5 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Method 15). EXAMPLE (2 mg, 4.09 pmol, 5.18% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8.42 - 8.34 (m, 1H), 7.16 (s, 1H), 6.56 - 6.51 (m, 1H), 4.38 - 4.35 (m, 3H), 4.29 - 4.16 (m, 2H), 3.86 - 3.76 (m, 4H), 3.76 - 3.64 (m, 1H), 3.06 - 2.94 (m, 2H), 2.79 - 2.73 (m, 2H), 2.41 - 2.38 (m, 1H), 2.13 - 2.04 (m, 1H), 1.98 - 1.82 (m, 2H), 1.72 - 1.65 (m, 3H), 1.15 - 1.05 (m, 6H) LCMS (Method/ ES+, RT = 2.663 min) 490.2/491.2 (M+H)+

[001130] EXAMPLE 55 (METHOD L): (l-(tert-butyl)-8-methoxy-9-(2-methyl-2H-tetrazol- 5-yl)-5,6-dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3, 3,3-tri fluoro- 1- hydroxypropyl)pyrrolidin- 1 -yl)methanone

[001131]To a solution of Intermediate 63 (100.00 mg, 179.07 pmol) and Intermediate (133.63 mg, 358.15 pmol, 2 eq) inDMF (1 mL) was addedXPHOS-Pd-G2 (14.09 mg, 17.91 pmol) at 20 °C under Ar. The mixture was stirred at 110°C for 5 h. The reaction mixture was added H20 (5 mL) at 20°C, and then extracted with EtOAc (2 mL x 3). The combined organic layers were washed with brine (3 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by prep-HPLC (Method 15). The title -449- WO 2024/184461 PCT/EP2024/056026 compound (46.93 mg, 47%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 = 8.30 (s, 1H), 7.27 (s, 1H), 5.46 (br d, J = 5.9 Hz, 1H), 4.81 (br dd, J = 5.6, 9.1 Hz, 1H), 4.43 (s, 3H), 4.34 -4.18 (m, 3H), 3.95 - 3.79 (m, 4H), 3.02 (br t, J= 6.1 Hz, 2H), 2.40 -2.17 (m, 2H), 2.(td, J = 8.5, 12.9 Hz, 1H), 1.88 - 1.70 (m, 2H), 1.65 - 1.56 (m, 1H), 1.52 (s, 3H), 1.42 (s, 9H) LCMS (Method S. ES+, RT = 3.18 min) 562.3/563.3 (M+H) + Example No. Precursor Structure/Name LCMSInt. 69Y |M 9CN ؟N' I W_/l N N'n /־n / (R)>! ( (R)-l-(l-isobutyl-8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-5,6-dihydroimidazo[5,l- a]isoquinoline-3-carbonyl)-2-methylpyrrolidine- 2-carbonitrile LCMS (Method g. ES+,RT = 3.min) 475.2/476.(M+H) +. 57 Int. 164HI* 0N ،؛؛< ؛yh .K N F^ F(R)-l-(l-(3,3-difluorocyclobutyl)-8-methoxy-9-(2-methyl-2H-tetr azol-5 -yl)-5 ,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile LCMS (Method r. ES+,RT = 3.0min) 509.1/510.(M+H) + WO 2024/184461 PCT/EP2024/056026

[001132] EXAMPLE 58 (METHOD A):(1 -isobutyl-8-methoxy-9-(2-methyl-2H-tetrazol-5- yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-l-hydroxypropyl)pyrrolidin- 1 -yl)methanone

[001133]To a solution of Intermediate 183 (100 mg, 262.17 umol) in DMF (1 mL) was added Intermediate 258 (73.51 mg, 314.61 umol, HC1 salt), HATU (119.62 mg, 314.61 umol) and DIEA (203.30 mg, 1.57 mmol, 273.99 uL). The mixture was stirred at 70°C for 16 hr. The mixture was without workup. The residue was purified by prep-HPLC (Method 15) to give the EXAMPLE (45.38 mg, 31%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.10 (s, 1 H), 7.21 (s, H), 6.42 (s, 1 H), 5.47 (d, J=6.48 Hz, 1 H), 4.76 (br dd, J=8.99, 7.15 Hz, 1 H), 4.42 (s, 3 H), 4.- 4.35 (m, 1 H), 4.15 (s, 1 H), 3.88 (s, 3 H), 3.66 - 3.83 (m, 2 H), 3.04 (s, 2 H), 2.54 (br d, J=6.Hz, 2 H), 2.26 - 2.40 (m, 1 H), 2.16 - 2.25 (m, 1 H), 2.06 (dt, 1=12.62, 8.60 Hz, 1 H), 1.68 - 1.(m, 3 H), 1.55 - 1.65 (m, 1 H), 1.53 (s, 3 H), 0.96 (dd, J=6.48, 2.93 Hz, 6 H). LCMS (Methodf. RT = 3.330 min) 560.3/561.3 (M+H) +.

WO 2024/184461 PCT/EP2024/056026 Example No. Precursor Structure/Name LCMSfnt. 248| Y 1 O HO F Jn-n 1 5■ 7־a(l-(tert-butyl)-8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3- trifluoro- 1 -hydroxypropyl)pyrrolidin- 1 - yl)methanone LCMS (method r. ES+,RT = 3.min) 561.3/562.(M+H) +

[001134] EXAMPLE 60 (METHOD O): (l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-5,6-dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-2,2,2-trifluoro-l-hydroxyethyl )pyrro lidin-1 -yl)methanone F

[001135]To a solution of Intermediate 237 (80 mg, 137.37 umol) and Intermediate 26 (102.mg, 274.73 umol) in DMF (1 mL) was added XPHOS-Pd-G2 (21.62 mg, 27.47 umol) at 20°C. The mixture was stirred at 130°C for 4hr. The reaction mixture was added H20 (5 mL), and then extracted with EtOAc (2 mL x 3). The combined organic layers were washed with brine (3 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by prep-HPLC (Method 15) to give EXAMPLE 60 (32.2 mg, 40.03%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 = 7.96 (s, 1H), 7.68 - 7.60 (m, 2H), 7.31 (s, 1H), 7.23 (t, J = 8.9 Hz, 2H), 6.62 (d, J = 6.6 Hz, 1H), 5.23 - 5.12 (m, 1H), 4.57 - 4.47 (m, 1H), 4.44 - 4.33 (m, 4H), 4.32 - 4.22 (m, 1H), 3.89 (s, 3H), 3.69 (dt, J = 6.8, 10.8 Hz, 1H), 3.21 - 3.12 (m, WO 2024/184461 PCT/EP2024/056026 2H), 2.41 (dt, J = 7.4, 11.5 Hz, 1H), 1.94 - 1.76 (m, 2H), 1.67 - 1.54 (m, 4H). LCMS (Method f.ES+, RT = 3.195 min) 586.1 (M+H) + Example No. Precursor Structure/Name LCMSInt. 239T T 1 0u -Y Im-n _/־n C / /—Y OHF(2R,4S)-1 -(1 -(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydroimidazo[5, 1 -a] isoquinoline-3- carbonyl)-4-hydroxy-2-methylpyrrolidine- 2-carbonitrile LCMS (Method h ES+,RT =1.7min) 529.2/530.(M+H) +

[001136] EXAMPLE 62 (METHOD P): (R)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2-methylallyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile

[001137]To a solution of Intermediate 241 (50 mg, 88.39 umol) in DCM (0.5 mL) was added BC13 (1 M, 441.96 pL) at -70°C. The mixture was stirred at -70°C for 10 min. The reaction mixture was added H20 (2 mL) at 0°C, and then extracted with DCM (1 mL x 3). The combined organic layers were washed with brine (2 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by prep-HPLC (Method 16") to give title compound (7.02 mg, 17.36%) as a white solid. 1H NMR (400 MHz, DMSO-d6) WO 2024/184461 PCT/EP2024/056026 6 = 8.00 (s, 1H), 7.23 (s, 1H), 6.58 (s, 1H), 4.79 (s, 1H), 4.64 (s, 1H), 4.55 (br t, J = 7.7 Hz, 2H), 4.46 - 4.33 (m, 5H), 3.88 (s, 3H), 3.36 (s, 2H), 3.06 (br t, J = 6.4 Hz, 2H), 2.73 (ddd, J = 6.3, 8.8, 11.4 Hz, 1H), 2.47 - 2.37 (m, 1H), 1.80 (d, J = 8.0 Hz, 6H). LCMS {Methods. ES+, RT= 3.min) 458.1/459.1 (M+H)+.

[001138] Biological Activity Assays

[001139] HTRF cAMP Assay in HEK293 cell lines expressing hFSHR/hTSHR/LHCGR

[001140]As noted above, glycoprotein hormone receptors, FSHR, TSHR and LHR/LHCGR predominantly activate the Gas class of intracellular G proteins, resulting in cAMP accumulation. The HTRF assay is based on a competition between native cAMP produced by cells and cAMP labeled with the dye d2 (red acceptor) for binding to a cryptate labeled antibody (Europium donor). The specific energy transfer signal is inversely proportional to the concentration of cAMP in the standard or sample.

[001141]Compounds were tested for agonist activity in cell lines over-expressing human FSHR or TSH or EHR. For each cell line, 5000 cells/well were plated in 5 pl lx Stimulation Buffer + 0.5M IBMX by Integra Multichannel Pipet in 384-well, solid white low volume plates (Greiner 784075). These plates contained 100 nl of the test compounds (in concentration-response curve format) in 100% DMSO. Then 5 pl lx Stimulation Buffer + 0.5M IBMX were added to a total reaction volume of 10 pl. Controls (FSK for positive control; lx Stimulation Buffer + 0.5M IBMX for negative control; EC 100 of the appropriate hormone) were added in columns 23 and 24. The plates were incubated at 37 °C 5% CO2 for 45 min. Following stimulation, cAMP was measured using HTRF reagents (CisBio #62AM4PEC) as described by the manufacturer. For detection, 5 pl cAMP-d2 (Acceptor) and 5 pl Anti-cAMP-Cryptate (Donor) of HTRF detection reagents were added per well and incubated at room temperature for 1 hour in darkness. The plates were read on EnVision multilabel plate reader (Perkin Elmer, CA) to measure calculated fluorescence ratio (6nm/620 nm). Dose response curves for rFSH, rTSH, rhCG and test compounds were generated using in-house analysis tool A-plus and GraphPad Prism 7 software. EC50 values and % response of the compounds compared to maximal response of the cognate hormone were calculated for each WO 2024/184461 PCT/EP2024/056026 compound in the three cell lines. The selectivity ratio for hFSHR over hTSHR was calculated as hTSHR EC50/hFSHR EC50.

[001142]The data is interpreted according to the following and shown in Tables 3 and 4: For human FSHR cAMP assay: + : > 10 nM; ++ : 9-1 nM; +++ : 0.9-0.1 nM.For human TSHR selectivity ratio (EC50 TSHR cAMP/EC50 FSHR cAMP): - : less than 1;+ : 10 to less than 25; ++ : 25 to less than 50; +++ : > 50.

[001143] Table3 Compound No. FSHR cAMP Assay TSHR Selectivity Ratio 4-1 +++ ++4-2 +++ +++4-3 ++ +++6-1 +++ ++6-2 ++ +++6-3 +++ +++6-4 ++ +++6-5 ++ +++6-6 ++ +++6-7 ++ +++6-8 ++ +++7-1 +++ ++7-2 +++ +7-3 +++ ++7-4 ++ +7-5 ++ +7-6 ++ ++7-7 ++ ++7-8 +++ +++ WO 2024/184461 PCT/EP2024/056026 Compound No. FSHR cAMP Assay TSHR Selectivity Ratio 7-9 ++ +++7-10 +++ +++7-11 ++ +++7-12 ++ +++7-13 ++ +++7-14 ++ +++7-15 +++ ++7-16 ++ +++7-17 ++ +++7-18 +++ +++7-19 +++ +++7-20 ++ +++7-21 +++ +++7-22 ++ +++7-23 ++ ++7-24 ++ +++7-25 ++ ++7-26 ++ ++7-27 ++ +++7-28 +++ ++8-1 +++ ++8-2 +++ +8-3 ++ ++8-4 + +8-5 + +8-6 +++ +8-7 + + WO 2024/184461 PCT/EP2024/056026 Compound No. FSHR cAMP Assay TSHR Selectivity Ratio 8-8 ++ +8-9 +++ ++8-10 ++ +++8-11 +++ +++8-12 ++ ++8-13 ++ +++8-14 ++ +++8-15 ++ ++8-16 ++ ++9-1 +++ ++9-2 +++ +++10-1 +++ ++10-2 ++ +10-3 ++ +10-4 +++ ++10-5 +++ ++10-6 +++ +++10-7 ++ ++10-8 +++ ++10-9 ++ +++10-10 +++ +10-11 +++ +10-12 +++ ++10-13 +++ +10-14 ++ ++10-15 +++ ++10-16 +++ +++ WO 2024/184461 PCT/EP2024/056026 Compound No. FSHR cAMP Assay TSHR Selectivity Ratio 10-17 ++ ++10-18 ++ +10-19 ++ +10-20 +++ ++10-21 ++ +++10-22 ++ +++10-23 +++ ++10-24 +++ ++10-25 ++ +++10-26 +++ +++10-27 +++ +++10-28 +++ ++10-29 +++ ++10-30 +++ +++10-31 ++ +++10-32 +++ +++10-33 +++ +++10-34 +++ +++10-35 +++ +++10-36 ++ +++10-37 +++ ++10-38 ++ +++10-39 +++ +++10-40 ++ ++10-41 +++ +++10-42 ++ ++10-43 +++ +++ WO 2024/184461 PCT/EP2024/056026 Compound No. FSHR cAMP Assay TSHR Selectivity Ratio 10-44 +++ +++10-45 ++ +++10-46 ++ +++10-47 ++ ++10-48 ++ ++11-1 +++ ++13-1 ++ ++13-2 ++ +13-3 ++ ++13-4 ++ +13-5 ++ +++13-6 ++ +13-7 ++ ++13-8 +++ +++13-9 +++ ++13-10 +++ +++13-11 +++ +++13-12 ++ +++18-1 +++ +++18-2 +++ +++18-3 +++ +++18-4 +++ +++18-5 +++ ++18-6 ++ +++18-7 +++ +++20-1 ++ +++20-2 ++ ++ WO 2024/184461 PCT/EP2024/056026 Compound No. FSHR cAMP Assay TSHR Selectivity Ratio 24-1 ++ +++24-2 ++ +++25-1 +++ +++26-1 ++ ++26-2 ++ ++32-1 ++ +++32-2 ++ +++33-1 +++ +++34-1 +++ +++MK-8389* ++ - *MK-8389:

[001144] Table 4 Example FSHR cAMP Assay TSHR Selectivity Ratio +++ +++++ +++++ ++++++ ++++++ +++++ ++++ +++++ ++ ++++ +++ WO 2024/184461 PCT/EP2024/056026 Example FSHR cAMP Assay TSHR Selectivity Ratio + +++++ ++++++ +++++ +++++ +++++ +++ ++++ ++++++ +++++ +++ ++++ ++++++ +++++ +++++ ++++ ++++ ++++++ +++++ ++++ ++++ +++++ +++++ +++++ ++++ ++++ ++++ + WO 2024/184461 PCT/EP2024/056026 Example FSHR cAMP Assay TSHR Selectivity Ratio ++ ++++ ++++ +++++ +++++ ++++ +++ ++++ +++++ ++++ +++++ ++++++ +++++ +++ ++ +++++ ++++++ +++++ +++++ ++++++ ++++++ ++++ ++++ ++++++ +++++ +++ WO 2024/184461 PCT/EP2024/056026

[001145] Progesterone release HTRF assay in GFSHR-17 cells

[001146]As noted above, the immortalized rat steroidogenic granulosa cell line, GFSHR-(ABM cat# T0605), stably expresses the rat FSH Receptor and is responsive to FSH stimulation with human FSH. This engineered cell line lacks the aromatase found in primary granulosa cells required for conversion of androgen precursors to estrogens. However it shows a robust progesterone response which can serve as a surrogate to verify the cellular activity of FSHR agonists. The cell-based assay evaluates the ability of compounds to activate FSHR in GFSHR-cells by measuring progesterone released into the supernatant using a progesterone HTRF kit from Cisbio. A ratiometric HTRF read-out to assess agonist activity of compounds is described below.

[001147]A concentration response curve was obtained in the following manner. After seeding cells and incubating at 37°C for 20 hours, test compounds were prepared at different concentrations starting at 2.7 pM with 3-fold dilutions to provide curves as a 10-point series and were dispensed to cells with the CyBi® SELMA 384/25pl. After incubation at 37°C and 5% CO2 for 20 hours, the supernatant was harvested with the CyBi® SELMA 384/25 pl and 10 pl supernatant transferred to the assay plate. Afterwards the supernatant was loaded with dyes (detection reagents), antibody labelled with Eu3+-Cryptate, and progesterone labelled with d2. An incubation step at room temperature for 1 hour in the dark followed. The plates were measured with the Envision plate reader. The progesterone present in the sample competes with the binding between the two detection reagents and thereby prevents FRET from occurring. The specific signal is inversely proportional to progesterone concentration. Compounds of the invention showed EC50 in this assay of 1650 nM or lower. Certain compounds of the invention showed EC50 in this assay of 100 nM or lower.

[001148] FSHR activation bioassay (modified Steelman-Pohley)

[001149]As noted above, the activity of the compounds described herein as agonists of the follicle-stimulating hormone receptor is investigated using a modification of the classic follicle- stimulating hormone bioassay (Steelman-Pohley) which is based on the increase in ovarian weight in immature female rats. See Steelman, S.L. and F.M. Pohley, Endocrinology, 1953, 53(6):604- 16. Immature (25-day old) female Sprague Dawley rats weighing approximately 55-70 grams are WO 2024/184461 PCT/EP2024/056026 used in the assay. FSH (5 -10 IU per injection) is used as a positive control. Alternatively, pregnant mare serum gonadotropin (PMSG) (30 IU) is used as a positive control as a single subcutaneous injection followed 48 hours later by an injection of human chorionic gonadotropin (hCG).

[001150]To stimulate follicle growth, FSH (subcutaneously) or a compound as disclosed herein (oral gavage) is administered twice daily for three days. Urinary hCG (25 IU) is then injected subcutaneously to stimulate ovulation, and animals are euthanized 18 hours later by anesthesia with isoflurane followed by exsanguination. Blood plasma is saved for pharmacokinetic analysis, including estradiol measurement as a marker of FSHR activation, or T4 measurement as a marker of off-target TSHR activation. Uterine tissue is weighed as a reflection of serum estradiol levels, and ovarian weights are measured as a reflection of increased follicular volume and/or corpora lutea formation. One ovary is frozen for tissue analysis and the other ovary is fixed in 4% formalin overnight and then transferred to a vial filled with 70% ethanol for histological analysis. To measure the number of ovulated oocytes, oviducts are collected and placed in a sterile petri dish containing a droplet of 100 pL of M2 medium supplemented with 300 pg/mL hyaluronidase under mineral oil. The ampullae of the oviducts is punctured with a fine needle and cumulus enclosed oocytes are released into the media. After 10 minutes, oocytes are transferred via capillary pipette into a new droplet of M2 media without hyaluronidase and enumerated.

[001151]All animal procedures are performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Research Council and are approved by the Institutional Animal Care and Use Committee of the Ferring Research Institute Inc. Animal Care Program, which has received accreditation from the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) and is licensed with the California Department of Health. Studies are conducted under an approved protocol (#FRI 07-0006).

[001152]While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology disclosed herein in its broader aspects.

Claims (52)

WO 2024/184461 PCT/EP2024/056026 WHAT IS CLAIMED IS:

1. A compound of Formula (A) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is -NRfRg, wherein (i) Rf and Rg together with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4 groups, wherein each Rgroup is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 13 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; or (ii) Rf is C1-C6 alkyl; and Rg is C1-C6 alkyl substituted with 1 to 4 R4c groups, wherein each R4c group is independently selected from halogen, hydroxy, and nitrile; R2 is selected from C1-C6 alkyl; C1-C6 alkenyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-Calkyl)-SO2CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6 alkyl)-NR5aR5b; phenyl; C4-C6 cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5 groups, wherein each R5 group is independently selected -465- WO 2024/184461 PCT/EP2024/056026 from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl; Xis CR20orN; R20 is selected from H, halogen, nitrile, C1-C6 alkyl, and C1-C6 haloalkyl; R3 is selected from -C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the -466- WO 2024/184461 PCT/EP2024/056026 heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11 and R12 together form a double bond, and R10 and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl;wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

2. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein X is CR20.

3. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X is N.

4. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R1 is -NRfRg, wherein: (i) Rf and Rg together with the nitrogen to which they are attached form a 4- to 8-memberedheterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4 groups, wherein each Rgroup is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; or -467- WO 2024/184461 PCT/EP2024/056026 (ii) Rf is C1-C6 alkyl; and Rg is C1-C6 alkyl substituted with 1 to 4 R4c groups, wherein each R4c group is independently selected from halogen, hydroxy, and nitrile.

5. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R1 is -NRfRg, wherein Rf and Rg together with the nitrogen to which they are attached form a 4-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl.

6. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R1 is -NRfRg, wherein Rf and Rg together with the nitrogen to which they are attached form a 5-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl.

7. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R is , wherein R is substituted with 1 to R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, - NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 Rgroups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl. -468- WO 2024/184461 PCT/EP2024/056026

8. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R1 is -NRfRg, wherein Rf and Rg together with the nitrogen to which they are attached form a 6-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl.

9. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R1 is -NRfRg, wherein Rf is C1-C6 alkyl; and Rg is C1-C6 alkyl substituted with 1 to 4 R4c groups, wherein each R4c group is independently selected from halogen, hydroxy, and nitrile.

10. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R2 is C1-C6 alkyl or C1-C6 alkenyl.

11. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R2 is C1-C6 haloalkyl.

12. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R2 is C1-C6 hydroxyalkyl.

13. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R2 is phenyl optionally substituted with 1 to 4 Rgroups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1- C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected fromH and C1-C3 alkyl.

14. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R2 is 4-fluorophenyl. -469- WO 2024/184461 PCT/EP2024/056026

15. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R2 is C4-C6 cycloalkyl optionally substituted with to 4 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl.

16. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R2 is a 5- to 6-membered heteroaryl ring containing to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl.

17. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R2 is 3,3-difluorocyclobutyl, 5-fluoropyridin-2-yl, 2- thiophenyl, 5-thiazolyl, or 1,3,4-thiadiazolyl.

18. A compound of Formula (B) Formula (B) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is י wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-Calkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms -470- WO 2024/184461 PCT/EP2024/056026 to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; Het is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 to 4 R5 groups independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl; R3 is selected from -C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and -471- WO 2024/184461 PCT/EP2024/056026 (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

19. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 18, wherein Het is a 5-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with to 4 R5 groups independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-Chaloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-Calkyl.

20. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 18, wherein Het is a 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with to 4 R5 groups independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-Chaloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-Calkyl.

21. A compound of Formula (C) -472- WO 2024/184461 PCT/EP2024/056026 Formula (C) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is , wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-Calkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; R3 is selected from C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring , wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or -473- WO 2024/184461 PCT/EP2024/056026 partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl;wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

22. A compound of Formula (D) -474- WO 2024/184461 PCT/EP2024/056026 Formula (D) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is , wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1- C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; R3 is selected from C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; m is 0, 1,2, 3, or 4; each R5 is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-Chaloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1- C3 alkyl; R6 is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein-475- WO 2024/184461 PCT/EP2024/056026 n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, , and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl;wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

23. A compound of Formula (E) -476- WO 2024/184461 PCT/EP2024/056026 Formula (E) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is , wherein R1 is substituted with 1 to 4 R4 groups, wherein each R4 group isindependently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-Calkyl optionally substituted with 1 to 4 substituents independently selected from C3-Ccycloalkyl, hydroxy and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; R3 is selected from C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; Aik is C1-C6 alkyl or C1-C6 alkenyl; R6 is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or -477- WO 2024/184461 PCT/EP2024/056026 partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl;wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

24. A compound of Formula (F) Formula (F) -478- WO 2024/184461 PCT/EP2024/056026 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is -NRfRg, wherein (i) Rf and Rg together with the nitrogen to which they are attached form a 4- to 8-memberedheterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4 groups, wherein each Rgroup is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4a and R4b is independently selected from C1- C3 alkyl; or (i) Rf is C1-C6 alkyl; and Rg is C1-C6 alkyl substituted with 1 to 4 R4c groups, wherein eachR4c group is independently selected from halogen, hydroxy, and nitrile; R2 is selected from C1-C6 alkyl; C1-C6 alkenyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-Calkyl)-SO2CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6 alkyl)-NR5aR5b; phenyl; C4-C6 cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl; R3 is selected from -C(O)NHR6, -S02-(C1-C3 alkyl), -S02-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl -479- WO 2024/184461 PCT/EP2024/056026 ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected -480- WO 2024/184461 PCT/EP2024/056026 from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11 and R12 together form a double bond, and R10 and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl;wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

25. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereofR4d4 according to any one of claims 1 to 4, 6, 7, and 10 to 24 and , wherein R1 is , whereineach R4 is independently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen.

26. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof R4^ R4bFn/Jaccording to any one of claims 1 to 4, 6, 7, and 10 to 24, wherein R1 is , wherein R4b isC1-C6 alkyl and R4a is selected from nitrile and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen.

27. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof R4- R4b Fn Jaccording to any one of claims 1 to 4, 6, 7 and 10 to 24, wherein R1 is , wherein R4a isC1-C6 alkyl and R4b is selected from nitrile and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen.

28. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-27, wherein R3 is a 5- to 6-membered heteroaryl ring containing to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5 - to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2. -481- WO 2024/184461 PCT/EP2024/056026

29. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-27, wherein R3 is 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heteroaryl ring contains 1 to 4 ring nitrogens, and wherein the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2.

30. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-27, wherein R3 is tetrazole, pyrazole, imidazole, oxazole, or pyridine, wherein R3 may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; optionally wherein R3 is tetrazole optionally substituted with C1-C3 alkyl.

31. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-27, wherein R3 is -C(O)NHR6.

32. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 31, wherein R6 is -(CR7R8)nC(O)NRdRe.

33. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 32, wherein each of R7 and R8 is independently selected from H and C1-Calkyl.

34. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 32, wherein R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen.

35. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 31, wherein R6 is C1-C6 alkyl optionally substituted with nitrile or 5- or 6- membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy. -482- WO 2024/184461 PCT/EP2024/056026

36. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 31, wherein R6 is C1-C6 alkyl optionally substituted with nitrile or tetrazole.

37. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 31, wherein R6 is phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to 7 independently selected halogens.

38. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 31, wherein R6 is cyclopropane optionally substituted with nitrile or is cyclobutane optionally substituted with nitrile.

39. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-38, wherein each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl.

40. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-38, wherein any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3 - to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl.

41. A compound of Formula (F) R R20 Formula (F) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, -483- WO 2024/184461 PCT/EP2024/056026 wherein R1 is -NRfRg, wherein Rf and Rg together with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4 groups, wherein each R4 group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4 groups, together with the atoms to which they are attached, form a 4- to 6- membered ring; and each R4a and R4b is independently selected from C1-C3 alkyl; R2 is selected from C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-C3 alkyl)-S02CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6 alkyl)- NR5aR5b; phenyl; C4-C6 cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5a and R5b is independently selected from H and C1-C3 alkyl; R20 is selected from H, halogen, nitrile, C1-C6 alkyl, and C1-C6 haloalkyl; R3 is selected from -C(O)NHR6, -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; -484- WO 2024/184461 PCT/EP2024/056026 each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11 and R12 together form a double bond, and R10 and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl;wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

42. A compound of Formula (1) -485- WO 2024/184461 PCT/EP2024/056026 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is -NRfRg, wherein Rf and Rg together with the nitrogen to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 3 R4 groups, wherein each R4 group is independently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen; R2 is selected from C1-C6 alkyl; C1-C6 haloalkyl; phenyl; and 5- to 6-membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 or 2 R5 groups, wherein each R5 group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; R3 is selected from C(O)NHR6 and 5- to 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6- membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl; R6 is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7 and R8 is independently selected from H and C1-C3 alkyl, or R7 and R8 together with the carbon to which they are attached form a 3- to 6-membered saturated or -486- WO 2024/184461 PCT/EP2024/056026 partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rd and Re is independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens; and each of R10, R11, R12, and R13 are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl,wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

43. A compound selected from the group consisting of: [8-methoxy-9-(l-methylpyrazol-3-yl)-l-thiazol-5-yl-5,6-dihydropyrrolo[2,l-«]isoquinolin-3-yl]-[(2S)-2-methyl-2- [(lA)-2,2,2-trifluoro-l-hydroxyethyl]pyrrolidin-l-yl]methanone; (l-(5-fluoropyridin-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3- yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-l-hydroxyethyl)pyrrolidin-l-yl)methanone; -487- WO 2024/184461 PCT/EP2024/056026 (A)-8-methoxy-5-methyl-3-((A)-2-methyl-2-((5)-2,2,2-trifluoro-l-hydroxyethyl) pyrrolidine-l-carbonyl)-N-(l- methyl-2-oxo-l,2-dihydropyridin-3-yl)-l-(2,2,2-triflu oroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9- carboxamide;(3S)-4-[8-methoxy-9-(l-methylpyrazol-3-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-«]isoquinoline-3-carbonyl]-3- methyl-morpholine-3 -carbonitrile; (2A)-l-[8-methoxy-9-(l-methylpyrazol-3-yl)-l-thiazol-5-yl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile;(A)-l-(l-(l-hydroxy-2-methylpropan-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile; (A)-l-(l-(2,2-difluoropropyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl)-2-methylpyrrolidine-2-carbonitrile; (A)-l-(l-(2,2-difluoropropyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl)-2-methylazetidine-2-carbonitrile;(A)-3-(2-cyano-2-methylazetidine-l-carbonyl)-N-(l-cyanocyclobutyl)-8-methoxy-l-(thiophen-2-yl)-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide;(A)-l-(l-(5-fluoropyridin-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl)-2-methylazetidine-2-carbonitrile;(A)-l-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl)-2-methylazetidine-2-carbonitrile;(2A)-l-[8-methoxy-9-oxazol-2-yl-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2-methyl- pyrrolidine-2-carbonitril e;4-[3-[(2A)-2-[( 1A)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6- dihydropyrrolo[2,l-a]isoquinolin-9-yl]-6-methyl-177-pyridin-2-one;(2A)-2-[(lA)-l-hydroxyethyl]-2-methyl-pyrrolidin-l-yl]-[8-methoxy-9-oxazol-2-yl-l-(2-thienyl)-5,6- dihydropyrrolo[2,1 -«]isoquinolin-3-yl]methanone;3-[3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-l-(4-fluorophenyl)-8-methoxy-5,6-dihydropyrrolo[2,l- a]isoquinolin-9-yl]pyridine-2-carbonitrile; 3-[3-[(2A)-2-[( 1A)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-propyl-5,6- dihydropyrrolo[2,1 -«]isoquinolin-9-yl]pyridine-2-carbonitrile; -488- WO 2024/184461 PCT/EP2024/056026 [8-methoxy-9-(2-methyltetrazol-5-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]-[(2A)-2-methyl-2- [(15)-2,2,2-tri fluoro-1 -hydroxy-ethyl]pyrrol id in-1 -yl] methanone; (2A)-l-[9-(17/-imidazol-2-yl)-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl] -2 -methyl -pyrrolidine -2 -carbonitrile;(2A)-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile;(2A)-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile; [ (27?)-2-[(17?)-l-hydroxyethyl]-2-methyl-pyrrolidin-l-yl]-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-(2-thienyl)-5, 6- dihydropyrrolo[2,1 -a] isoquinol in-3-yl] methanone; (2A)-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl] -2 -methyl -pyrrolidine -2 -carbonitrile;[(5A)-8 -metho xy-5 -methyl-9 -(2 -methyltetrazol-5 -yl)-1 -(2 -thienyl)-5,6-dihydropyrrolo [2,1 -a] isoquinolin-3 -yl] - [(2.S')-2-methyl-2-[( I /?)-2,2,2-tri fluoro-1 -hydroxy-ethyl] pyrrol idin-1 -yl] methanone; [(5A)-8-methoxy-5-methyl-9-(2-methyltetrazol-5-yl)-l-thiazol-5-yl-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]- [(2/?)-2-methyl-2-[( l .S')-2,2,2-tri lluoro-1 -hydroxy-ethyl] pyrrol idin-1 -yl] methanone; (2A)-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-thiazol-5-yl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile;(/?)-3-(3-(2-cyano-2-methylpyrrolidine-1 -carbonyl )-8-methoxy-1 -(2,2,2-trilluoroethyl )-5,6-dihydropyrrolo[2,1 - a]isoquinolin-9-yl)-5-(trifluoromethyl)picolinonitrile; (A)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl)-2-methylazetidine-2-carbonitrile;(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(l,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3- yl )((.S')-2-methyl-2-((/? )-2,2,2-tri lluoro-1 -hydroxyethyl )pyrrol idin-1 -yl )methanone; (/?)-!-(1-(3,3-difluorocyclobutyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile; (A)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl)-2-methylazetidine-2-carbonitrile; -489- WO 2024/184461 PCT/EP2024/056026 (R)-l-(l-(5-fluoropyridin-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl)-2-methylpyrrolidine-2-carbonitrile;(A)-l-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl)-2-methylpyrrolidine-2-carbonitrile;((A)-8-methoxy-5-methyl-9-(2-methyl-2H-tetrazol-5-yl)-l-(thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3- yl)((R)-2-methyl-2-((S)-2,2,2-trilluoro-l-hydroxyethyl)pyrrolidin-l-yl)methanone;5-((R)-8-methoxy-5-methyl-3-((R)-2-methyl-2-((S)-2,2,2-trifluoro-l-hydroxyethyl)pyrrolidine-l-carbonyl)-!- (2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-9-yl)nicotinamide; 3-((R)-8-methoxy-5-methyl-3-((R)-2-methyl-2-((S)-2,2,2-trifluoro-l-hydroxyethyl)pyrrolidine-l-carbonyl)-!- (2,2,2-trifluoroethyl)-5,6-dihy dropyrrolo[2,l-a]isoquinolin-9-yl)picolinonitrile;((R)-8-methoxy-5-methyl-9-(2-methyl-2H-tetrazol-5-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l- a] isoquinol in-3-yl)((//)-2-methyl-2-((.S')-2,2,2-tri fluoro-1 -hydroxyethyl )pyrrol idin-1 -yl )methanone; ((laR,9bR)-8-methoxy-7-(2-methyl-2H-tetrazol-5-yl)-5-(thiophen-2-yl)-la,9b-dihydro-lH-cyclopropa[c]pyrrolo[2, l -a] isoquinol in-3-y2-(//))(؛-methyl-2-((.S')-2,2,2-tri lluoro-1 -hydroxyethyl )pyrrol idi n-1 - yl)methanone;[(2/?)-2-[( I /?)-I -hydroxyethylJ-2-methyl-pyrrolidin-1 -yl]-[8-methoxy-9-(2-methyltetrazol-5-yl)-l -thiazol-5-yl-5,6- dihydropyrrolo[2,1 -،/] isoquinol in-3-yl] methanone; [8-methoxy-9-(2-methyltetrazol-5-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]-[(2S)-2-methyl-2- [(1 /?)-2,2,2-tri fluoro-1 -hydroxy-ethyl] pyrrol idin-1 -yl] methanone; (2R)-l-[8-methoxy-9-(l-methylpyrazol-3-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile;(2R)-l-[8-methoxy-9-(17/-pyrazol-3-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile;(2R)-1 -[ 1 -(4-fluorophenyl)-8-methoxy-9-(l -methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,1 -a] isoquinol ine-3- carbonyl] -2 -methyl -pyrrolidine -2 -carbonitrile;(2R)-1 -[8-methoxy-9-( 1 -methylpyrazol-3 -yl)-1 -propyl-5,6-dihydropyrrolo[2,1 -a]isoquinoline-3-carbonyl] -2- methyl-pyrrolidine-2-carbonitrile; 4-[3 -[(2R)-2-[( 1R)-1 -hydroxyethyl] -2-methyl-pyrrolidine-1 -carbonyl] -8-methoxy-1 -propyl-5,6- dihydropyrrolo[2,l-a]isoquinolin-9-yl]-l-methyl-pyri din-2-one; -490- WO 2024/184461 PCT/EP2024/056026 [(2R)-2-[(lR)-l-hydroxyethyl]-2-methyl-pyrrolidin-l-yl]-[8-methoxy-9-(17/-pyrazol-3-yl)-l-(2-thienyl)-5,6- dihydropyrrolo[2,1 -a] isoquinol in-3-yl] methanone;6-[8-methoxy-3-[(2/?)-2-methyl-2-[( l .S')-2,2,2-tri fluoro-1 -hydroxy-ethyl] pyrrol idi ne-1 -carbonyl]-l -(2-thienyl )-5,6- dihydropyrrolo[2,l-a]isoquinolin-9-yl]-177-pyridin-2-one;4-[3-[(2A)-2-[( 1A)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6- dihydropyrrolo[2,l-a]isoquinolin-9-yl]-l-methyl-pyri din-2-one;3-[3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l- a]isoquinolin-9-yl]pyridine-2-carbonitrile; [(5/?)-8-methoxy-5-methyl-9-( 1 -methylpyrazol-3-yl)-l -thiazol-5-yl-5,6-dihydropyrrolo[2,l -،/]isoquinolin-3-yl]- [(2/?)-2-methyl-2-[( l .S')-2,2,2-tri lluoro-1 -hydroxy-ethyl] pyrrol idin-1 -yl] methanone; (A)-l-(8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-l-(thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl)-2-methylazetidine-2-carbonitrile;(A)-1 -(8-methoxy-6-methyl-9-( 1 -methyl-1 H-pyrazol-3 -yl)-1 -(thiophen-2-yl)-5,6-dihydropyrrolo[2,1 - a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile;((A)-8-methoxy-5-methyl-9-(l-methyl-lH-pyrazol-3-yl)-l-(thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3- yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-l-hydroxyethyl)pyrrolidin-l-yl)methanone;((R)-2-((R)-1 -hydroxyethyl)-2-methylpyrrolidin-1 -yl)((S)-8-methoxy-5 -methyl-9-( 1 -methyl-1 H-pyrazol-3 -yl)-1 - (thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl)methanone((1 a/?,9bR)-8-methoxy-7-(1 -methyl-1 H-pyrazol-3 -yl)-5-(thiophen-2-yl)-1 a,9b-dihydro-1H- cyclopropa[c]pyrrolo[2, l -a] isoquinol in-3-yl)((//)-2-methyl-2-((S )-2,2,2-tri lluoro-1 -hydroxyethyl )pyrrol id in-1 - yl)methanone;(8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-l-(l,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3- yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-l-hydroxyethyl)pyrrolidin-l-yl)methanone;[(2R)-2-[(lR) -l-hydroxyethyl]-2-methyl-pyrrolidin-l-yl]-[9-(17/-imidazol-2-yl)-8-methoxy-l-(2-thienyl)-5,6- dihydropyrrolo[2,1 -a] isoquinol in-3-yl] methanone;(2R)-l-[9-(17/-imidazol-2-yl)-8-methoxy-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile; 7V-(l-cyanocyclobutyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l-(2-thienyl)-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide; -491- WO 2024/184461 PCT/EP2024/056026 N-( 1 -cyano-1 -methyl-ethyl)-3 -[(2A)-2-cyano-2-methyl -pyrrolidine-1 -carbonyl] -1 -(4-fluorophenyl)-8-methoxy-5,6- dihydropyrrolo[2,1 -a] i soqu mol me-9-carboxam ide; 3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-l-(4-fluorophenyl)-8-methoxy-7V-(2-oxo-17/-pyridin-3-yl)-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide; 3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-l-(4-fluorophenyl)-8-methoxy-7V-(l-methyl-2-oxo-3-pyridyl)- 5,6-dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide;3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-7V-(2-oxo-17/-pyridin-3-yl)-l-propyl-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide; 3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-7V-(l-methyl-2-oxo-3-pyridyl)-l-propyl-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide;N-( 1 -cyano-1 -methyl-ethyl)-3 -[(2A)-2-[( 1A)-1 -hydroxyethyl] -2-methyl-pyrrolidine-1 -carbonyl] -8-methoxy-1 - propyl-5,6-dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide;N-( 1 -cyanocyclobutyl)-3 -[(2A)-2-[( 1A)-1 -hydroxyethyl] -2-methyl-pyrrolidine-1 -carbonyl] -8-methoxy-1 -propyl- 5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide;N-( 1 -cyano-1 -methyl-ethyl)-3 -[(2A)-2-cyano-2-methyl -pyrrolidine-1 -carbonyl] -8-methoxy-1 -propyl-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide;Af-[2-(dimethylamino)-2-oxo-ethyl]-3-[(2A)-2-(hydroxymethyl)-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l- (2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide;3-(2,2-d imethylpyrrol idi ne-1 -carbonyl )-8-methoxy-.V-( I //-tetrazol-5-yl methyl )-I -(2-thienyl )-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide;3-[(2/?)-2-cyano-2-methyl-pyrrolidine-l -carbonyl]-8-methoxy-.V-( 1 -methyl-2-oxo-3-pyridyl)-l -(2-thienyl)-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide;3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-A?-(2-oxo-17/-pyridin-3-yl)-l-(2-thienyl)-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide; Af-(l-cyano-l-methyl-ethyl)-8-methoxy-3-[(2A)-2-methyl-2-[(15)-2,2,2-trifluoro-l-hydroxy-ethyl]pyrrolidine-l- carbonyl] -1 -(2 -thienyl)-5,6-dihydropyrrolo[2,1 -a] isoquinoline-9 -carboxamide; N-( 1 -cyanocyclobutyl)-3 -[(2A)-2-[( 1A)-1 -hydroxyethyl] -2-methyl-pyrrolidine-1 -carbonyl] -8-methoxy-1 -(2- thienyl)-5,6-dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide; -492- WO 2024/184461 PCT/EP2024/056026 N-( 1 -cyano-1 -methyl-ethyl)-3 -[(2A)-2-[( 1A)-1 -hydroxyethyl] -2-methyl-pyrrolidine-1 -carbonyl] -8-methoxy-1 -(2- thienyl)-5,6-dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide; N-( 1 -cyanocyclobutyl)-1 -(4-fluorophenyl)-3 -[(2A)-2-[(lA)-1 -hydroxyethyl] -2-methyl-pyrrolidine-1 -carbonyl] -8- methoxy-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide;N-( 1 -cyano-1 -methyl-ethyl)-1 -(4-fluorophenyl)-3-[(2A)-2-[( 1A)-1 -hydroxyethyl] -2-methyl-pyrrolidine-1 - carbonyl]-8-methoxy-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide;l -cyanocyclopropyl )-8-methoxy-3-[(2/?)-2-methyl-2-[( l .S')-2,2,2-trifluoro-1 -hydroxy-ethyl]pyrrolidine-1 - carbonyl] -1 -(2 -thienyl)-5,6-dihydropyrrolo[2,1 -a] isoquinoline-9 -carboxamide; N-(l-cyanocyclopropyl)-3-[(2A)-2-[(lA)-l-hydroxyethyl]-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l-(2- thienyl)-5,6-dihydropyrrolo[2,1 -a] isoquinol i ne-9-carboxam ide; 8-methoxy-A'-( l-methyl-2-oxo-3-pyridyl)-3-[(2/?)-2-methyl-2-[( l .S')-2,2,2-tri fluoro-1 -hydroxy-ethyl ]pyrrol id ine-1 - carbonyl] -1 -(2 -thienyl)-5,6-dihydropyrrolo[2,1 -a] isoquinoline-9 -carboxamide; A^-(l-cyanocyclobutyl)-8-methoxy-3-[(27?)-2-methyl-2-[(15)-2,2,2-trifluoro-l-hydroxy-ethyl]pyrrolidine-l- carbonyl] -1 -(2 -thienyl)-5,6-dihydropyrrolo[2,1 -a] isoquinoline-9 -carboxamide;,V-( l -cyanocyclobutyl )-3-[(2/? )-2-[( l /?)-I -hydroxyethyl]-2-methyl-pyrrolidine-1 -carbonyl]-8-methoxy-1 -(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide;N-( 1 -cyanocyclobutyl)-3 -[(2A)-2-cyano-2-methyl-pyrrolidine-1 -carbonyl] -1 -(4-fluorophenyl)-8-methoxy-5,6- dihydropyrrolo[2,1 -a] isoquinol ine-9-carboxamide; ,V-(3-cyanooxetan-3-yl)-8-methoxy-3-[(2/?)-2-methyl-2-[( I.S')-2,2,2-trifluoro-1 -hydroxy-ethyl]pyrrolidine-1 - carbonyl] -1 -(2 -thienyl)-5,6-dihydropyrrolo[2,1 -a] isoquinoline-9 -carboxamide; AL( 3-cyanooxetan-3 -yl)-3 -[(2A)-2-[( 1R)-1 -hydroxyethyl] -2-methyl-pyrrolidine-1 -carbonyl] -8-methoxy-1 -(2- thienyl)-5,6-dihydropyrrolo[2,1 -a] isoquinol i ne-9-carboxam ide; N-( 1 -cyano-1 -methyl-ethyl)-3 -[(2A)-2-cyano-2-methyl -pyrrolidine-1 -carbonyl] -8-methoxy-1 -(2-thienyl)-5,6- dihydropyrrolo[2,1 -r/J isoquinol ine-9-carboxamide; 3-[(2/?)-2-cyano-2-methyl-pyrrolidine-l -carbonyl]-.V-[(3/?)-3-cyanotetrahydrol'uran-3-yl]-8-methoxy-l -(2- thienyl)-5,6-dihydropyrrolo[2,1 -r/J isoquinol i ne-9-carboxam ide; 3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-A?-[(35)-3-cyanotetrahydroluran-3-yl]-8-methoxy-l-(2-thienyl)- 5,6-dihydropyrrolo[2,1 -r/J isoquinol i ne-9-carboxamide; -493- WO 2024/184461 PCT/EP2024/056026 3-[(2R)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-7V-(3-cyanooxetan-3-yl)-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide;N-( 1 -cyanocyclopropyl)-3-[(2R)-2-cyano-2-methyl -pyrrolidine-1 -carbonyl] -8-methoxy-1 -(2,2,2-trifluoroethyl)- 5,6-dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide; N-( 1 -cyanocyclobutyl)-3 -[(2A)-2-cyano-2-methyl-pyrrolidine-1 -carbonyl] -8-methoxy-1 -propyl-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide;3-[(2R)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-A^-(3-cyanooxetan-3-yl)-8-methoxy-l-propyl-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-7V-(3-cyanooxetan-3-yl)-8-methoxy-l-(2-thienyl)-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide;Af-(l-cyanocyclobutyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l-thiazol-5-yl-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide;(A)-3-(2-cyano-2-methylazetidine-l-carbonyl)-8-methoxy-N-(l-methyl-2-oxo-l,2-dihydropyridin-3-yl)-l-(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide;(A)-3-(2-cyano-2-methylazetidine-l-carbonyl)-8-methoxy-N-(2-oxo-l,2-dihydropyridin-3-yl)-l-(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide;N-(l-cyanocyclobutyl)-8-methoxy-3-((S)-2-methyl-2-((R)-2,2,2-trifluoro-l-hydroxy ethyl) pyrrolidine-1- carbonyl)-! -(1,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-9-carboxamide; (R)-3-(2-cyano-2-methylazetidine-l-carbonyl)-N-(l-cyanocyclobutyl)-8-methoxy-l-(thiophen-2-yl)-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide; N-( 1 -cyanocyclobutyl)-3 -((R)-2-((R)-1 -hydroxyethyl)-2-methylpyrrolidine-1 -carbonyl)-8-methoxy-6-methyl-1 - (thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide;3-((R)-2-cyano-2-methylpyrrolidine-l-carbonyl)-N-(l-cyanocyclobutyl)-8-methoxy-6-methyl-l-(thiophen-2-yl)- 5,6-dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide; (R)-N-(l-cyanocyclobutyl)-8-methoxy-5-methyl-3-((R)-2-methyl-2-((S)-2,2,2-trifluoro-l-hydroxyethyl)pyrrolidine-l-carbonyl)-l-(thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide; (S)-N-( 1 -cyanocyclobutyl)-3 -((R)-2-((R)-1 -hydroxyethyl)-2-methylpyrrolidine-1 -carbonyl)-8-methoxy-5 -methyl- l-(thiophen-2-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide; -494- WO 2024/184461 PCT/EP2024/056026 (4S)-N-(1-cyanocyclobutyl)-?-methoxy-4-methyl-3-((7?)-2-methyl-2-((S)-2,2,2-trifluoro-l-hydroxyethyl)pyrrolidine-l-carbonyl)-!-(thiophen-2-yl)-3a,5-dihydro-4H-cyclopenta[a]naphthalene-8- carboxamide;(5)-3-((A)-2-cyano-2-methylpyrrolidine-l-carbonyl)-N-(l-cyanocyclobutyl)-8-methoxy-5-methyl-l-(thiophen-2- yl)-5,6-dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide;(7?)-N-(l-cyanocyclobutyl)-8-methoxy-5-methyl-3-((7?)-2-methyl-2-((S)-2,2,2-tri fluoro-1-hydroxyethyl)pyrrolidine-1 -carbonyl)-! -(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1 -a] isoquinoline-9- carboxamide; (la/?,9bA)-N-(l-cyanocyclobutyl)-8-methoxy-3-((A)-2-methyl-2-((5)-2,2,2-trifluoro-l-hydroxyethyl)pyrrolidine-l- carbonyl)-5-(thiophen-2-yl)-la,9b-dihydro-lH-cyclopropa[c]pyrrolo[2,l-a]isoquinoline-7-carboxamide;Af-[2-(dimethylamino)-2-oxo-ethyl]-3-[(2S)-2-ethyl-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l-(2-thienyl)- 5,6-dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide; [ (27?)-2-[(17?)-l-hydroxyethyl]-2-methyl-pyrrolidin-l-yl]-[8-methoxy-9-(l-methylpyrazol-3-yl)-l-(2-thienyl)-5, 6- dihydropyrrolo[2,1 -a]isoquinolin-3-yl]methanone;[8-methoxy-9-(l-methylpyrazol-3-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]-[(2A)-2-methyl-2- [(15)-2,2,2-trifluoro-l-hydroxy-ethyl]pyrrolidin-l-yl]methanone;[ (27?)-2-[(15)-1-hydroxyethyl]-2-methyl-pyrrolidin-l-yl]-[8-methoxy-9-(l-methylpyrazol-3-yl)-l-propyl-5,6- dihydropyrrolo[2,1 -a]isoquinolin-3-yl]methanone;[l-(4-fluorophenyl)-8-methoxy-9-(l-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]-[(2S)-2- methyl-2-[(lA)-2,2,2-trifluoro-l-hydroxy-ethyl]pyrrolidin-l-yl]methanone;[l-(4-fluorophenyl)-8-methoxy-9-(l-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]-[(2A)-2- [(15)-1 -hydroxyethyl] -2-methyl-pyrrolidin-1 -yl] methanone; [l-(4-fluorophenyl)-8-methoxy-9-(l-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]-[(2A)-2-[(1 A)-1 -hydroxyethyl] -2 -methyl-pyrrolidin-1 -yl] methanone; [l-(4-fluorophenyl)-8-methoxy-9-(l-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]-[(2S)-2- [(15)-1 -hydroxyethyl] -2-methyl-pyrrolidin-1 -yl] methanone;[(25)-2-[( 15)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[8-methoxy-9-(1-methylpyrazol-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1 -a]isoquinolin-3-yl]methanone; [l-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]-[(2S)-2- methyl-2-[(lA)-2,2,2-trifluoro-l-hydroxy-ethyl]pyrrolidin-l-yl]methanone; -495- WO 2024/184461 PCT/EP2024/056026 [l-(4-lluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]-[(2S)-2-[l- hydroxypropyl] -2 -methyl -pyrrolidin-1 -yl] methanone; [l-(4-lluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]-[(2S)-2- [(15)-1 -hydroxyethyl] -2-methyl-pyrrolidin-1 -yl] methanone;2-cyclopropyl(hydroxy)methyl)-2-methylpyrrolidin-l-yl)(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol- 5-yl)-5,6-dihydropyrrolo[2,1 -a]isoquinolin-3-yl)methanone;(A)-3-(2-cyano-2-methylpyrrolidine-l-carbonyl)-N-(2-cyanopropan-2-yl)-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide; Af-(l-cyanocyclobutyl)-3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide;3-[(2A)-2-[(lA)-l-hydroxyethyl]-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-7V-(l-methyl-2-oxo-3-pyridyl)-l -(2- thienyl)-5,6-dihydropyrrolo[2,1 -a] isoquinol i ne-9-carboxam ide; 3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-7V-(l-methyl-2-oxo-3-pyridyl)-l-(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide;3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-8-methoxy-7V-(2-oxo-17/-pyri din-3-yl)-l-(2,2,2-tri fluoroethyl)- 5,6-dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide;3-[(2A)-2-cyano-2-methyl-pyrrolidine-l-carbonyl]-7V-[(3A or S)-3-cyanotetrahydrofuran-3-yl]-8-methoxy-l-(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide;3-[(2/?)-2-cyano-2-methyl-pyrrolidine-l -carbonyl]-.V-[(3.S' or 7?)-3-cyanotetrahydrofuran-3-yl]-8-methoxy-l-(2,2,2- trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide; [l-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl]-[(2A or S)- 4,4-difluoro-2-methyl-2-[(lA or .S')-1 -hydroxyethyl ]pyrrol id in-1 -yl] methanone; N-( 1 -cyanocyclobutyl)-3 -[(2A)-2-[( 1A)-1 -hydroxyethyl] -2-methyl-pyrrolidine-1 -carbonyl] -8-methoxy-1 -thiazol-5 - yl-5,6-dihydropyrrolo[2,1 -a]isoquinoline-9-carboxamide; A^-(l-cyanocyclobutyl)-8-methoxy-3-[(27?)-2-methyl-2-[(15)-2,2,2-trifluoro-l-hydroxy-ethyl]pyrrolidine-l- carbonyl]-l-thiazol-5-yl-5,6-dihydropyrrolo[2,l-a]isoquinoline-9-carboxamide; 2-ethyl-l-[8-methoxy-9-(l-methylpyrazol-3-yl)-l-(2-thienyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl]pyrrolidine-2-carbonitrile; -496- WO 2024/184461 PCT/EP2024/056026 re/-(2R3»3-(؟-hydroxy-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl] -2 -methyl -pyrrolidine -2 -carbonitrile;rel-(2R,3S)-1 -[ 1 -(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2, 1 -a]isoquinoline-3- carbonyl]-3-hydroxy-2-methyl-pyrrolidine-2-carbonitrile;2-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2- azabicyclo[4.2.0]octane-l-carbonitrile;(lS,5S)-2-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)- 5-methyl-2-azabicyclo[3.2.0]heptane-l-carbonitrile; (2A,45)-4-hydroxy-l-[8-methoxy-9-(2-methyltetrazol-5-yl)-l-propyl-5,6-dihydropyrro-lo[2,l-a]isoquinoline-3- carbonyl] -2 -methyl-pyrrolidine-2-carbonitrile; and(2A,45)-l-[l-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-3- carbonyl]-4-hydroxy-2-methyl-pyrrolidine-2-carbonitrile; (2R,4S)-4-hydroxy-1 -(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1 -(thiophen- 2-yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine- 2-carbonitrile; (R)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(thiophen-2-yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-3,3,3-trifluoro-l- hydroxypropyl)pyrro lidin-1 -yl)methanone; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-l- hydroxypropyl)pyrro lidin-1 -yl)methanone; -497- WO 2024/184461 PCT/EP2024/056026 (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8-methoxy-N-methyl-9-(2-methyl- 2H-tetrazol-5-yl)-1 -(thiophen-2-yl)-5,6-dihydroimidazo[5,1 -a]isoquinoline-3- carboxamide; (2R,4S)-1-(1-(3,3-difluorocyclobutyl)-8-methoxy-9-(2-methyl-2H-tetr azol-5- yl)-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-4-hydroxy-2- methylpyrrolidine-2-carbonitrile; (R)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2,2,2-trifluoroethyl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (8-methoxy-9-( 1 -methyl- lH-pyrazol-3-yl)-1 -(thiophen-2-yl)-5,6-dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-l- hydroxyethyl)pyrrolidin-1 -yl)m ethanone; (8-methoxy-9-( 1 -methyl- lH-pyrazol-3-yl)-1 -(thiophen-2-yl)-5,6-dihydroimidazo[5,la]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-l- hydroxyethyl)pyrrolidin-1 -yl) methanone; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(thiophen-2-yl)-5,6- dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-l- hydroxyethyl)pyrrolidin-1 -yl)m ethanone; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(thiophen-2-yl)-5,6- dihydroimidazo[5,l-a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-l- hydroxyethyl)pyrrolidin-1 -yl)m ethanone; (R)-3-(2-cyano-2-methylpyrrolidine-l-carbonyl)-8-methoxy-N-(l-methyl-2- oxo-1,2-dihydropyridin-3 -yl)-1 -(thiophen-2-yl)-5,6-dihydroimidazo[5,1 - a]isoquinoline-9-carboxamide; -498- WO 2024/184461 PCT/EP2024/056026 (R)-3-(2-cyano-2-methylpyrrolidine-1 -carbonyl)-8-methoxy-N-(2-oxo-1,2- dihydropyridin-3-yl)-1 -(thiophen-2-yl)-5,6-dihydroimidazo[5,1 - a]isoquinoline-9-carboxamide; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6-dihydropyrrolo[2,l- a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-tri fluoro-1- hydroxypropyl)pyrro lidin-1 -yl)methanone; ((S)-2-((R)-1,2-dihydroxy-2-methylpropyl)-2-methylpyrrolidin-1 -yl)( 1 -(4- fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1 -a]isoquinolin-3-yl)methanone; (l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-3,3,3-trifluoro-l- hydroxypropyl)pyrrolidin-1 -yl)methanone; (l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-tri fluoro-1- hydroxypropyl)pyrro lidin-1 -yl)methanone; (R)-3-(2-cyano-2-methylazetidine-l-carbonyl)-8-methoxy-N-(l-methyl-2-oxo- 1,2-dihydropyridin-3-yl)-1 -propyl-5,6-dihydropyrrolo[2,1 -a]isoquinoline-9- carboxamide; (R)-3-(2-cyano-2-methylazetidine-1 -carbonyl)-8-methoxy-N-(2-oxo-1,2- dihydropyridin-3-yl)-1 -propyl-5,6-dihydropyrrolo[2,1 -a]isoquinoline-9- carboxamide; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6-dihydroimidazo[5,l- a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-l- hydroxyethyl)pyrrolidin-1 -yl)m ethanone; -499- WO 2024/184461 PCT/EP2024/056026 (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6-dihydroimidazo[5,l- a]isoquinolin-3-yl) ((R)-2-methyl-2-((S)-2,2,2-trifluoro-l- hydroxyethyl)pyrrolidin-1 -yl)m ethanone; (R)-3-(2-cyano-2-methylazetidine-1 -carbonyl)-1 -isobutyl-8-methoxy-N-(2- oxo-1,2-dihydropyridin-3-yl)-5,6-dihydropyrrolo[2,1 -a]isoquinoline-9- carboxamide; (R)-3-(2-cyano-2-methylazetidine-1 -carbonyl)-1 -isobutyl-8-methoxy-N-(l - methyl-2-oxo-l,2-dihydropyridin-3-yl)-5,6-dihydropyrrolo[2,l-a]isoquinoline- 9-carboxamide; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-tri fluoro-1- hydroxypropyl)pyrro lidin-1 -yl)methanone; (R)-3-(2-cyano-2-methylazetidine-l-carbonyl)-8-methoxy-N-(l-methyl-2-oxo- 1,2-dihydropyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1 - a]isoquinoline-9-carboxamide; (l-(4-fluorophenyl)-8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)-5,6- dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-l- hydroxyethyl)pyrrolidin-1 -yl)m ethanone; (l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-l- hydroxyethyl)pyrrolidin-1 -yl)m ethanone; (R)-3-(2-cyano-2-methylpyrrolidine-1 -carbonyl)-1 -(4-fluorophenyl)-8- methoxy-N-(l-methyl-2-oxo-l,2-dihydropyridin-3-yl)-5,6- dihydroimidazo[5,1 -a]isoquinoline-9-carboxamide; -500- WO 2024/184461 PCT/EP2024/056026 (l-(3,5-difluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-tri fluoro-1- hydroxypropyl)pyrro lidin-1 -yl)methanone; {(S)-2- [(S)-3,3,3 -trifluoro-1 -hydroxypropyl] -2-methyl-1 -pyrrolidinyl} {11 - methoxy-12-(2-methyl-2H-tetraazol-5-yl)-3-(2-thienyl)-6- azatricyclo[7.4.0.02,6]trideca-l(13),2,4,9,l l-pentaen-5-yl}methanone; (R)-1 -(8-methoxy-9-( 1 -methyl-1 H-pyrazol-3-yl)-1 -(thiophen-2-yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (R)-1 -(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1 -(2-methylprop-1 -en-1 -yl)- 5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carbonitrile; (S)-3-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4- carbonitrile; (S)-3-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4- carbonitrile; (R)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-propyl-5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (R)-1 -(8-methoxy-9-( 1 -methyl-1 H-pyrazol-3-yl)-1 -(2,2,2-trifluoroethyl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; -501- WO 2024/184461 PCT/EP2024/056026 (R)-l-(l-(3,3-difluorocyclobutyl)-8-methoxy-9-(l-methyl-lH-pyrazol-3-yl)- 5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (S)-3-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4- carbonitrile; (R)-1 -(1 -(4-fluorophenyl)-8 -methoxy-9-( 1 -methyl-1 H-pyrazol-3 -yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (R)-1 -(1 -(4-fluorophenyl)-8 -methoxy-9-( 1 -methyl-1 H-pyrazol-3 -yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carbonitrile; (R)-l-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (R)-l-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carbonitrile; (R)-3-(3-(2-cyano-2-methylpyrrolidine-1 -carbonyl)-1 -(4-fluorophenyl)-8- methoxy-5,6-dihydroimidazo[5,l-a]isoquinolin-9-yl)picolinonitrile; (R)-3-(3-(2-cyano-2-methylazetidine-1 -carbonyl)-1 -(4-fluorophenyl)-8- methoxy-5,6-dihydroimidazo[5,l-a]isoquinolin-9-yl)picolinonitrile; (R)-1 -(9-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-8-methoxy- 1 -(thiophen-2-yl)- 5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; -502- WO 2024/184461 PCT/EP2024/056026 (R)-8-methoxy-5-methyl-3-((R)-2-methyl-2-((S)-2,2,2-trifluoro-l- hydroxyethyl)pyrrolidine-1 -carbonyl)-N-( 1 -methyl-2-oxo-1,2-dihydropyridin- 3-yl)-l-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,l-a]isoquinoline-9- carboxamide; 3-((R)-3-((2R,4S)-2-cyano-4-hydroxy-2-methylpyrrolidine-l-carbonyl)-8- methoxy-5-methyl-1 -(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1 - a]isoquinolin-9-yl)picolinonitrile; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 1 -(2-methylprop-1 -en-1 -yl)-5,6- dihydropyrrolo[2,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-tri fluoro-1- hydroxypropyl)pyrro lidin-1 -yl)methanone; (2R,4S)-4-hydroxy-l-(l-isobutyl-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8-methoxy-N-methyl-9-(2-methyl- 2H-tetrazol-5-yl)-1 -(2-methylprop-1 -en-1 -yl)-5,6-dihydropyrrolo[2,1 - a]isoquinoline-3-carboxamide; (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-1 -(2,2-diflu oropropyl)-8-methoxy- N-methyl-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxamide; (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8-methoxy-N-methyl-9-(2-methyl- 2H-tetrazol-5-yl)-1 -(1,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo[2, 1 - a]isoquinoline-3-carboxamide; (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-l-(5-fluoropyridin-2-yl)-8-methoxy- N-methyl-9-(2-methyl-2H-l,2,3-triazol-4-yl)-5,6-dihydropyrrolo[2,l- a]isoquinoline-3-carboxamide; -503- WO 2024/184461 PCT/EP2024/056026 ((R)-1 -(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1 -(2-methylprop-1 -en-1 -yl)- 5,6-dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (l-(tert-butyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dibydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-l- hydroxypropyl)pyrro lidin-1 -yl)methanone; (R)-l-(l-isobutyl-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (R)-l-(l-(3,3-difluorocyclobutyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 5,6-dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (l-isobutyl-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l- a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-tri fluoro-1- hydroxypropyl)pyrro lidin-1 -yl)methanone; (l-(tert-butyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-tri fluoro-1- hydroxypropyl)pyrro lidin-1 -yl)methanone; (l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,l-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-2,2,2-tri fluoro-1- hydroxyethyl)pyrrolidin-1 -yl)m ethanone; (2R,4S)-l-(l-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,l-a]isoquinoline-3-carbonyl)-4-hydroxy-2- methylpyrrolidine-2-carbonitrile; -504- WO 2024/184461 PCT/EP2024/056026 (R)-l-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-l-(2-methylallyl)-5,6- dihydropyrrolo[2,l-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carbonitrile; or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

44. A pharmaceutical composition comprising the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any of one of claims 1-43, and a pharmaceutically acceptable carrier.

45. A method of modulating follicle-stimulating hormone receptor (FSHR) activity in a subject, comprising administering to a subject in need thereof the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any of one of claims 1-43, or the composition according to claim 44.

46. A method of modulating follicle-stimulating hormone receptor (FSHR) activity in a biological sample, comprising contacting the biological sample with the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any of one of claims 1-43, or the composition of claim 44.

47. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any of one of claims 1-43, or the composition of claim 44, optionally wherein the disease or disorder is a fertility disorder.

48. A compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-43, or a composition of claim 44, for use in modulating follicle-stimulating hormone receptor (FSHR) activity in a subject in need thereof.

49. A compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-43, or a composition of claim 44, for use in in treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is a fertility disorder. -505- WO 2024/184461 PCT/EP2024/056026

50. Use of a compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-43, or a composition of claim 44, in the preparation of a medicament for modulating follicle-stimulating hormone receptor (FSHR) activity in a subject.

51. Use of a compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-43, or a composition of claim 44, in the preparation of a medicament for treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is a fertility disorder.

52. The method of claim 47, the compound for use of claim 49, or the use of claim 51, wherein the disease or disorder is selected from hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngiomas, combined pituitary hormone deficiency, fertile eunuch syndrome, abnormal beta subunit of LH, abnormal beta subunit of FSH, mass lesions, pituitary adenomas, cysts, metastatic cancer to the sella (breast in women, lung and prostate in men), infiltrative lesions, hemochromatosis, sarcoidosis, histiocytosis, lymphoma, lymphocytic hypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, hypothyroidism, intentional (iatrogenic) secondary hypogonadism, empty sella, pituitary infarction, Sheehan syndrome, anorexia nervosa, congenital adrenal hyperplasia, and disorders related to GnRH deficiency. -506-