IL324450A - GSK3A inhibitors and methods of using them - Google Patents

GSK3A inhibitors and methods of using them

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Publication number
IL324450A
IL324450A IL324450A IL32445025A IL324450A IL 324450 A IL324450 A IL 324450A IL 324450 A IL324450 A IL 324450A IL 32445025 A IL32445025 A IL 32445025A IL 324450 A IL324450 A IL 324450A
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c4alkyl
optionally substituted
halo
independently selected
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IL324450A
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Blueprint Medicines Corp
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Description

WO 2024/233900 PCT/US2024/028806 GSK3a INHIBITORS AND METHODS OF USE THEREOF RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63/465,428 filed on May 10, 2023, and U.S. Provisional Application No. 63/530,858, filed August 4, 2023, the entire teachings of which are incorporated herein by reference in their entirety. FIELD This application is directed to GSK3a-selective inhibitors and methods for their use, such as in enhancing anti-turn or immunity in a subject.
BACKGROUND Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed serine/threonine kinase that is encoded by two genes, GSK3a and GSK3p, first cloned by Woodgett JR [Woodgett JR, EMBO J 1990;9(8):2431-8], GSK3 kinases are key regulators of cellular signaling pathways downstream of PI3K/mTOR/AKT. GSK3 kinases phosphorylate abroad range of substrates including several transcription factors, for example NEAT [Beals CR, et. al., Science 1997;275(5308): 1930-4], and c-Jun [Wei W, et. al., Cancer Cell 2005;8(1):25- 33]. In many cases, phosphorylation of substrates by GSK3 leads to subsequent ubiquitination by ubiquitin E3 ligase (e.g., FBXW7 or P־TrCP) followed by proteasomal degradation. Conversely, GSK3 inhibition can lead to stabilization and nuclear translocation of transcription factors that can then activate multiple downstream pathways.Given the important roles that GSK3 plays in various cellular processes, targeting of GSK3 with small molecule inhibitors may have therapeutic potential for different diseases including but not limited to diabetes, cancer, viral infections, Alzheimer’s disease and other CNS disorders. Several molecules have been tested in the clinic, including AZD10[Georgievska B, et. al., JNeurochem 2013;125(3):446-56], LY2090314 [NCT01287520, NCT01214603], and others. However, dual inhibition of both GSK3a and GSK3p leads to the activation of the Wnt/p-catenin pathway through stabilization of P־catenin, a potent oncogene that is associated with the development of hyperplasia in preclinical animal models [Hall AP, et. al., Toxicol Pathol 2015;43(3):384-99].Although the two isoforms GSK3a and GSK3p were initially thought to be functionally redundant, genetic studies have revealed paralog-specific functions. Notably, while genetic knockout of GSK3p in mice is lethal [Hoeflich KP, et. al., Nature 2000; 406(6791):86-90], GSK3a knockout mice are viable [Zhou J, et. al., J Clin Invest 2013; 123(4): 1821-32]. GSK3a knockout mice exhibit mild aging phenotypes related to blockade 1 WO 2024/233900 PCT/US2024/028806 of autophagy and mTOR pathway activation, which could be reversed by treatment with mTORCI inhibitor everolimus, an immune suppressive drug. Selective, acute inhibition of either GSK3a or GSK3p in mouse embryonic stem cells (ESCs) also lead to distinct morphological phenotypes and transcriptional profiles [Chen X, et. al., Dev Cell 2017; 43(5):563-576.e4]. Furthermore, Doble et. al. reported that deletion of either GSK3a or GSK3p alone in murine embryonic stem cells (ESCs) does not lead to P־catenin accumulation, while deletion of both paralogs is required to stabilize P-catenin, consistent with observations with dual GSK3 inhibitors [Doble BW, et. al., Dev Cell 2007;12(6):957- 71]. These lines of evidence suggest that paralog-selective inhibition of GSK3a could have different pharmacology and better safety/tolerability than dual GSK3 inhibition. There are earlier reports toward such GSK3 a-selective compounds, however, the degree of reported selectivity is limited, in the range of 3 to 40-fold [US20220112216A1, Wagner FF, et. al, Sci Transl Med 2018;10(43 l):eaam8460; Amaral B, et al., ACS Chem. Neurosci. 2023; 14(6): 1080-94],T cells are critical for immune surveillance and control of cancer progression. It is well known that GSK3 inhibition bypasses the requirement for CD28-mediated co- stimulation of T cells, leading to proliferation and production of cytokines such as IL2 and IFNy [Garcia CA, et. al., J Immunol 2008;181(12):8363-71]. Dual GSK3 inhibitors have been identified in a phenotypic screen of a highly annotated kinase inhibitor library for enhancer of antigen-specific T cell activation and cytotoxicity toward tumor cells. Inhibition of GSK3a instead of GSK3p may be responsible for anti-tumor immunity, and inhibition of GSK3a may be well-tolerated. This hypothesis is supported by work from Pamela Ohashi’s lab [Tran CW, et. al., J Immunol 2017;199 (12):4056-4065] demonstrating that deletion of GSK3a in CD4 T cells reduces the level of negative T cell regulator Cbl-b post T cell stimulation. Additional literature supporting selective targeting of GSK3a in immune and cancer cells come from works of Christopher E Rudd [Taylor A, et. al., Immunity 2016; 44(2):274-86] and Alejandro Gutierrez [Hinze L, et. al., Cancer Cell 2019;35(4):664- 676.e7], through other proposed mechanisms.Herein, the identification of paralog-selective inhibitors of GSK3a and their use as single agents or in combination with anti-PD-1 or anti-PD-Ll in cancer immunotherapy is described. Without wishing to be bound by any theory, the mechanism, while still under further investigation, is thought to be mediated via both T cells and other immune cell types WO 2024/233900 PCT/US2024/028806 (e.g., myeloid compartment) in the tumor microenvironment. GSK3a-selective inhibitors may be useful as novel therapies for treating cancer and other diseases.
SUMMARY Provided herein are compounds and compositions which inhibit GSK3, morespecifically, GSK3a, thereby enhancing an immune response in a subject. For example, the IC50 values for inhibition of GSK3a provided in Table 1demonstrate that these compounds are potent inhibitors of GSK3a. Compounds provided herein are selective inhibitors of GSK3a. Also disclosed are methods of using the compounds and compositions describedherein for treating cancer.In the first aspect, the present disclosure provides a compound of Formula (F) or Formula (X): or a pharmaceutically acceptable salt thereof, wherein: is a single bond or a double bond; WO 2024/233900 PCT/US2024/028806 X1isCR3orN; X2 is selected from the group consisting of CR7, N, and NRd; X3 is selected from the group consisting of CR12, N, and NRd; X4 is selected from the group consisting of CR13, N, and NRd; Z is O or S; R1 is selected from the group consisting of halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to groups each independently selected from the group consisting of halo, OH and CN; R2 is selected from the group consisting of H, D, halo, C1-C4alkyl, and C3-C10cycloalkyl; R3 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, -(C(Ra)2)n-ORb, - (C(Ra)2)״-C(O)ORb, -(C(Ra)2)n-SO2-Rb, -N(Ra)2, C3-C10cycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12-membered heteroaryl, wherein the C1-C4alkyl, C3-C10cycloalkyl, and 4 to 12-membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl and 4 to 12- membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; R4 is selected from the group consisting of H, D, halo, C1-C4alkyl, and C3-C10cycloalkyl; R5 is selected from the group consisting of halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to groups each independently selected from the group consisting of halo, OH and CN; R6 is H or D; R7 is selected from the group consisting of H, D, halo, C1-C4alkyl, C1-C4alkoxy, C3- Ciocycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12- membered heteroaryl, wherein the C1-C4alkyl, C1-C4alkoxy, C3-C10cycloalkyl, and to 12-membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; WO 2024/233900 PCT/US2024/028806 R8 is selected from the group consisting of H, D, halo, C1-C4alkyl, and C3-C10cycloalkyl; R9 are each independently selected from the group consisting of H, D, C1-C4alkyl, C2- C4alkenyl, C2-C4alkynyl, -(C(Ra)2)n-ORb, C3-C10cycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12-membered heteroaryl, wherein the C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C10cycloalkyl, and 4 to 12-membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; or R7 and R9 are taken together with the carbon atoms to which they are attached to form Ring A, wherein Ring A is C3-C10cycloalkyl or 4 to 12-membered heterocyclyl, wherein the C3-C10cycloalkyl is optionally substituted with 1 to 4 Rc, wherein the 4 to 12- membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 4 Rc; or R8 and R9 are taken together with the carbon atom to which they are attached to form Ring B, wherein Ring B is C3-C10cycloalkyl or 4 to 12-membered heterocyclyl, wherein the C3-C10cycloalkyl is optionally substituted with 1 to 4 Rc, wherein the 4 to 12- membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 4 Rc; or R8 and R9 are taken together form a =0; R10 is selected from the group consisting of H, D, C1-C4 alkyl, -(C(Ra)2)n-ORb, -(C(Ra)2)n- SO2Rb, C3-C10cycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and to 12-membered heteroaryl, wherein the C1-C4alkyl, C3-C10cycloalkyl, and 4 to 12- membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12- membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; or R9 and R10 are taken together with the carbon atom and the nitrogen atom to which they are attached, respectively, to form Ring C, wherein Ring C is a 4 to 12-membered WO 2024/233900 PCT/US2024/028806 heterocyclyl having 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 4 Rc; or R7 and R9 are taken together with the carbon atoms to which they are attached to form Ring A, and R8 and R10 are taken together with the carbon atom and the nitrogen atom to which they are attached, respectively, to form Ring C, wherein Ring A and Ring C are each optionally substituted on a ring carbon by 1 to 4 Rc; R11 is selected from the group consisting of H, D, C1-C4alkyl, C1-C4haloalkyl, and C3- Ciocycloalkyl; R12 is selected from the group consisting of H, D, halo, C1-C4alkyl, and C3-C10cycloalkyl; or R11 and R12 are taken together with the nitrogen atom and the carbon atom to which they are attached, respectively, to form Ring D, wherein Ring D is selected from the group consisting of a 4 to 12-membered heterocyclyl 4 to 12-membered heteroaryl, wherein the 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd, and then are each optionally substituted on a ring carbon by 1 to 4 Rc; R13 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, C1-C4alkoxy, C3- Ciocycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12- membered heteroaryl, wherein the C1-C4alkyl, C1-C4alkoxy, C3-C10cycloalkyl, and to 12-membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; R14 is selected from the group consisting of H, D, and C1-C4alkyl; Each Ra is independently selected from the group consisting of H, D, halo, CN, C1-C4alkyl, and C1-C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN; Each Rb is independently selected from the group consisting of H, D, C1-C4alkyl, C3- Ciocycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12- WO 2024/233900 PCT/US2024/028806 membered heteroaryl, wherein the C1-C4alkyl, C3-C10cycloalkyl, and 4 to 12- membered aryl are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN, wherein the 4 to 12- membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are optionally substituted on a ring carbon with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN; Each Rc is independently selected from the group consisting of H, D, halo, OH, CN, C1- C4alkyl, and C1-C4alkoxy, or two Rc, attached to the same atom, form a =0, wherein said C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN; Each Rd is independently selected from the group consisting of H, D, C1-C4alkyl, and C(O)C1- 4alkyl; and m is 1, 2, or 3, and n is 0, 1, 2, or 3.
Another aspect of the disclosure is a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, or diluent and a compound disclosed herein, or a pharmaceutically acceptable salt thereof.Another aspect of the disclosure is a method of treating a disease or disorder responsive to inhibition of GSK3 (e.g, GSK3a), comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound(s) or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or disorder is a cancer.Another aspect of the disclosure is the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound(s) or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating a disease or disorder responsive to inhibition of GSK3 (e.g, GSK3a). In some embodiments, the disease or disorder is a cancer.Another aspect of the disclosure is a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound(s) or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder responsive ר WO 2024/233900 PCT/US2024/028806 to inhibition of GSK3 (e.g, GSK3a). In some embodiments, the disease or disorder is acancer.
BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows tumor volume in an MC38 mouse model of colorectal cancer with treatment with anti-PD-Ll antibody, Compound 178 or a combination of anti-PD-Ll antibody and Compound 178.
DETAILED DESCRIPTION The disclosed compounds are GSK3a inhibitors, which can be used for treating a a disease or disorder responsive to inhibition of GSK3a. Such diseases or disorders include cancer.
Compound Embodiments Example embodiments include:First embodiment: a compound represented by Formula (1): or a pharmaceutically acceptable salt thereof. The variables in Formula (I) are as described above for Formula (F) in the first aspect.Second embodiment: a compound represented by Formula (II): WO 2024/233900 PCT/US2024/028806 or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formula (II) are as defined in the first embodiment.
Third embodiment: a compound represented by Formula (Ila), (11b) or (lie): WO 2024/233900 PCT/US2024/028806 or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formulae (Ila), (11b) and (lie) are as defined in the first embodiment.
Fourth embodiment: a compound represented by Formula (F), (1), (X), (Ila), (11b) or(11c), or a pharmaceutically acceptable salt thereof, wherein Ring A is C3-C6 cycloalkyl or 4to 9-membered heterocyclyl, wherein the C3-C6 cycloalkyl is optionally substituted with 1 to Rc, wherein the 4 to 9-membered heterocyclyl has 1 to 2 ring heteroatoms each independently selected from the group consisting of 0, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 2 Rc. The remainder of the variables in Formula (F), (I),(X), (Ila), (lib) or (lie) are as defined in the first embodiment. In some embodiments, thecompound is represented by Formula (lie) or a pharmaceutically acceptable salt thereof.
Fifth embodiment: a compound represented by Formula (F), (I), (X), (Ila), (11b) or (11c), or a pharmaceutically acceptable salt thereof, wherein Ring A is represented by and the remainder of the variables in Formula(!’), (I), (X), (Ila), (11b) and (lie) are as defined in the first or fourth embodiment. In some embodiments, the compound is represented by Formula (lie) or a pharmaceutically acceptable salt thereof.
Sixth embodiment: a compound represented by Formula (III): WO 2024/233900 PCT/US2024/028806 or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formula (III) are as defined in the first embodiment.
Seventh embodiment: a compound represented by Formula (Illa) or (Illb): or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables inFormulae (Illa) and (Illb) are as defined in the first embodiment.
Eighth embodiment: a compound represented by Formula (F), (1), (X), (III), (Ilia) or(Illb), or a pharmaceutically acceptable salt thereof, wherein Ring B is C3-C6 cycloalkyl or 4 WO 2024/233900 PCT/US2024/028806 to 6-membered heterocyclyl, wherein the C3-C6 cycloalkyl is optionally substituted with 1 to Rc, wherein the 4 to 6-membered heterocyclyl has 1 to 2 ring heteroatoms each independently selected from the group consisting of 0, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 2 Rc. The remainder of the variables in Formulae (F), (1), (X), (III), (Illa) and (Illb) are as defined in the first aspect or first embodiment.
Ninth embodiment: a compound represented by Formula (F), (1), (X), (III), (Ilia) or (Illb), or a pharmaceutically acceptable salt thereof, wherein Ring B is cyclopropane, cyclobutane, cyclopentane, or tetrahydropyran, each of which is optionally substituted on a ring carbon by 1 to 2 Rc. The remainder of the variables in Formulae (F), (I), (X), (III), (Illa) and (Illb) are as defined in the first aspect or first embodiment.
Tenth embodiment: a compound represented by Formula (IV): or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formula (IV) are as defined in the first embodiment.
Eleventh embodiment: a compound represented by Formula (IVa), (IVb), (IVc) or(IVd): WO 2024/233900 PCT/US2024/028806 or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formulae (IVa), (IVb), (IVc) and (IVd) are as defined in the first embodiment. In some embodiments, the compound is represented by Formula (IVc) or (IVd) or a pharmaceutically acceptable salt thereof.
Twelfth embodiment: a compound represented by Formula (F), (1), (X), (IV), (IVa), (IVb), (IVc) or (IVd), or a pharmaceutically acceptable salt thereof, wherein Ring C is a 4 to 10-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from the group consisting of 0, S, and NRd, and then is optionally substituted on a ring carbon by to 2 Rc. The remainder of the variables in Formulae (F), (I), (X), (IV), (IVa), (IVb), (IVc) WO 2024/233900 PCT/US2024/028806 and (IVd) are as defined in the first embodiment. In some embodiments, the compound is represented by Formula (IVc) or (IVd) or a pharmaceutically acceptable salt thereof.
Thirteenth embodiment: a compound represented by Formula (F), (1), (X), (IV), (IVa), (IVb), (IVc) or (IVd), or a pharmaceutically acceptable salt thereof, wherein Ring C is piperidine, 1,4-oxazepane, azetidine, morpholine, pyrrolidine, piperazine, piperazine-2-one, octahydrocyclopenta[c]pyrrole, or azepane, each of which is optionally substituted on a ring carbon by 1 to 2 Rc. The remainder of the variables in Formulae (F), (I), (X), (IV), (IVa), (IVb), (IVc) and (IVd) are as defined in the first embodiment. In some embodiments, the compound is represented by Formula (IVc) or (IVd) or a pharmaceutically acceptable salt thereof.
Fourteenth embodiment: a compound represented by Formula (F), (I), (X), (IV), (IVa), (IVb), (IVc) or (IVd), or a pharmaceutically acceptable salt thereof, wherein Ring C is represented by independently C1-C3alkyl optionally substituted with halo or OH. Alternatively, Rc is -CHor -CHOH. The remainder of the variables in Formulae (F), (I), (X), (IV), (IVa), (IVb), (IVc) and (IVd) are as defined in the first embodiment. In some embodiments, the compound is represented by Formula (IVc) or (IVd) or a pharmaceutically acceptable salt thereof.
Fifteenth embodiment: a compound represented by Formula (V): WO 2024/233900 PCT/US2024/028806 or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formula (V) are as defined in the first embodiment. 5Sixteenth embodiment: a compound represented by Formula (Va) or (Vb): or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formulae (Va) and (Vb) are as defined in the first embodiment.
Seventeenth embodiment: a compound represented by Formula (VI): WO 2024/233900 PCT/US2024/028806 or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formula (VI) are as defined in the first embodiment.
Eighteenth embodiment: a compound represented by Formula (VI), or a pharmaceutically acceptable salt thereof, wherein:X1isCR3orN; X2isCR7orN; X3isCR12 orN; X4isCR13 orN; Z is O or S; R1 is selected from the group consisting of halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C1- C4haloalkyl; R2 is selected from the group consisting of H, D, C1-C4alkyl, and C3-C10cycloalkyl; R3 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, -(C(Ra)2)n-ORb, - (C(Ra)2)״-C(O)ORb, -(C(Ra)2)n-SO2-Rb, -N(Ra)2, C3-C10cycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12-membered heteroaryl, wherein the C1-C4alkyl, C3-C10cycloalkyl, and 4 to 12-membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl and 4 to 12- membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; R4 is selected from the group consisting of H, D, C1-C4alkyl, and C3-C10cycloalkyl; WO 2024/233900 PCT/US2024/028806 R5 is selected from the group consisting of halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C1- C4haloalkyl; R6 is H or D; R7 is selected from the group consisting of H, D, halo, C1-C4alkyl, C1-C4alkoxy, C3- Ciocycloalkyl, and 4 to 12-membered heterocyclyl, wherein the C1-C4alkyl, C1- C4alkoxy, and C3-C10cycloalkyl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; R8 is selected from the group consisting of H, D, C1-C4alkyl, and C3-C10cycloalkyl; R9 are each independently selected from the group consisting of H, D, C1-C4alkyl, C2- C4alkenyl, C2-C4alkynyl, -(C(Ra)2)n-ORb, C3-C10cycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12-membered heteroaryl, wherein the C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C10cycloalkyl, and 4 to 12-membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; or R7 and R9 are taken together with the carbon atoms to which they are attached to form Ring A, wherein Ring A is C3-C10cycloalkyl or 4 to 12-membered heterocyclyl, wherein the C3-C10cycloalkyl is optionally substituted with 1 to 4 Rc, wherein the 4 to 12- membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 4 Rc; and/or R8 and R9 are taken together with the carbon atom to which they are attached to form Ring B, wherein Ring B is C3-C10cycloalkyl or 4 to 12-membered heterocyclyl, wherein the C3-C10cycloalkyl is optionally substituted with 1 to 4 Rc, wherein the 4 to 12- membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 4 Rc; or R8 and R9 are taken together form a =0;17 WO 2024/233900 PCT/US2024/028806 R10 is selected from the group consisting of H, D, C1-C4 alkyl, -(C(Ra)2)n-ORb, -(C(Ra)2)n- SO2Rb, C3-C10cycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and to 12-membered heteroaryl, wherein the C1-C4alkyl, C3-C10cycloalkyl, and 4 to 12- membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12- membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; or R9 and R10 are taken together with the carbon atom and the nitrogen atom to which they are attached, respectively, to form Ring C, wherein Ring C is a 4 to 12-membered heterocyclyl having 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 4 Rc; R11 is selected from the group consisting of H, D, C1-C4alkyl, and C3-C10cycloalkyl; R12 is selected from the group consisting of H, D, halo, C1-C4alkyl, and C3-C10cycloalkyl; R13 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, C1-C4alkoxy, C3- Ciocycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12- membered heteroaryl, wherein the C1-C4alkyl, C1-C4alkoxy, C3-C10cycloalkyl, and to 12-membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; R14 is selected from the group consisting of H, D, and C1-C4alkyl; Each Ra is independently selected from the group consisting of H, D, halo, CN, C1-C4alkyl, and C1-C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN; Each Rb is independently selected from the group consisting of H, D, C1-C4alkyl, C3- Ciocycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12- membered heteroaryl, wherein the C1-C4alkyl, C3-C10cycloalkyl, and 4 to 12- membered aryl are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN, wherein the 4 to 12- 18 WO 2024/233900 PCT/US2024/028806 membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are optionally substituted on a ring carbon with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN; Each Rc is independently selected from the group consisting of H, D, halo, OH, CN, C1- C4alkyl, and C1-C4alkoxy, or two Rc, attached to the same atom, form a =0, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN; Each Rd is independently selected from the group consisting of H, D, C1-C4alkyl, and C(O)C1- 4alkyl; and n is 0, 1, 2, or 3.
Nineteenth embodiment: a compound represented by Formula (VI), or a pharmaceutically acceptable salt thereof, wherein:X1isCR3orN; X2isCR7orN; X3isCR12 orN; X4isCR13 orN; Z is O; R1 is selected from the group consisting of halo, OH, C1-C4alkyl, C1-C4alkoxy, and C1- C4haloalkyl; R2 is selected from the group consisting of H, D, and C1-C4alkyl; R3 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, -(C(Ra)2)n-ORb, - (C(Ra)2)״-C(O)ORb, -(C(Ra)2)n-SO2-Rb, -N(Ra)2, C3-C8cycloalkyl, 4 to 10-membered heterocyclyl, 4 to 10-membered aryl, and 4 to 10-membered heteroaryl, wherein the C1-C4alkyl, C3-C8cycloalkyl, and 4 to 10-membered aryl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 10-membered heterocyclyl and 4 to 10- membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 3 Rc; WO 2024/233900 PCT/US2024/028806 R4 is selected from the group consisting of H, D, and C1-C4alkyl; R5 is selected from the group consisting of halo, OH, C1-C4alkyl, C1-C4alkoxy, and C1- C4haloalkyl; R6 is H or D; R7 is selected from the group consisting of H, D, halo, C1-C4alkyl, C1-C4alkoxy, C3- C8cycloalkyl, and 4 to 10-membered heterocyclyl, wherein the C1-C4alkyl, C1- C4alkoxy, and C3-C8cycloalkyl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are each optionally substituted on a ring carbon with 1 to 3 Rc; R8 is selected from the group consisting of H, D, and C1-C4alkyl; R9 are each independently selected from the group consisting of H, D, C1-C4alkyl, C2- C4alkenyl, C2-C4alkynyl, -(C(Ra)2)n-ORb, C3-C8cycloalkyl, and 4 to 10-membered heterocyclyl, wherein the C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, and C3- C8cycloalkyl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 10- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are each optionally substituted on a ring carbon with 1 to 3 Rc; or R7 and R9 are taken together with the carbon atoms to which they are attached to form Ring A, wherein Ring A is C3-C8cycloalkyl or 4 to 10-membered heterocyclyl, wherein the C3-C8cycloalkyl is optionally substituted with 1 to 3 Rc, wherein the 4 to 10- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 3 Rc; and/or R8 and R9 are taken together with the carbon atom to which they are attached to form Ring B, wherein Ring B is C3-C8cycloalkyl or 4 to 10- membered heterocyclyl, wherein the C3-C8cycloalkyl is optionally substituted with 1 to 3 Rc, wherein the 4 to 10- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 3 Rc; or WO 2024/233900 PCT/US2024/028806 R8 and R9 are taken together form a =0; R10 is selected from the group consisting of H, D, C1-C4 alkyl, -(C(Ra)2)n-ORb, -(C(Ra)2)n- SO2Rb, C3-C8cycloalkyl, 4 to 10-membered heterocyclyl, 4 to 10-membered aryl, and to 10-membered heteroaryl, wherein the C1-C4alkyl, C3-C8cycloalkyl, and 4 to 10- membered aryl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 10- membered heterocyclyl and 4 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 3 Rc; or R9 and R10 are taken together with the carbon atom and the nitrogen atom to which they are attached, respectively, to form Ring C, wherein Ring C is a 4 to 10-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 3 Rc; R11 is selected from the group consisting of H, D, and C1-C4alkyl; R12 is selected from the group consisting of H, D, halo, and C1-C4alkyl; R13 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, and C1-C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to Rc; R14 is selected from the group consisting of H, D, and C1-C4alkyl; Each Ra is independently selected from the group consisting of H, D, halo, CN, C1-C4alkyl, and C1-C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH and CN; Each Rb is independently selected from the group consisting of H, D, C1-C4alkyl, C3- C8cycloalkyl, 4 to 10-membered heterocyclyl, 4 to 10-membered aryl, and 4 to 10- membered heteroaryl, wherein the C1-C4alkyl, C3-C8cycloalkyl, and 4 to 10- membered aryl are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH and CN, wherein the 4 to 10- membered heterocyclyl and 4 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, N, and WO 2024/233900 PCT/US2024/028806 NRd and then are optionally substituted on a ring carbon with 1 to 3 groups each independently selected from the group consisting of halo, OH and CN; Each Rc is independently selected from the group consisting of H, D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, or two Rc, attached to the same atom, form a =0, whereinthe C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groupseach independently selected from the group consisting of halo, OH and CN; Each Rd is independently selected from the group consisting of H, D, C1-C4alkyl, and C(O)C1- 4alkyl; and n is 0, 1, 2, or 3.
Twentieth embodiment: a compound represented by Formula (Via), (VIb), (Vic), (Vid),(Vie), (VIf), (Vig), or (Vlh): WO 2024/233900 PCT/US2024/028806 WO 2024/233900 PCT/US2024/028806 or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables inFormulae (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), and (VIh) are as defined in the first, eighteenth, or nineteenth embodiment.
Twenty-first embodiment: a compound represented by Formula (VII): or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formula (VII) are as defined in the first, eighteenth, or nineteenth embodiment.
Twenty-second embodiment: a compound represented by Formula (Vila) or (Vllb): WO 2024/233900 PCT/US2024/028806 or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formula (Vila) and Formula (Vllb) are as defined in the first, eighteenth, or nineteenth embodiment.
Twenty-third embodiment: a compound represented by Formulae (I), (Vila) or (Vllb), or a pharmaceutically acceptable salt thereof, wherein X1isCR3orN; X4 is selected from the group consisting of CR13, N, and NRd; R1 is selected from the group consisting of halo, C1-C4alkyl, and C1-C4haloalkyl; R2 is selected from the group consisting of H, D, and C1-C4alkyl; R3 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, -(C(Ra)2)n-ORb, - (C(Ra)2)״-C(O)ORb , -(C(Ra)2)n-SO2-Rb, -N(Ra)2, C3-C8cycloalkyl, and 4 to 10-membered heterocyclyl, wherein the C1-C4alkyl and C3-C10cycloalkyl are eachoptionally substituted with 1 to 3 Rc, wherein the 4 to 10-membered heterocyclyl has WO 2024/233900 PCT/US2024/028806 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are optionally substituted on a ring carbon with 1 to 3 Rc; R4 is selected from the group consisting of H, D, and C1-C4alkyl; R5 is selected from the group consisting of halo, C1-C4alkyl, and C1-C4haloalkyl; R6 is H or D; R7 is selected from the group consisting of H, D, halo, C1-C4alkyl, and C1-C4alkoxy, C3- C6cycloalkyl, and 4 to 7-membered heterocyclyl, wherein the C1-C4alkyl, C1- C4alkoxy, and C3-C6cycloalkyl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 7-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are each optionally substituted on a ring carbon with 1 to 3 Rc; R8 is selected from the group consisting of H, D, and C1-C4alkyl; R9 are each independently selected from the group consisting of H, D, C1-C4alkyl, C2- C4alkynyl, -(C(Ra)2)n-ORb, C3-C8cycloalkyl, and 4 to 10-membered heterocyclyl, wherein the C1-C4alkyl, C2-C4alkynyl, and C3-C8cycloalkyl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are optionally substituted on a ring carbon with 1 to 3 Rc; or R8 and R9 are taken together with the carbon atom to which they are attached to form Ring B, wherein Ring B is C3-C8cycloalkyl or 4 to 10- membered heterocyclyl, wherein the C3-C8cycloalkyl is optionally substituted with 1 to 3 Rc, wherein the 4 to 10- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 3 Rc; or R8 and R9 are taken together form a =0; R10 is selected from the group consisting of H, D, C1-C4 alkyl, -(C(Ra)2)n-ORb, -(C(Ra)2)n- SO2Rb,C3-C8cycloalkyl, and 4 to 10-membered heterocyclyl, wherein the C1-C4 alkyl and C3-C8cycloalkyl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected WO 2024/233900 PCT/US2024/028806 from the group consisting of O, S, and NRd and then are optionally substituted on a ring carbon with 1 to 3 Rc; or R9 and R10 are taken together with the carbon atom and the nitrogen atom to which they are attached, respectively, to form Ring C, wherein Ring C is a 4 to 10-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 3 Rc; R11 is selected from the group consisting of H, D, and C1-C4alkyl; R12 is selected from the group consisting of H, D, halo, and C1-C4alkyl; R13 is selected from the group consisting of H, D, halo, CN, and C1-C4alkyl; R14 is selected from the group consisting of H, D, and C1-C4alkyl; Each Ra is independently selected from the group consisting of H, D, and C1-C4alkyl; Each Rb is independently selected from the group consisting of H, D, C1-C4alkyl, C1- C4alkoxy, C3-C8cycloalkyl, and 4 to 10-membered heterocyclyl, wherein the C1- C4alkyl and C3-C8cycloalkyl are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH and CN, wherein the to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are optionally substituted on a ring atom with 1 to 3 groups each independently selected from the group consisting of halo, OH and CN; Each Rc is independently selected from the group consisting of D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, or two Ra, attached to the same atom, form a =0, wherein the C1- C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH and CN; Each Rd is independently selected from the group consisting of H, D, C1-C4alkyl, and C(O)C1- 4alkyl; and n is 0, 1, 2, or 3.
Twenty-fourth embodiment: a compound represented by Formula (Villa), (VIIIb), (VIIIc), or (Vllld), TI WO 2024/233900 PCT/US2024/028806 WO 2024/233900 PCT/US2024/028806 or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formulae (Villa), (VIIIb), (VIIIc) and (Vllld) are as defined in the first, eighteenth, nineteenth, or twenty-third embodiment.
Twenty-fifth embodiment: a compound represented by Formula (Ville), (VIIIf), (VIIIg) or (Vlllh): (VIIIg), or WO 2024/233900 PCT/US2024/028806 or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formulae (Ville), (VIIIf), (VIIIg) and (Vlllh) are as defined in the first, eighteenth, nineteenth, or twenty-third embodiment.
Twenty-sixth embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (VIIIf), (VIIIg), (Vlllh) and (X), or a pharmaceutically acceptable salt thereof, wherein R1 is halo, -OH, C1-C4alkyl, or C1-C4alkoxy; and the remainder of the variables are as defined in the first aspect, or the first, eighteenth, nineteenth, or twenty-third embodiment.
Twenty-seventh embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (VIHb), (VIIIc), (Vllld), (Ville), (VIIIf), (VIIIg), (Vlllh) and (X), or a pharmaceutically acceptable salt thereof, wherein R1 is -CH3, -Cl, -OH, or -OMe; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, or twenty-third embodiment.
Twenty-eighth embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (VIHb), (VIIIc), (Vllld), (Ville), (VIIIf), (VIIIg), (Vlllh), and (X) or a pharmaceutically acceptable salt thereof, wherein R2 is H, D, halo, or C1-C4alkyl; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, or twenty-seventh embodiment.
WO 2024/233900 PCT/US2024/028806 Twenty-ninth embodiment: a compound represented by any one of Formulae (F), (1), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (Vine), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R2 is H; and the remainder of the variables are as defined in the first aspec or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, or twenty- seventh embodiment.
Thirtieth embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (lib), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, - (C(Ra)2)n-ORb, -(C(Ra)2)n-C(O)ORb, -(C(Ra)2)n-SO2-Rb, -N(Ra)2, C3-C6cycloalkyl, 4 to 7- membered heterocyclyl, phenyl, and 4 to 6-membered heteroaryl, wherein the C1-C4alkyl, C3- C6cycloalkyl, and phenyl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 7- membered heterocyclyl and 4 to 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 3 Rc; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, or twenty-ninth embodiment.
Thirty-first embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of-CH2CH3, - CH2OCH3, -CF3, -OCH3, H, -CN, -CHF2, -CHFCH3, -CHF-CHF, -CH(CH3)OMe, -OCHF2, Cl, -OCH2CH3, F, -CH3, -O-cyclopropyl, -O-CH2CH2CH3, -O-CF3, -N(CH3)2, -O-CH(CH3)2, -CH2OCH2CH3, -CHCHF2, -CHCHF, -CHSO.CH3, -CF2Me, -C(=O)OCH3, - C(=O)OCH2CH2CH3, -CH2CF3, and -CH2CO2H, or is represented by one of the following structures: N^ ס־ך ־ /^ MeO^/X WO 2024/233900 PCT/US2024/028806 and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, or twenty-ninth embodiment.
Thirty-second embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (Vine), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R3 is -CHCH3, -CHOCH3, -CF3, or -OCH3; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, or twenty-ninth embodiment.
Thirty-third embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (Vine), (vnid), (Ville), (Vlllf), (vnig), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R4 is H, D, halo, or C1-C4alkyl; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, or thirty- second embodiment.
Thirty-fourth embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (lib), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vnid), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R4 is H; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, or thirty-second embodiment.
Thirty-fifth embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R5 is halo, OH, C1-C4alkyl, C1-C4haloalkyl or C1-C4alkoxy; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, WO 2024/233900 PCT/US2024/028806 nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, or thirty-fourth embodiment.
Thirty-sixth embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (Vine), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R5 is Me, Cl, -OH, -CHF2 or -OCH3; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, or thirty-fourth embodiment.
Thirty-seventh embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (Vine), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R7 is H, D, halo, C1-C4alkyl, C1-C4alkoxy, or 4 to 7- membered heterocyclyl, wherein the C1-C4alkyl, and C1-C4alkoxy are each optionally substituted with 1 to 3 Rc, wherein the 4 to 7-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are each optionally substituted on a ring carbon with 1 to 3 Rc; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, or thirty-sixth embodiment.
Thirty-eighth embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (Vine), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R7 is H, morpholin-N-yl, -CF3, -F, -OCHF2, -OCHCH3, or - OCH3; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty- ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, or thirty-sixth embodiment.
WO 2024/233900 PCT/US2024/028806 Thirty-ninth embodiment: a compound represented by any one of Formulae (F), (1), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (Vine), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R7 is H; and the remainder of the variables are as defined in the first aspect or in the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty- seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty- fourth, thirty-fifth, or thirty-sixth embodiments.
Fortieth embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (lib), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R8 is H, D, halo, or C1-C4alkyl; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiments.
Forty-first embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R8 is H or -CH3; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment.
Forty-second embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R8 is H; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, WO 2024/233900 PCT/US2024/028806 twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment.
Forty-third embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R9 are each independently H, D, C1-C4alkyl, C2-C4alkynyl, - (C(Ra)2)n-ORb, or C3-C8cycloalkyl, wherein the C1-C4alkyl, C2-C4alkynyl, and C3- C8cycloalkyl are each optionally substituted with 1 to 3 Rc; and the remainder of the variables are as defined in the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, or forty- second embodiment.
Forty-fourth embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R9 is H, Me, -CHOCHCH3, -CHCHCH3, -CHCH3, - CH2OCH3, -CHCHF2, cyclopropyl, -CH2C=CH, -CH2CH2OCH3, or -CHF2; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, or forty-second embodiment.
Forty-fifth embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R9 is H, Me, -CHOCHCH3, -CHCHCH3, -CHCH3, or - CH2OCH3; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty- ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, or forty-second embodiment.
WO 2024/233900 PCT/US2024/028806 Forty-sixth embodiment: a compound represented by any one of Formulae (F), (1), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R10 is H, D, C1-C4 alkyl, -(C(Ra)2)n-ORb, -(C(Ra)2)n-SO2Rb, or C3-C8cycloalkyl, wherein the C1-C4 alkyl and C3-C8cycloalkyl are each optionally substituted with 1 to 3 Rc; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty- sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, or forty-fifth embodiment.
Forty-seventh embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R10 is selected from the group consisting of H, -CH3, - CH2CH3, -CH2CH2CH3, -CH2CH2SO2CH3, -CD,CD3, -CHCHOH, -CH2CH2OCH3, - CH(CH3)2, or -CD3; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty- sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, or forty-fifth embodiment.
Forty-eighth embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R10 is H, -CH3, or -CH2CH3; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, or forty-fifth embodiment.
WO 2024/233900 PCT/US2024/028806 Forty-ninth embodiment: a compound represented by any one of Formulae (F), (1), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R11 is H, D, halo, or C1-C4alkyl; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty- seventh, or forty-eighth embodiment.
Fiftieth embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (lib), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R11 is H; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty- eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty- third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, or forty-eighth embodiment.
Fifty-first embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (lib), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R12 is H, D, halo, or C1-C4alkyl; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty- first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty- eighth, forty-ninth, or fiftieth embodiment.
Fifty-second embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), WO 2024/233900 PCT/US2024/028806 (Vlllb), (Vine), (vnid), (Vine), (vnif), (vnig), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R12 is selected from the group consisting of H, D, or halo; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, forty- fifth, forty-sixth, forty-seventh, forty-eighth, forty-ninth, or fiftieth embodiment.
Fifty-third embodiment: a compound represented by any one of Formulae (F), (1), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (Vine), (vnid), (Ville), (Vlllf), (vnig), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R12 is H or F; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty- first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty- eighth, forty-ninth, or fiftieth embodiment.
Fifty-fourth embodiment: a compound represented by any one of Formulae (F), (1), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (Vine), (vnid), (Ville), (Vlllf), (vnig), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R12 is H; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty- second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty-eighth, forty- ninth, or fiftieth embodiment.
Fifty-fifth embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (lib), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R13 is H, D, halo, or C1-C4alkyl; and the remainder of the variables are WO 2024/233900 PCT/US2024/028806 as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty- first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty- eighth, forty-ninth, fiftieth, fifty-first, fifty-second, fifty-third or fifty-fourth embodiment.
Fifty-sixth embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R13 is selected from the group consisting of H, D, or halo; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, forty- fifth, forty-sixth, forty-seventh, forty-eighth, forty-ninth, fiftieth, fifty-first, fifty-second, fifty-third or fifty-fourth embodiment.
Fifty-seventh embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R13 is H or F; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty- first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty- eighth, forty-ninth, fiftieth, fifty-first, fifty-second, fifty-third or fifty-fourth embodiment.
Fifty-eighth embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R13 is H; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, WO 2024/233900 PCT/US2024/028806 twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty- second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty-eighth, forty- ninth, fiftieth, fifty-first, fifty-second, or fifty-third embodiment.
Fifty-ninth embodiment: a compound represented by any one of Formulae (F), (I), (II), (Ila), (11b), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (VlUb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (VHIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R14 is H; and the remainder of the variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty- second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty-eighth, forty- ninth, fiftieth, fifty-first, fifty-second, fifty-third, fifty-fourth, fifty-fifth, fifty-sixth, fifty- seventh or fifty-eighth embodiment.
Sixtieth embodiment: a compound represented by Formula (IXa) or (IXb): or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of halo, C1-C4alkyl, and C1-C4haloalkyl; WO 2024/233900 PCT/US2024/028806 R3 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, -(C(Ra)2)n-ORb, - (C(Ra)2)״-C(O)ORb , -(C(Ra)2)n-SO2-Rb, -N(Ra)2, C3-C8cycloalkyl, and 4 to 10- membered heterocyclyl, wherein the C1-C4alkyl and C3-C8cycloalkyl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 10-membered heterocyclyl has to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are optionally substituted on a ring carbon with 1 to 3 Rc; R5 is selected from the group consisting of halo, C1-C4alkyl, and C1-C4haloalkyl; R8 is selected from the group consisting of H, D, and C1-C4alkyl; R9 is selected from the group consisting of H, D, C1-C4alkyl, -(C(Ra)2)n-ORb, C3- C8cycloalkyl, and 4 to 10-membered heterocyclyl, wherein the C1-C4alkyl and C3- C8cycloalkyl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 10- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are optionally substituted on a ring carbon with 1 to 3 Rc; R10 is selected from the group consisting of H, D, C1-C4 alkyl, C3-C10cycloalkyl, and 4 to 12- membered heterocyclyl, wherein the C1-C4 alkyl and C3-C10cycloalkyl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl has to 4 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are optionally substituted on a ring carbon with 1 to 4 Rc; or R9 and R10 are taken together with the carbon atom and the nitrogen atom to which they are attached, respectively, to form Ring C, wherein Ring C is a 4 to 10-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 3 Rc; R11 is selected from the group consisting of H, D, and C1-C4alkyl; R13 is selected from the group consisting of H, D, halo, CN, and C1-C4alkyl; Each Ra is independently selected from the group consisting of H, D, and C1-C4alkyl; Each Rb is independently selected from the group consisting of H, D, C1-C4alkyl, and C1- C4alkoxy; WO 2024/233900 PCT/US2024/028806 Each Rc is independently selected from the group consisting of D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, or two Ra, attached to the same atom, form a =0; and Each Rd is independently selected from the group consisting of H, D, and C1-C4alkyl; and n is 0, 1, or 2.
Sixty-first embodiment: a compound represented by Formula (IXa) or (IXb), or a pharmaceutically acceptable salt thereof, wherein: R1 is halo or C1-C3alkyl; R3 is C1-C3alkyl or -(C(Ra)2)n-ORb, wherein n is 0, and Rb is C1-C3alkyl, wherein the C1- C3alkyl is optionally substituted with 1 to 3 Rc, wherein Rc is independently halo or C1-C3 alkoxy; R5 is halo or C1-C3alkyl; R8 is H; R9 is C1-C3alkyl or -(C(Ra)2)n-ORb, wherein n is 0, and Rb is C1-C3alkyl, wherein the C1- C3alkyl is optionally substituted with 1 to 3 Rc, wherein Rc is independently halo or C1-C3 alkoxy; R10 is H or C1-C3alkyl; or R9 and R10 are taken together with the carbon atom and the nitrogen atom to which they are attached, respectively, to form Ring C, wherein Ring C is a 4 to 6-membered heterocyclycl; R11 is H; and R13 is H.
Sixty-second embodiment: a compound represented by Formula (IXa) or (IXb), or a pharmaceutically acceptable salt thereof, wherein R1 is -CH3 or -Cl;R3 is -CHCH3, -CHOCH3, -CF3 or-OCH3;R5 is -CH3 or -Cl;R8 is H;R9 is H, -CH3, -CH2OCH2CH3, -CHCHCH3, -CHCH3, or -CHOCH3;R10 is H, -CH3, or -CHCH3; or WO 2024/233900 PCT/US2024/028806 R9 and R10 are taken together with the carbon atom and the nitrogen atom to which they areattached, respectively, to form Ring C, wherein Ring C is represented by R11 is H; and R13 is H.
The disclosure also includes the compounds prepared in the Exemplification, in both the neutral form and pharmaceutically acceptable salts thereof. The synthetic protocol used to prepare the disclosed compounds is described in the Exemplification.
Another embodiment of the disclosure is a compound disclosed herein, including a compound of any one of Formulae (F), (I), (II), (Ila), (lib), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (Vlb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (Vlllb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (Vlllh), (IXa), (IXb), and (X), or a compound as disclosed in the Exemplification, or a pharmaceutically acceptable salt of any of the foregoing, in which one or more hydrogen atoms is replaced with deuterium. The deuterium enrichment at any one of the sites where hydrogen has been replaced by deuterium is at least 50%, 75%, 85%, 90%, 95%, 98% or 99%. Deuterium enrichment is a mole percent and is obtained by dividing the number of compounds with deuterium enrichment at the site of enrichment with the number of compounds having hydrogen or deuterium at the site of enrichment.
In some embodiments, the compound is selected from the table below, which shows structures of compounds described herein.
WO 2024/233900 PCT/US2024/028806 3 1 413^nt nh h r CXN oo NX^1 NHMe 4 1 446 ,N__ NH2AAA MeO— Me N Or,N___NH2؛؛ T Y H M ؟ AnWMeO Me N1 433Q^N^Y^NYjLN^Me Cl ،n nh 2 6 1 450 F^y cl 0 0 A WAAL™6 Cl NPNH3 1516 ■TFA1 464h yn 2N N0 *LJchf 21 406 N NHo? i^T h AA״xy־• 9 1 4581ejj^NVn Yj^NHMe N or rNYNHH ؟'jYnT YNAA'NHMeNA^ci° 0 Y1 499 N NH2 I AxN^YY)TAMeF^O^^^CI NV WO 2024/233900 PCT/US2024/028806 11 1 462 N NH2 0 0ך< MeF1 468 ،NH&So UI UI INI orMe/VWNY^NHMeci^^ci0 ° V1 468 ___ NH&o ” ui ui ____________ ini or/N^^NHo* Y h ؟׳fY «Y yy^nhm־01^^01° ° V1 483 N NH2 F 0 0 )NF1 476? >h2j]Y N ITT N MeO^L^A c| O O ،N JJ1 484FNYNHh Vr^ NTYNYYI'H'CD3 F^ X 0 0 )F>^ Me NF orCI (*NYNHhfNsMNYYx [|'CDi F^ Jk 0 0 )F>|^ Me N 17 1 463 C| NH2 MeO CI N WO 2024/233900 PCT/US2024/028806 18 1 463 MeO^^^CI ° ° AT or 1 !eNxnn Nk^j NHMe o o lMeO— Cl N1 463CI Me N חח NV^^NHMe o o k XMeO— Cl N or ץ 1N NHMe ؟ f MeO^^OI ° ° JV1 477FNrNHH le־• ؛ tr ״ kk MeO^^^CI ^IT1 489 N NHkksxT° MeO CI N1 503 N NH2 F-. OO k >CI N 23 1 518 N NH2A-A^s•^׳“ F 0 0 k >F^Y^^ CI N 24 1 477nt nh h ^ !יNk^j NHMe רזח 1 " 1 /ך kk-<^k o o k > Me^ O — CI N or، NH2* T H ؟'/k /N. ^N.XkMe^^O^^^CI ° ° WO 2024/233900 PCT/US2024/028806 1 507C| NH2_ Cno Me^ Cl N1 493 Cl nh 2 Me^o AAC| ° ° M1 449x>N^NH_Rs Me N orx>N/NH2-■ Ay .־ j5c .» Me N1 464 Me^V-A, 0 ° V 29 1 424,, /N^NH2 Me/oMeO ° V 1 424 NH2 ___ N . , ,״jVr^yrA MeO^A^kM 0 0 ،rN Me N1 493 /N״NH2? IT H H2N Me fifN n Y nMeo?Vc ° ° or /N،،NH2Cl l^־ y |_| H2N Me،ך^^ YNY וו N ו^؛MeO^^CI0 ° WO 2024/233900 PCT/US2024/028806 32 1 515NH2 ؟ Cl ^N N ora fNyNH2־״Y n-xy5<5 NP1 480„b7ok 34 1 489 MeO CI N1 537r Nr NHH MeO^A^k M 0 0 ، JMe N or1e fN!n r 2fSr NYn NYY^Me MeO^A^L, 0 0 ، J Me N1 454 N NH2 MeO ^^ Me1 442 N NH2 38 1 455 N NH2 WO 2024/233900 PCT/US2024/028806 39 1 442 40 1 445 41 1 463 N or 42 1 453Cl,M^r• 43 1 444&&7o” N orPNM2 ؟'YX-Xr'- 44 1 474ci yhaa ־^״• NX orXrX p Ro’o WO 2024/233900 PCT/US2024/028806 45 1 459 N NH2 46 1 525&Ro9 F O^^CI N1 515LO"o ‘o r U UI IM orCl AyA NH2 xXXXXXr״1 495 cr ^^ ci n1 484 , NH ״ N ،AAY׳* ui ui im or At 'Vy'Y^ Cl^-Cl0 0 V 0Me1 453J1 ^N¥NHh y H2=A:,A־xr-• ui ui im or 4 42 51 1 475Cl ן^ץך uh2^:Ay-. ‘ ؟"¥ 9 : Y WO 2024/233900 PCT/US2024/028806 WO 2024/233900 PCT/US2024/028806 58 1 499r/N!n r 2 !י CI° ° V 0Me ؟^ F F orci y H2 Fy^Aci 0 0 Sr 0Me F1 525 F or? 1-Y' ■O CrQ~ F1 477C| NH2 61 1 503 62 1 4933&7o” OMe orCl r/Nr N^ UH2 /^Cl0 ° 0Me OMe1 493C| NH2 WO 2024/233900 PCT/US2024/028806 64 1 491nh h ^! ؟׳.yVYrn -MeO^Ac|O 01 489 N NH2 Me0^^k c| 0 0 y 66 1 463Cl ijh2jjYN nn NY^^Me 0 A A — Cl NOMe or 1 jAj N1YNyV' ״e 0 0 )^^^01 NOMe1 463c! ijh2jjYN nn 0 A- A— Cl NOMe or 1 ST2j N1YNyV' ״e 0 0 )^^^01 NOMe1 507ci ^NYNI"h -HMe/ynmn/Yx1V 0Me OMe orCl ^NYNI"h NHMer^NYn NYYS ^^c,0 0 V 0Me OMe WO 2024/233900 PCT/US2024/028806 69 1 507 oooOMe Me 0!־ 01 ^2 AMOMe Me1 513ClAM OMe or 1 1H2AAxA OMe1 456.N__ NH2 AAe° 0 v ؛ M 72 1 472h2 ؟ J AyAArNYn NYA^/0Me Me—O^Me0 ° A 73 1 475NH2 ؟ Cl ^NcoR CI N1 449C. YNYNHh yH2־. AA'xr .
MeO^^^CI ° ° WO 2024/233900 PCT/US2024/028806 WO 2024/233900 PCT/US2024/028806 79 1 489AYtY MeO^^CI N or c! ^nynh h rv Cl N orA^rY MeO CI N orc! fNyNHn r'؟"׳، n ״ A ־ A MeO CI N1 493c! NHMeAfNo NyV^AA 0 0 A > OMeMeO CI N orCl yyNHH NHMe S ך^ל"' N רןו^ N ؛؛ JMeo?Vco 0 MP 0Me1 503 8900Q.
WO 2024/233900 PCT/US2024/028806 82 1 499Cl UH2 MeoPVciO 0 V FPFor،NH2 83 1 503 &M709- 84 1 503 YYxY ״•..
WO 2024/233900 PCT/US2024/028806 85 1 499ci yn 2 Meo?Vc° ° VrAor nYYSMeo?Vco ° N” F^F1 491Cl ^Ny NHH “«s/vW °1 487 _ NH2 ___ N . / ,״ F ornh 2 ״ M ,n F>^ Me NF or״ /N__ NH2 _ F orM x>N^NH2 Me N 88 1 461Me yH2n '؟ FAn F3C Me N or^nynh h rCO‘ F3C Me N WO 2024/233900 PCT/US2024/028806 WO 2024/233900 PCT/US2024/028806 ״ /N^NH2_ con Me O^^ Me N Or^n^nh2_ j5*n c=" Me O^^ Me N1 463 ״״ /N__ NH2 __ _xyV^r/^'* Me^ oAAMO 0 ״ ^N״NH2 Me^ 0AAMe0 0 V ، __ N^NH2 / ״ Me^ 0 Me N OrM ^N^NH2 __ _ Me^ 0 Me N1 451^N¥NHH ?h2 [Y N Yt T N EtO^^Me0 ° M1 477 WO 2024/233900 PCT/US2024/028806 96 1 477 N،،NH2 / ... con ״Me^ (T Me N orM ,n،،nh EYoP _ Me O^^ Me N OrNH2 ״ M ^N o & ״Me^ 0 Me N OrM /NX/NH2 '؟' j5 “Asn ״Me^ 0 Me N1 469 olok F1 463 _R7o91 423^N^NH2 MeO^k^k 0 0 ، ,JJMe N100 1 477 -6000 _8200 WO 2024/233900 PCT/US2024/028806 WO 2024/233900 PCT/US2024/028806 NH2 ___ N . ״ _Gron Me IN of M ^N^NH2ERm Me N104 1 423Me y H2{VyVty ^6EOMeo 0 V 1 PNz jfSf N^n NYY^MeEtO^^^Me 0 ° 4T105 1 429 N NH2 V^Me 0 ° MP F106 1 503ץ r Nr NHH F107 1 483^N^NH2؟' r:A sv -/ F orNH2 ___ N . , ״״ F or WO 2024/233900 PCT/US2024/028806 WO 2024/233900 PCT/US2024/028806 WO 2024/233900 PCT/US2024/028806 114 1 443FNYNH; ForN^NHzNH2 Mef ץFor 1e P"z T2 F Y Me NForN NHoVe FT h F115 1 497 EoPYAMeo O ؟ FF 69909F &&7o9 F Y Me NF or or or N H nh 2 ״ M .n F WO 2024/233900 PCT/US2024/028806 116 1 483C| NH2 F ora ^NyNH2 F117 1 483C| NH2״• Asxr ,^ F orC1 ^NyNH2 F118 1 514 N NH2 119 1 527&9909 120 1 473 N NH2־' AABxr ؛ 121 1 531Cl NNF2 NHM־N¥¥NY£A ؛ fFsC^^CI0 ° M OMeor CI NYNHz NHM־ FsC^^CI0 ° °Me WO 2024/233900 PCT/US2024/028806 122 1 517Cl NHMef^NYTNYiY^ f 3cAAi° 0 V OMeor Cl NHMefjf N Y¥ nY^"' S f 3cAAi° 0 V 0Me 123 1 502 124 1 517 Me/ 0 Cl N125 1 477M /N״NH2 126 1 437Me y H2 NYY"MeIproPVMeo 0 V !e ^nt nh h FjpY NYYT^^ nprO^Me 0 ° V 127 1 437 N NH2ArNYSrRrpNHMe npro/VMeO 0 V128 1 443Ve ^NTNHh =H21jY NYn NYY^S/MeF'/^Me° 0 F or T f nTnhh T2 F WO 2024/233900 PCT/US2024/028806 129 1 492Cl ANH; «h2Y/ N x>< N Me0 ، JCI N or fN!n 1H2 !יY- N > 130 1 437Me ^Y^h y HjpY NYYN^^Me Mev A AA. 0 0 ، J Me N oj-Me f^Y^H NH2 Mex/ 0xAA 0 0 )Me N131 1 477... A/NH2 XX /xNy^xV?XAV 0 V 132 1 490Me HN^ J^j^ Nרן^vNף^^x''Me^AAA. 0 0 XXMe N orN NHo /—aMe Y h HN ) Me^O^xA^ 0 0 ، JMe N133 1 503rN!NH״ O ״ CO Me^ 0^^^ Cl N134 1 490!י fN!n !י^nyi nt /s _ __ A5.A_,0 0 A ע OMe EtO CI N orTNHh ^ ؟'^nyt nyYs _ __ A5.A_,0 0 A ע OMe EtO CI N WO 2024/233900 PCT/US2024/028806 135 1 519&Go — L׳l IM of EtO^^CI00 Yr 136 1 477ci yn 2 Eto/c° 0 V Me137 1 463y H2 ؛ ؟J^YN nYNYYYMeEtO^^CI ° ° 74 or 138 1 482.N__ NH2? Y Y H Dv D_Antrs ™ Me^ O Cl N139 1 489 N NH9? f Y h_ CY"Ov Me^ 0 CI N orN NH9. Mo% Me^ 0 CI N140 1 507 N NHo Me^oAAcl o 0 CI Ar NHHYxNTTNxAY^/0^Me e/'nMc| ^ O ،NJJ ״ WO 2024/233900 PCT/US2024/028806 141 1 507= 1 * Nr NHH t hm ؟׳ EO®c° ° M °Me or ™® 1 ן ؟'Af nty NxA"׳ SEOc 0 V 0Me142 1 464Cl ^nYnh^NY^T^MeEtcr^^ci ° ° or 143 1 513ס! yH2J:;Axn, _ EtO/ci° ° V CHF2144 1 443ץ r Nr NHH y H2 r A^kMe° ° chf 2 orTe ^nt nh h r CY‘ chf 2145 1 433 .JxSx/?146 1 447 WO 2024/233900 PCT/US2024/028806 147 1 393Me yH2 Me^^Me0 ° M ،NH7e r r h Me^^Me0 ° V148 1 461 YAY YAV149 1 463 N NHAY״ 150 1 487Cl uh2.Y01 BOVc° 0 V II151 1 487?׳ a nynh h N ר!חNEo®c° ° 10rN NHoAVr=^ Eo®c° 0 V 11152 1 460 A??xA WO 2024/233900 PCT/US2024/028806 153 1 434Cl UH2f^NY1T nYY'x N~c° 0 V Me or YO0r ^Cl0 0 V Me154 1 483Cl PNNHz rY/rrn^ MeO'^^^^^CI °155 1 425Me UH2 Yy ‘■ YV- 156 1 457N nh 2 157 1 449 J4 NH2 158 1 511 ،NH2^ oVxr .״^ 159 1 478 HY ,»nynh; rV Me N orHMe r Ny° WO 2024/233900 PCT/US2024/028806 160 1 478 HM ^N^NH2MV MeO^^A^A 0 0M© N 0j ־H،NH2 /N^OV6 F Y h F Y[l AYl^AAti MeO^A^V 0 0 A AMe N161 1 437 ,NH2AY״ AAAYn F Me N TFA162 1 503m A^NH2AArA F3C^A/YMes N TFA163 1 479r PYM A j[Y NYnnYYj fl 164 1 442 NHMeri X11* II H 1N N° °Me165 1 555X fN)n %*_ A A xt :~1 Me^ 0 CI N166 1 491؛°רOMe [^Ny NHH ^N^HN-XY'A'YA — — orAOMe [^Ny NHH N”HNA AAA" WO 2024/233900 PCT/US2024/028806 167 1 N NHo 6:^ ui orW 168 1 462W W or65W 169 11MeO ؟׳SM"OH W or 170 1 470 N NHdz/co F^F NH2 TFA 171 1 472C| [^NYNH|4 CF3 Som WO 2024/233900 PCT/US2024/028806 172 1 490Lo Meo2co ° V or &5709 173 1 441&RR7ob OH N174 1 437 [|YNYn 0 kJ ץ Me NMe or !'י I6j^V NYn NןYV^MeMeO^AA,, 0 0 ، J ץ Me NMe orfNr NHH y H2j[Y NYn N)YY^Me MeOAA^ 0 0 JY Me NMe or1e fNTNH1 ״H2j[Y NYn N)YY^Me MeO^AA o 0 kJ Y Me NMe175 1 437Me ^NYNH^ y H2f ^ רן N ؟ JMeO^AA, 0 0 ، J Me N ץMe or! e fN!n !Hj|Y NYTN)YV^Me > 0 0 ״ MeOAAMe N ץMe or WO 2024/233900 PCT/US2024/028806 Me UH2 MeO^VAx 0 0 .Y Me NMe or !e tj^Y NYn )YY^Me ע ، 0 0 , MeO^AAY Me NMe176 1 451Me yH 2[|YN YnN MeMeO^A^A,, 0 0Me N177 1 467Me r/NTN^ y H2 RMoMeMeO^^l O O ، J Me N or !e ^nt nh h r 2RMoMeMeO^^l O O ، J Me N178 1 477ci ^nyNH2_ CO Me^ Cl N179 1 475 N NH a Y 180 1 458 181 1 461 N NH yxA8■^ 182 1 505270 MeO CI N WO 2024/233900 PCT/US2024/028806 183 1 489 N NHoo 184 1 465 Y Me NF orM /N״NH2 F185 1 465 M /N^NH&ro . Me NF orM ^n^nh 2 F186 1 483 M ^n^nh 2 187 1 505 WO 2024/233900 PCT/US2024/028806 188 1 505 189 1 473 UI orc.tiyr-o 190 1 473 l/l orc. ^מ״-ט191 1 474ci r /0H yviy^ W or " CW !י6:Au = 192 1 501 ^n״nh 2 h 193 1 & FGI 510 N NH2 WO 2024/233900 PCT/US2024/028806 194 1 & FGI 501nh2 ؟ n ^n 195 1 & FGI 489 ,N__ NH2XANxr NHMe ؟) VJ UI IM of 196 1 & FGI 517 197 1 463Cl ui im or!NH” rAAxA' “־ 198 1 & FGI 491 NH2 ؟ Cl ^N 0 Oy،K c| O ־ M 199 1 505 N NH2 Et^OYYAcl o 0 200 1 & FGI 500 N NH2 WO 2024/233900 PCT/US2024/028806 201 1 & FGI 500 NH2 ؟ Cl ^N 202 1 & FGI 515C| NH2 203 1 & FGI 497Cl ^Ny NH2''־• JuX/fXP , 204 1 & Deprotection 485 m.cAAi0 0 V F or ؟' AA,° ° V F205 1 & FGI 449 NH2 ״ N / ...AArA MeO Me N206 1 & Double deprotection 420 N NH2 MeO^Me 0 ° O N NH2 MeO^Me 0 ° O 207 1 & FGI 477 WO 2024/233900 PCT/US2024/028806 208 1 505r A&Rom 209 1 & FGI 514 N NH2r Co% 210 1 476 36%00 211 1 474 or ؛-׳؛ 212 1 492_&R%o9 JW WO 2024/233900 PCT/US2024/028806 213 1 461 Cl ^Ny NH2 Meo2a ° ° 44 or N NH2 Me(J^Y)l ° ° 44214 1 475? אYnh h ri'“6PfNY1NYl" NHMeo20c° 0 M 9׳ Yynh h n1׳Me jlY NYTNYYr NH 215 1 475? P")A ״c? N NHo /---- 216 1 487ERRo9 F3C — Me N217 1 44289%6P WO 2024/233900 PCT/US2024/028806 Definitions 218 1 407Me ^2 Me^Ae° ° V Me nh 2 MeAA O O ، JMe N219 1 464a NYn NYNY^Me__ !1 A 0 0 ، JMe/ O^^^ 01 N or 1 1H2yy Y ז MeH J n n k IJMe/ O Cl N220 1 448a NNHz oMefVWAA ° u221 1 434Cl OMeI 1 H I&A-wA FGIA0 O U222 1 506A O YntpMeO^^^ ClF or f nynh h n !י/J.Jk o'k JxiAY)' "MeO^^^ Cl F As used herein, the term “pharmaceutically acceptable salt” refers to pharmaceutical salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response,and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts 84 WO 2024/233900 PCT/US2024/028806 are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci. (1977) 66:1-19. Compounds of the present teachings with basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic acid, benzenesulfonic, benzoic, methanesulfonic, and /?-toluenesulfonic acids). Compounds of the present teachings with acidic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
The term “alkyl” used alone or as part of a larger moiety, such as “alkoxy”, “hydroxyalkyl” and the like, means a saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to carbon atoms (C1-C6alkyl), alternatively, 1 to 3 carbon atoms (C1-C3alkyl). “C1-C6alkyl” means a radical having 1 to 6 carbon atoms in a linear or branched arrangement, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.
“Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl, wherein alkyl is as defined above. For example, “C1-C6alkoxy” includes methoxy, ethoxy, propoxy, butoxy, pentoxy, isopentoxy, isopropoxy, and hexoxy.
"Alkynyl" refers to a branched or unbranched hydrocarbon moiety containing at least one triple bond. Unless otherwise specified, an alkynyl group comprises 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Representative examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-methypropynyl, 2-methypropynyl, 3- methypropynyl and the like.
"Alkenyl" refers to a branched or unbranched hydrocarbon moiety containing at least one double bond. Unless otherwise specified, an alkenyl group comprises 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Representative examples of alkenyl include, but are not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-methypropenyl, and the like.
“Aryl”, when used alone or as part of another moiety such as aralkyl, refers to an aromatic hydrocarbon of six to 10 ring atoms, such as phenyl or naphthyl.
WO 2024/233900 PCT/US2024/028806 The term “halogen”, “halo”, or “hal” means fluorine or fluoro (F), chlorine or chloro (Cl), bromine or bromo (Br), or iodine or iodo (1).
“Cycloalkyl” means a saturated aliphatic cyclic hydrocarbon ring radical. Unless otherwise specified, a cycloalkyl has 3 to 8 ring carbon atoms (C3-C8cycloalkyl) (i.e., 3, 4, 5, 6, 7, 8, 9, or 10), alternatively, 3 to 6 ring carbon atoms (C3-C6cycloalkyl) (z.e., 3, 4, 5, or 6), alternatively, 3 to 5 carbon atoms (C3-C5cycloalkyl)(z.e., 3, 4, or 5). “C3-C6Cycloalkyl” means a radical having from 3 to 6 carbon atoms arranged in a monocyclic ring. A C3-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A C3-Ccycloalkyl includes cyclopropyl, cyclobutyl, and cyclopentyl.
The term "heterocyclyl" refers to a monocyclic or bicyclic non-aromatic ring radical containing unless otherwise specified, 3 to 12 or 3 to 8 ring atoms (i.e., “3, 4, 5, 6, 7, or membered”) selected from carbon atom and 1 to 4 heteroatoms. Each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO); oxygen; and sulfur, including sulfoxide and sulfone. Representative heterocycles include piperi dinyl, 1,4-oxazepanyl, azetidinyl, morpholinyl, pyrrolidinyl, piperazinyl, piperazine-2- onyl, octahydrocyclopenta[c]pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, azepanyl, and the like. In some embodiments, the heterocyclyl is a saturated monocyclic ring. In some embodiments, the heterocyclyl is a saturated bicyclic ring.
"Heteroaryl" refers to an aromatic 4- to 12-membered monocyclic or bicyclic ring system, having 1 to 4 heteroatoms independently selected from O, N, S, and NRd, and wherein N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. A monocyclic heteroaryl has 5 or 6 ring atoms, i.e., is 5 to membered. Examples of 5- to 6-membered monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, triazinyl, tetrazinyl, and the like. A bicyclic heteroaryl has 8 to 10 ring atoms, i.e., is 8 to 10 membered. Examples of 8- to 10-membered bicyclic heteroaryls include, but are not limited to indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothiofuranyl, quinolinyl, isoquinolinyl and the like.
The term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of a hydrogen substituent in a given structure with a non-hydrogen substituent. Thus, for example, a substituted alkyl is an alkyl wherein at least one non-hydrogen WO 2024/233900 PCT/US2024/028806 substituent is in the place of a hydrogen substituent on the alkyl group. To illustrate, monofluoroalkyl is an alkyl substituted with a fluoro substituent, and difluoroalkyl is an alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent can be identical or different (unless otherwise stated).
If a group is described as being “optionally substituted”, the group can be either (1) not substituted or (2) substituted.
If a group is described as being optionally substituted with up to a particular number of non-hydrogen substituents, that group can be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a group is described as a cycloalkyl optionally substituted with up to 3 non-hydrogen substituents, then any cycloalkyl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the cycloalkyl has substitutable positions.
Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identifeal and are not mirror images of each other.
When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g, where the configuration is indicated in the chemical name by “R” or “5”) or structure (e.g, the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9% (except when the designation “rac” or “racemate accompanies the structure or name, as explained in the following two paragraphs). “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total WO 2024/233900 PCT/US2024/028806 number of all of the compounds with the same or opposite stereochemical configuration in a mixture.
When the stereochemical configuration at a chiral center in a compound is depicted by chemical name (e.g, where the configuration is indicated in the name by “R” or “5”) or structure (e.g, the configuration is indicated by “wedge” bonds) and the designation “rac” or “racemate” accompanies the structure or is designated in the chemical name, a racemic mixture is intended.
When two or more stereoisomers are depicted by their chemical names or structures, and the names or structures are connected by an “or”, one or the other of the two or more stereoisomers is intended, but not both.
When a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the 5 configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and configuration at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “5” or “R”, the name is meant to encompass the compound with the 5 configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and 5 configuration at that chiral center.
A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds described herein.
Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
WO 2024/233900 PCT/US2024/028806 “Peak 1” or “first eluting isomer” in the Experimental section refers to an intended reaction product compound obtained from a chromatography separation/purification that elutes earlier than a second intended reaction product compound from the same preceding reaction. The second intended product compound is referred to as “peak 2” or “second eluting isomer”.
When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as "enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.
When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
The number of carbon atoms in a group is specified herein by the prefix “Cx-Cxx”, wherein x and xx are integers. For example, "C1-C3alkyl" is an alkyl group which has from to 3 carbon atoms.
The suffix “yl” added to the end of a chemical name indicates that the named moiety is bonded to the molecule at one point, i.e., monovalent. The suffix “ene” added to the end of a chemical name indicates that the named moiety is bonded to the molecule at two points, i.e., bivalent.
Methods of Use Compounds of the disclosure are GSK3 inhibitors, more specifically, GSK3a inhibitors. The use of the word “inhibitor” means that a compound or a pharmaceutically acceptable salt thereof inhibits activity of GSK3 (e.g., GSK3a). By “inhibit” herein is meant to decrease the activity of the target enzyme as compared to the activity of that enzyme in the WO 2024/233900 PCT/US2024/028806 absence of the inhibitor. In some alternatives, the term “inhibit” means a decrease in GSK(e.g., GSK30) activity of at least 5%, at least 10%, at least 20%, at least 50%, at least 60%, at least 79%, at least 80%, at least 90% or at least 95%. In other alternatives, inhibit means a decrease in GSK3a activity of 5% to 25%, 25% to 50%, 50 to 70%, 75 to 100%. In some embodiments, inhibit means a decrease in GSK3 (e.g., GSK3a) activity about 95% to 100%, e.g., a decrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such decreases can be measured using a variety of techniques that would be recognizable by one of skill in the art, including in vitro kinase assays.
Compounds of the disclosure are selective GSK3a inhibitors. As used herein, a “selective GSK3a inhibitor” refers to a compound or a pharmaceutically acceptable salt thereof that has the ability to selectively inhibit GSK3a kinase over other targets. More specifically, a selective GSK3a inhibitor has the ability to selectively inhibit GSK3a over another kinase. A selective GSK3a inhibitor has the ability to selectively reduce target signaling activity relative to off-target signaling activity, via direct or indirect interaction with the target. The ability to selectively target GSK3a with a compound or pharmaceutically acceptable salt thereof provides advantages in terms of improved potency, less off-target activity and an increased probability of clinical success in comparison with a non-selective compound or salt. A GSK3a inhibitor that selectively inhibits GSK3a may have an activity that is at least 2-fold relative to another kinase (e.g., at least 10-fold; at least 15-fold; at least 20-fold; at least 30-fold; at least 40-fold selectivity; at least 50-fold; at least 60-fold; at least 70-fold; at least 80-fold; at least 90-fold; at least 100-fold; at least 125-fold; at least 150-fold; at least 175-fold; or at least 200-fold. In some alternatives, a selective GSK3a inhibitor exhibits at least 15-fold selectivity over another kinase, e.g., GSK3p. In some alternatives, the selective GSK3a inhibitors are selective over GSK3p.
The disclosure provides methods of modulating (e.g., inhibiting) GSK3 (more specifically GSK3a) activity in a patient in need thereof, said method comprising administering to the patient a compound provided herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for therapeutic administration to enhance, stimulate and/or increase immunity in patients in need thereof, e.g., in cancer patients or patients with viral infection, diabetes, Alzheimer’s disease and other CNS disorders.
WO 2024/233900 PCT/US2024/028806 In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for therapeutic administration to enhance at least one of activation, priming, migration, proliferation, survival and cytolytic activity of T cells relative to prior to administration. In certain aspects, T cell activation is characterized by enhanced levels of IL- 2, IFN-gamma, or granzyme B production by T cells or surface markers relative to prior to administration of the compound or pharmaceutically acceptable salt thereof. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for therapeutic administration to enhance differentiation of T cells toward cytotoxic/exhausted phenotypes. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for modulating the levels of phosphorylation, stability, and activity of immune pathway transcription factors such as NEAT and c-Jun. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for modulating autophagy pathway in both tumor and immune cells.
In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for decreasing recruitment, infiltration, and differentiation of monocytes, tumor-associated macrophage, and myeloid-derived suppressor cell. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for modulating regulatory T cells. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for enhancing cytotoxic function of NK cells. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for enhancing secretion of inflammatory cytokines by immune cell types other than T lymphocytes. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, indirectly inhibit the growth of cancer cells via modulation of the tumor microenvironment. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for priming of the immune response (i.e., vaccines) to tumors or viruses for boosting or generating anti-viral/anti-tumor immunity. In one instance, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for enhancing or boosting response to a vaccine (such as a cancer vaccine or a personalized cancer vaccine (PCV)) or a CAR-T cell therapy.
Methods of treating a disease or disorder responsive to inhibition of GSK3 (e.g., GSK3a) activity can include administering to a patient in need thereof a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt 91 WO 2024/233900 PCT/US2024/028806 thereof. For example, the disease or disorder is a cancer. The term “cancer” encompasses all forms of cancer including, but not limited to, all forms of carcinoma, melanomas, blastomas, sarcomas, lymphomas, leukemias. In some embodiments, cancer includes metastatic forms. Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure or pharmaceutically acceptable salts thereof,. For the uses described herein, any of the compounds of the disclosure, or pharmaceutically acceptable salts thereof, may be used alone or in combination with other therapeutic agents.
In some embodiments, the treatment results in a sustained response in the subject after cessation of the treatment. “Sustained response” refers to the sustained effect on reducing tumor growth after cessation of a treatment. For example, the tumor size may remain the same or smaller as compared to the size at the beginning of the administration phase. In some embodiments, the sustained response has a duration at least the same as the treatment duration, at least 1.5X, 2.OX, 2.5X, or 3.OX length of the treatment duration.
The treatment methods disclosed herein may result in a partial or complete response. As used herein,“complete response” or“CR” refers to disappearance of all target lesions; “partial response” or“PR” refers to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD; and“stable disease” or “SD” refers to neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest SLD since the treatment started. As used herein, “overall response rate” (ORR) refers to the sum of complete response (CR) rate and partial response (PR) rate.
The treatment methods disclosed herein can lead to an increase in progression free survival and overall survival of the subject administered the selective GSK3a inhibitor. As used herein, “progression free survival” (PFS) refers to the length of time during and after treatment during which the disease being treated (e.g., cancer) does not get worse. Progression-free survival may include the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease.
As used herein, “overall survival” (OS) refers to the percentage of subjects in a group who are likely to be alive after a particular duration of time.
WO 2024/233900 PCT/US2024/028806 Other cancers include, for example, sweat gland cancer, spinal axis tumor, chest cancer, and environmentally induced cancers including those induced by asbestos.In some embodiments, the cancer that are treatable using the compounds of the disclosure or pharmaceutically acceptable salts thereof, include, but are not limited to, an advanced solid tumor with an inflamed phenotype. In some embodiments, an inflamed solid tumor is a tumor mutational burden-high (TMB-H) cancer. In some embodiments, the cancer is selected from the group consisting of bladder cancer (including urothelial carcinoma and Bacille Calmette- Guerin (BCG)-unresponsive high-risk nonmuscle invasive bladder cancer (NMIBC)), breast cancer (including triple-negative breast cancer), cervical cancer, colorectal cancer, endometrial carcinoma, cutaneous squamous cell carcinoma, gastroesophageal cancer (including gastric carcinoma, gastro-oesophageal junction cancer, and oesophageal squamous cell carcinoma), hepatocellular carcinoma, leukemia (including acute myeloid leukemia (AML)), lung cancer (including malignant pleural mesothelioma, non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC)), melanoma (including metastatic melanoma), lymphoma (including Hodgkin’s lymphoma, non-Hodgkin lymphoma (NHL, including diffuse large B cell lymphoma (DLBCL)), and primary mediastinal large B-cell lymphoma), Merkel cell carcinoma, microsatellite instability-high (MSI-H) cancer, mismatch repair deficiency (dMMR) cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck (SCCHN), tumor mutational burden-high (TMB-H) cancer, and uterine cancer. In some embodiments, the cancer is selected from the group consisting of AML, bladder cancer, breast cancer, colorectal cancer, endometrial carcinoma, gastroesophageal cancer, hepatocellular carcinoma, melanoma, NHL, NSCLC, ovarian cancer, renal cell carcinoma, SCLC, and SCCHN. In some embodiments, the cancer is selected from the group consisting of bladder cancer, breast cancer, gastroesophageal cancer, hepatocellular carcinoma, malignant melanoma, NSCLC, renal cell carcinoma, and SCCHN. In some embodiments, the cancer is selected from the group consisting of hepatocellular carcinoma, melanoma, NSCLC, SCLC, and urothelial carcinoma. In some embodiments, the cancer is selected from the group consisting of melanoma, NSCLC, and urothelial carcinoma.In some embodiments, diseases and disorders that are treatable using the compounds of the disclosure or pharmaceutically acceptable salts thereof include, but are not limited to hematological cancer, sarcomas, respiratory cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.93 WO 2024/233900 PCT/US2024/028806 Exemplary hematological cancer includes, for example, lymphomas and leukemias such as acute lymphotic leukemia (ALL), AML, acute promyelocyte leukemia (APL), chronic lymphotic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (NHL), including Primary mediastinal B-cell lymphoma (PMBCL), relapsed or refractory NHL, recurrent follicular, and primary CNS lymphoma, Hodgkin’s lymphoma, myeloproliferative diseases, including, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia, hairy cell lymphoma, chronic myelogenic lymphoma, and Burkitt's lymphoma.
Exemplary sarcoma includes, for example, chondrosarcoma, Ewing's sarcoma, Kaposi’s sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, sarcoma of the soft tissue, and teratoma.
Exemplary respiratory tract cancer includes, for example, lung cancer such as non- small cell lung cancer (NSCLC), small cell lung cancer, epidermoid cancer, bronchogenic carcinoma, including squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, mesothelioma, and pleuropulmonary blastoma.
Exemplary gastrointestinal cancer includes, for example, cancers of the esophagus, including squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; stomach, including carcinoma, lymphoma, and leiomyosarcoma; pancreas, including ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; small instestine, including adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; large intestine, including adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma; colon; and gall bladder, including adenocarcinoma; and intestinal type and diffuse type gastric adenocarcinoma, rectum carcinoma, familiar adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer (CRC).
Exemplary genitourinary tract cancer includes, for example, cancers of the kidney, including adenocarcinoma, Wilm's tumor [nephroblastoma], renal cell carcinoma, urothelial carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, renal oncocytoma, WO 2024/233900 PCT/US2024/028806 Bellinio duct carcinoma, clear-cell sarcoma of the kidney, and mesoblastic nephroma; adrenal gland; renal pelvis; bladder, including transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma; urethra, including squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; prostate, including adenocarcinoma, sarcoma, and carcinoma; testis, including seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma; penis; and pancreas.
Exemplary liver cancer includes, for example, hepatoma, including hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, biliary tract cancer, and hemangioma.
Exemplary bone cancer includes, for example, osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, including reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, including osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors Exemplary nervous system cancer includes, for example, cancer of the skull, including osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; meninges including, meningioma, meningiosarcoma, and gliomatosis; brain, including astrocytoma, meduoblastoma, glioma, ependymoma, germinoma (pinealoma), neuroectodermal tumor, glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, brain stem and hypopthamic glioma; and spinal cord, including neurofibroma, meningioma, glioma, and sarcoma; as well as neuroblastoma and Lhermitte- Duclos disease.
Exemplary gynecological cancer includes, for example, cancer of the uterus, including endometrial carcinoma; cervix, including cervical carcinoma, pre-tumor cervical dysplasia, squamouse cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumor, glassy cell carcinoma and villoglandular adenocarcinoma; ovaries, including ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, endometroid tumor, high-grade serous carcinoma(HGSC) or high-grade serous ovarian cancer (HGSOC)), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma, and arrhenoblastoma; vulva (squamous cell carcinoma, intraepithelial carcinoma, WO 2024/233900 PCT/US2024/028806 adenocarcinoma, fibrosarcoma, and melanoma; vagina, including clear cell carcinoma, squamous cell carcinoma, and botryoid sarcoma (embryonal rhabdomyosarcoma); labia; and fallopian tubes.
Exemplary skin cancer includes, for example, melanoma, sebaceous gland carcinoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.
Examples of breast cancer include, for example, ER+/HER2- breast cancer, triple- negative breast cancer (TNBC), invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
Exemplary head and neck cancer includes, for example, glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas, adenocarcinomas, oral cancer, throat cancer, including oropharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal cancer, salivary gland cancer, mouth cancer, eye cancer, acoustic neuroma, pituitary adenoma, hypopharngx, and thyroid (medullary and papillary) and parathyroid cancer.
Other cancers include, for example, sweat gland cancer, spinal axis tumor, chest cancer, and environmentally induced cancers including those induced by asbestos.
In some instances, the disease or disorder that are treatable using the compounds of the disclosure or pharmaceutically acceptable salts thereof is a viral infection, such as infection caused by hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, and human immunodeficiency virus (HIV).
Combination Therapies Compounds of the disclosure or pharmaceutically acceptable salts thereof, can be administered as the sole pharmaceutical agent or in combination with one or more other anti- cancer agents for the treatment of cancer, where the combination causes no unacceptable adverse effects. In some embodiments, the other anti-cancer agents are immune-oncology agent, anticancer agents that are enzyme/protein/receptor inhibitors, radiation or chemotherapy.
WO 2024/233900 PCT/US2024/028806 Compounds of the disclosure or pharmaceutically acceptable salts thereof, can be co- formulated with an immuno-oncology agent. Immuno-oncology agents include, for example, a small molecule drug, antibody, or other biologic or small molecule. Examples of biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human. In another aspect, the antibody is a bispecific antibody.
In one aspect, the immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co-inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators).
Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane bound ligands that bind to co-stimulatory or co- inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILRI/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, ED AR, XEDAR, TACI, APRIL, BCMA, LTfiR, LIGHT, DcR3, HVEM, VEGETL1A, TRAMP/DR3, EDAR, EDAI, XEDAR, EDA2,TNFR1, Lymphotoxin a/TNPp, TNFR2, TNF a, LT R, Lymphotoxin a 1p2, FAS, FASL, RELT, DR6, TROY, NGFR.
In one aspect, T cell responses can be stimulated by a combination of a compound of the disclosure or a pharmaceutically acceptable salt thereof, and one or more of (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.
WO 2024/233900 PCT/US2024/028806 In one aspect, compounds of the disclosure or pharmaceutically acceptable salts thereof can be administered in combination with at least one other immune checkpoint inhibitor. In other aspects, compounds of the disclosure or pharmaceutically acceptable salts thereof can be administered for the treatment of immune checkpoint inhibitor-resistant NSCLC, including where the subject is refractory to, or had a partial response to, platinium and/or paclitaxel and/or docetaxel therapy. Optionally, compounds of the diclosure or pharmaceutically acceptable salts thereof can be administered in combination with at least one other anti-cancer agent, such as paclitaxel, docetaxel or platinum anticancer therapy. In some aspects, compounds of the disclosure or pharmaceutically acceptable salts thereof can be administered post-platinium therapy as second or third line treatment. Compounds of the disclosure or pharmaceutically acceptable salts thereof can be administered for the treatment of first line NSCLC expressing high PD-El (>50% Tumor Proportion Score (TPS)), wild- type EGFR, or wild-type ALK.
Other agents that can be combined with compounds of the disclosure or pharmaceutically acceptable salts thereof, for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, compounds of the disclosure can be combined with antagonists of KIR, such as lirilumab.
Yet other agents for combination therapies include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 or FPA-008.
In another aspect, compounds of the disclosure or pharmaceutically acceptable salts thereof, can be used with one or more of agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-Ll/PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti- CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse/prevent T cell anergy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites.
In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, WO 2024/233900 PCT/US2024/028806 YERVOY (ipilimumab) or tremelimumab. In another aspect, the immuno-oncology agent is a PD-1 antagonist, such as an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP- 514; WO2012/145493). The immuno-oncology agent may also include pidilizumab (CT- Oil), though its specificity for PD-1 binding has been questioned. Another approach to target the PD-1 receptor is the recombinant protein composed of the extracellular domain of PD-E(B7-DC) fused to the Fc portion of IgGl, called AMP-224 In another aspect, the immuno-oncology agent is a PD-El antagonist, such as an antagonistic PD-Ll antibody. Suitable PD-El antibodies include, for example, TECENTRIQ (atezolizumab) (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS-9365(WO2007/005874), and MSB0010718C (WO2013/79174).
In another aspect, the immuno-oncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-9860(WO10/19570, WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO09/44273).
In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (W012/32433).
In another aspect, the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06/105021, WO09/009116) and MK-4166 (WO1 1/028683).
In another aspect, the immuno-oncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO2006/122150, WO07/75598, WO08/36653, WO08/36642), indoximod, orNLG-919 (WO09/73620, WO09/1156652, WO111/56652, W012/142237).
In another aspect, the immuno-oncology agent is an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MED1-6383 or MEDI-6469. In another aspect, the immuno-oncology agent is an OX40L antagonist, such as an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-78(WO06/029879).
In another aspect, the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the immuno-oncology agent is a CD4099 WO 2024/233900 PCT/US2024/028806 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.
In another aspect, the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.
In another aspect, the immuno-oncology agent is MGA271 (to B7H3) (WOI 1/109400).
The compounds of the disclosure or pharmaceutically acceptable salts thereof, can be used in combination with anticancer agents that are enzyme/protein/receptor inhibitors, exhibiting different preferences in the targets which they modulate the activities of, to treat such conditions. Targeting more than one signaling pathway (or more than one biological molecule involved in a given signaling pathway) may reduce the likelihood of drug-resistance arising in a cell population, and/or reduce the toxicity of treatment.
The compounds of the disclosure or pharmaceutically acceptable salts thereof, can be used in combination with one or more other enzyme/protein/receptor inhibitors for the treatment of cancer. For example, the compounds of the disclosure or pharmaceutically acceptable salts thereof, can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Aktl, Akt2, Akt3, TGF־pPv, PKA, PKG, PKC, CaM- kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-IR, IR-R, PDGFotR, PDGFpR, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphAl, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lek, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf.
In some embodiments, the compounds of the disclosure or pharmaceutically acceptable salts thereof, can be combined with one or more of the following inhibitors for the treatment of cancer. Non-limiting examples of inhibitors that can be combined with the compounds of the present disclosure for treatment of cancers include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 0rFGFR4, e.g., fisogatinib, AZD4547, BAY 1187982, ARQ087, BGJ398, BIBF1120, TKI258, lucitanib, dovitinib, TAS-120, J J-42756493, Debi01347, INCB54828, INCB62079, and INCB63904), a JAK inhibitor (JAKI and/or JAK2, e.g., ruxolitinib, baricitinib, or itacitinib (INCB391 10)), an IDO inhibitor (e.g., epacadostat and NLG919), an ESDI inhibitor (e.g., GSK2979552, INCB59872 and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797 and INCB50465), a PI3K-gamma inhibitor 100 WO 2024/233900 PCT/US2024/028806 such as a PI3K-gamma selective inhibitor (eganelisib) or a dual PI3K-delta/gamma selective inhibitor (duvelisib), a CSF1R inhibitor (e.g., PLX3397 and LY3022855), a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), an angiogenesis inhibitor (Such as Avastin (bevacizumab)), an interleukin receptor inhibitor, bromo and extra terminal family members inhibitors (for example, bromodomain inhibitors or BET inhibitors such as OTX015, CPI- 0610, INCB54329, and INCB57643), and an adenosine receptor antagonist or combinations thereof. Inhibitors of HD AC such as panobinostat and vorinostat can be combined with the compounds of the disclosure. Inhibitors of c-Met such as onartumzumab, tivantnib, and capmatinib (INC-280) be combined with the compounds of the disclosure or pharmaceutically acceptable salts thereof. Inhibitors of BTK such as ibrutinib can be combined with the compounds of the disclosure or pharmaceutically acceptable salts thereof. Inhibitors of mTOR such as rapamycin, sirolimus, temsirolimus, and everolimus can be combined with the compounds of the disclosure or pharmaceutically acceptable salts thereof. Inhibitors of Raf, such as vemurafenib and dabrafenib can be combined with the compounds of the disclosure or pharmaceutically acceptable salts thereof. Inhibitors of MEK such as trametinib, selumetinib and GDC-0973 can be combined with the compounds of the disclosure or pharmaceutically acceptable salts thereof. Inhibitors of KIT, including avapritinib, imatinib, sunitinib, regorafenib, ripritinib (DCC2618), PLX9486, PLX3397, crenolanib, CDX-0158, CDX-0159. Inhibitors of RET including pralsetinib, selperctinib, alectinib, levatinib, cabozantinib, BOS172738 (DS-5010), SL-1001, TPX-0046, sitravatinib (MGCD516), and RXDX-105. Inhibitors of Hsp90 (e.g., tanespimycin), cyclin dependent kinases (e.g., palbociclib), PARP (e.g., olaparib) and Pim kinases (LGH447, INCB053914, and SGI-1776), and KRAS (e.g., sotorasib) can also be combined with compounds of the disclosure or pharmaceutically acceptable salts thereof.
Compounds of the disclosure or pharmaceutically acceptable salts thereof, can be used in combination with one or more agents for the treatment of cancer. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of an alkylating agent include bendamustine, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes, uracil mustard, chlormethine, cyclophosphamide (CYTOXAN), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide. In some embodiments, 101 WO 2024/233900 PCT/US2024/028806 the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX).
The compounds of the disclosure or pharmaceutically acceptable salts thereof, can be administered in combination with one or more anti-cancer drugs, such as a chemotherapeutics. Example chemotherapeutics include any of: abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib, buparlisib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carmustine, cediranib, cetuximab, chlorambucil, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, nofetumomab, oserelin, paclitaxel, pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin, cisplatin, carboplatin, oxaliplatin, ponatinib, prednisone, procarbazine, quinacrine, rasburicase, regorafenib, reloxafine, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.
Other anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin). 102 WO 2024/233900 PCT/US2024/028806 Compounds of the disclosure or pharmaceutically acceptable salts thereof, can be administered as the sole pharmaceutical agent or in combination with one or more anti-viral agents for the treatment of chronic viral infections, where the combination causes no unacceptable adverse effects. Chronic viral infections include, but are not limited to, diseases caused by: hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV). Parasitic infections (e.g., malaria) may also be treated by the above methods wherein compounds known to treat the parasitic conditions are optionally added in place of the antiviral agents.
Suitable antiviral agents contemplated for use in combination with the compounds of the disclosure or pharmaceutically acceptable salts thereof, can comprise nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral drugs.
Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emitricitabine [(-)-FTC]; beta-L- FD4 (also called beta-L-D4C and named beta-L-2',3'-dicleoxy-5-fluoro-cytidene); DAPD, ((- )-beta-D-2,6-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721 ; AG-1549; MKC-442 (l-(ethoxy-methyl)-5-(l-methylethyl)-6-(phenylmethyl)- (2,4(lH,3H)-pyrirnidinedione); and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK- 639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Vissum Project No. 11607.
When more than one pharmaceutical agent is administered to a patient, they can be administered simultaneously, separately, sequentially, or in combination (e.g., for more than two agents). For examples, when administered together with an additional anti-cancer or antiviral agent, the disclosed compounds or pharmaceutically acceptable salts thereof, can be administered simultaneously in the same pharmaceutical formulation or simultaneously in separate pharmaceutical formulations. Alternatively, when administered together with an additional anti-cancer or antiviral agent, the disclosed compounds or pharmaceutically 103 WO 2024/233900 PCT/US2024/028806 acceptable salts thereof, can be administered at separate times, depending the dosing requirements of the additional anti-cancer or antiviral agent.
Pharmaceutical compositions are disclosed that include one or more compounds provided herein (such as the compound of any one of Formulae (F), (1), (II), (Ila), (lib), (11c), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (Vlb), (Vic), (Vid), (Vie), (VIf), (Vig), (VIh), (VII), (Vila), (Vllb), (Villa), (VlUb), (VIIIc), (Vllld), (Ville), (VHIf), (Vlllg), (VHIh), (IXa), (IXb), and (X), or a compound as disclosed in the Exemplification) or pharmaceutically acceptable salts thereof, and typically at least one additional substance, such as an excipient, a known therapeutic other than those of the disclosure, and combinations thereof. In some embodiments, the disclosed compounds or pharmaceutically acceptable salts thereof, can be used in combination with other agents known to have beneficial activity targeting diseases or disorders listed above. For example, disclosed compounds or pharmaceutically acceptable salts thereof, can be administered alone or in combination with one or more anti-cancer or antiviral agent, and the pharmaceutically acceptable salts of these compounds.
The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.
A “subject” is a mammal in need of medical treatment, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
The precise amount of compound or pharmaceutically acceptable salt thereof, administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease or condition, and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The skilled 104 WO 2024/233900 PCT/US2024/028806 artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, e.g., when administered in combination with an anti-cancer or antiviral agent, an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the disclosure or pharmaceutically acceptable salt thereof, being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57th ed., 2003).
The term “effective amount” means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control.
The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years.
The pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. In an embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings. In preferred embodiments, the pharmaceutical composition is formulated for intravenous administration.
“Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject. Non limiting examples of pharmaceutically acceptable excipients include water, NaCI, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid 105 WO 2024/233900 PCT/US2024/028806 esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds.
General Synthetic Methods and Intermediates Compounds of the disclosure, including salts and N-oxides thereof, can be prepared using organic synthesis techniques known to one of ordinary skill in the art and/or by reference to the schemes shown below and the synthetic examples. The below Schemes are synthetic protocols that are meant to provide general guidance in connection with preparing the compounds of the disclosure. One skilled in the art would understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the disclosure.
The reactions for preparing compounds of the disclosure can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent’s freezing temperature to the solvent’s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.
Preparation of compounds of the disclosure can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, Sth ed., John Wiley & Sons: New Jersey, (2014), which is incorporated herein by reference in its entirety.
Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance (NMR) spectroscopy (e.g., 1H or 13C), infrared (JR) spectroscopy, 106 WO 2024/233900 PCT/US2024/028806 spectrophotometry (e.g., UV-visible), mass spectrometry (MS), or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
.N /NH2 LG is a leaving group, typically OMe In Scheme 1, a compound of Formula (I) may be prepared from compounds of Formula (ii) and (iii) using an amide coupling reaction typically in the presence of Me3Al in an aprotic solvent such as toluene at elevated temperature. A protecting group such a tBoc may be removed in situ or as a separate step using a suitable acid such as TFA or HCI.
Compounds of Formula (I) may undergo further reaction to provide an alternative compound of Formula (I). For example, when X1 = CR3 where R3 = Halo, single or multiple functional group interconversions as known by those skilled in the art, may be carried out to obtain alternative compounds where R3 is defined in Formula (1).
It will be appreciated by those skilled in the art that it may be necessary to utilise a suitable protecting group strategy for the preparation of compounds of Formula (1). Typical protecting groups may comprise, 4-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, carbamate or phthalimide, preferably Boc or phthalimide for the protection of primary or secondary aliphatic amines.
Also, it will be further appreciated that it may be necessary and/or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.
In particular, typical functional group interconversions (FGIs) include, where X1 = CR3 where CR3 is = CHal, conversion into other compounds of Formula (I) where X1 = CRwhere R3 is defined in Formula (1); a) palladium catalysed cross-coupling with a heterocyclic107 Scheme 1 WO 2024/233900 PCT/US2024/028806 boronic acid or boronate; b) conversion of CHal to a boronic acid followed by palladium catalysed cross-coupling; c) reaction of CHal with an appropriate alcohol to afford the corresponding ethers; d) conversion of CHal into alternative compounds where R3 is described in Formula (1).
Scheme 2 TFA R4 (ii) LG1 a leaving group, typically a Cl. OR’ is an alkyloxy group, typically OMe.
PG is an amine protecting group, typically 4-methoxybenzyl, 2,4-dimethoxylbenzyl and Boc In Scheme 2, compounds of Formula (ii) may be typically prepared from compounds of Formulae (iv), (v), (vi), (vii), (viii) and (ix) using the steps outlined.
Compounds of Formula (v) may prepared by the hydrolysis of compounds of Formula (iv) in AcOH at elevated temperatures.
Compounds of Formula (vii) may be prepared by reaction of compounds of Formula (v) with an appropriate amine (PG)2NH of Formula (vi) in the presence of an organic base such as DIPEA in an aprotic solvent such as DMSO at elevated temperature.
Compounds of Formula (ix) may be prepared by reaction of compounds of Formulae (vii) and (viii) in the presence of a base such as K2CO3 or DIPEA in DMF or DMSO at elevated temperatures.
Compounds of Formula (ii) may be prepared by deprotection of compounds of Formula (ix) in excess TFA at elevated temperatures. 108 WO 2024/233900 PCT/US2024/028806 Compounds of Formula (ii) and/or (ix) may undergo further reaction to provide an alternative compound of Formula (I). For example, when X1 = CR3 where R3 = Halo, single or multiple functional group interconversions may be carried out to obtain alternative compounds where R3 is defined in Formula (1).
It will be appreciated that it may be necessary and/or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.
Compounds that contain one or more stereocenters may be separated into their separate stereoisomers by typical methods such as chiral SFC or chiral HPLC techniques as indicated in the Intermediates and Examples below.
The following examples are intended to be illustrative, and are not meant in any way to be limiting.
EXEMPLIFICATION Abbreviations 9-BBN 9-borabicyclo[3.3.1 ]nonaneA angstromAc20 acetic anhydrideAcOH acetic acidATP adenosine-5 '-triphosphateBINAP 2,2’ -bis(diphenylphosphino)-1,1’ -binaphthylBID twice a day dosingBIW twice a week dosingBoc tert-butyl oxy carb onyl(Boc)2OBOPdi-fert-butyl dicarbonate(lH-Benzotriazol-l-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphateC CelsiusCSA camphorsulfonic acidDAST Diethylaminosulfur trifluorideDCE di chloroethaneDCM di chloromethane 109 WO 2024/233900 PCT/US2024/028806 DEAD diethyl azodi carboxyl ateDIPA N,N-diisopropylamineDIPEA N,N-diisopropylethylamineDME dimethoxyethaneDMF dimethyl formamideDMAP 4-DimethylaminopyridineDMSO dimethylsulfoxideDPPA diphenylphosphoryl azideDTT dithiothreitolEDC-HC1 (3-dimethylaminopropyl)-ethyl-carbodiimide hydrochlorideEDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimideEDTA ethylenediaminetetraacetic acidEtOAc ethyl acetateEtMgBr ethylmagnesium bromideEtOH ethanolh hour(s)HATU l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateHEPES N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acidHex hexaneHOBt 1 -hydroxybenzotri azoleHP-B-CD 2-hydroxypropyl־P־cyclodextrinHPLC high performance liquid chromatographyIC50 inhibitory concentration 50%IP A or i-PrOH isopropyl alcoholIr[dF(CF3)ppy]2(dtbpy))PF6 [4,4׳-BA(l J-dimethylethyl)-2,2׳-bipyridine-Al,Al']Z>A[3,5- difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-7V]phenyl-C]Iridium(III) hexafluorophosphateipintraperitonealiv intravenousKHMDS potassium hexamethyldisilazide or potassium bis(trimethylsilyl)amideKOAc potassium acetateLCMS liquid chromatography mass spectrometryLDA lithium diisopropylamideLiHMDS lithium bis(trimethylsilyl)amide110 WO 2024/233900 PCT/US2024/028806 m/z mass to charge ratiomin minutesMTBE methyl tert-butyl etherMeCN acetonitrileMeOH methanolMPLC medium pressure liquid chromatographyNaOAc sodium acetateBu ؛ NaO sodium tert-butoxiden-BuLi n-butyllithiumNMO N-methylmorpholine N-oxideNMP N-Methyl -2-pyrrol i donePBS phosphate-buffered salinePdC12(PPh3)2 bis(triphenylphosphine)palladium(II) dichloridePd2(dba)3 tris(dibenzylideneacetone)palladium(0)Pd(dppf)C12 [ 1,1 ’ -bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pd(OAc)2 palladium(!!) acetatePd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0)PE petroleum etherPPh3 triphenylphosphinePPTS pyridinium p-toluenesulfonateprep-HPLC preparative high performance liquid chromatographyprep-TLC preparative thin layer chromatographyit room temperaturesat. aq. saturated aqueousSEC supercritical fluid chromatographyt-BuOH tert-butyl alcoholTBAB tetrabutylammonium bromideTBAE tetrabutylammonium fluorideTBHP tert-butyl hydroperoxideTEA trifluoroacetic acidTEA triethylamineTHE tetrahydrofuran( Pr ؛ Ti(O titanium(IV) isopropoxide or tetraisopropoxytitaniumTMSN3 trimethylsilyl azideill WO 2024/233900 PCT/US2024/028806 HPLC Codes and Methods.
Organic gradient 0-100%, optimised for each sample.
HPLC-1 (Phenomenex Luna C18 75 x 30 mm, 3 pm; MeCN/H2O (0.2% HCQ2H)); HPLC-(Phenomenex Luna C18; 150 x 30 mm, 5 pm; MeCN/H2O (0.2% HCO2H); HPLC-(Phenomenex Luna Cl8; 200 x 40 mm, 10 pm; MeCN/H2O (0.2% HCO2H); HPLC-(Phenomenex Luna C18; 100 x 30 mm, 5 pm; MeCN/H2O (0.2% HCO2H); HPLC-(Phenomenex Luna C18; 100 x 25 mm, 4 pm; MeCN/H2O (0.2% HCO2H); HPLC-(Phenomenex Luna C18; 100 x 40 mm, 3 pm; MeCN/H2O (0.2% HCO2H); HPLC-(Phenomenex Luna C18; 80 x 30 mm, 3 pm; MeCN/H2O (0.2% HCO2H); HPLC-(Phenomenex Luna C18; 75 x 30 mm, 3 pm; MeCN/H2O (0.2% HCO2H); HPLC-(Phenomenex Luna C18; 200 x 40 mm, 10 pm; MeCN/H2O (0.2% HCO2H); HPLC-(Gilson C18 150 x 20 pm; MeCN/H2O (0.1% TFA); HPLC-11 (Waters Xbridge OBD 150 x mm, 10 pm; MeCN/H2O (NH4HCO3); HPLC-12 (Waters XBridge C18 150 x 19 mm, pm; MeCN/H2O (0.1% TFA); HPLC-13 (Waters XBridge BEH C18 100 x 30 mm, 10 pm; MeCN/H2O (0.2% HCO2H); HPLC-14 (Phenomenex Synergi Polar-RP, 100 x 25 mm, 4 pm; MeCN/H2O (0.2% HCO2H); HPLC-15 (Phenomenex Luna C18, 75 x 30 mm, 3 pm;MeCN/H2O (NH4HCO3); HPLC-16 (Phenomenex Gemini NX Cl 8, 75 x 30 mm, 3 pm; MeCN/H2O (0.05% NH4OH + 10 mM NH4HCO3); HPLC-17 (Xtimate C18 250 x 80 mm, pm; MeCN/H2O (0.05% NHOH + 10 mM NH4HCO3); HPLC-18 (YMC-Triart Prep C18, 250 x 50 mm, 10 pm; MeCN/H2O (0.05% NH4OH + 10 mM NH4HCO3)); HPLC-19 (Agela DuraShell C18, 250 x 70 mm, 10 pm; MeCN/H2O (0.05% NHOH + 10 mM NH4HCO3)); HPLC-20 ((Phenomenex luna Cl8, 250 x 70 mm, 15 pm); 1-13% MeCN/H2O (+ HC1);HPLC-21 (Phenomenex Titank Cl8 Bulk 250 x 70 mm, 10 pm; MeCN/H2O (0.05% NHOH + 10 mM NH4HCO3)); HPLC-22 (Phenomenex Luna Cl 8, 250 x 70 mm, 15 pm);MeCN/H2O (0.2% HCO2H)); HPLC-23 (Kromasil Cl8, 250 x 50 mm, 10 pm); MeCN/H2O (0.05% NHOH + 10 mM NH4HCO3)); HPLC-24 (Phenomenex Luna Cl8 75 x 30 mm, pm; MeCN/(H2O(+TFA)); HPLC-25 (Waters XBridge BEH Cl8 100 x 30 mm, 10 pm; M6CN/H2O (0.05% NHOH + 10 mM NHHCO3); HPLC-26 (Welch Xtimate Cl8, 250 x 70mm, 10 pm; MeCN/H2O (0.05% NHOH + 10 mM NH4HCO3)); HPLC-27 ((Waters Xbridge BEH Cl8, 250 x 50 mm, 10 pm; MeCN/H2O (0.05% NHOH + 10 mM NH4HCO3)). 112 WO 2024/233900 PCT/US2024/028806 Intermediate Al.(S)-3-(l-amino-2-methoxyethyl)aniline.
Step 1. Synthesis of 2-amino-2-(3-nitrophenyl)acetic acid To a solution of 2-amino-2-phenyl-acetic acid (20 g, 132 mmol) in H2SO4 (60 mL) was added the mixture of HNO3 (24.9 mL) in HSO4 (24 mL) at 0°C and the mixture stirred at 0 °C for h. The reaction was quenched by adding to iced H20 (300 mL) and the solids collected by filtration. The solids were triturated with H20 (200 mL) at 250C and stirred 20 min. Then solids were collected by filtration to afford the title compound as a pale yellow solid (25 g, 96%). LCMS m/z = 197 [M+H]+.
Step 2. Synthesis of 2-((tert-butoxycarbonyl)amino)-2-(3-nitrophenyl)acetic acid To a solution of 2-amino-2-(3-nitrophenyl)acetic acid (25 g, 127 mmol) and (Boc)2O (27.8 g, 127 mmol) in THE (50 mL) and H20 (50 mL) was added Na2CO3 (27 g, 255 mmol) and the mixture stirred at 25 °C for l h. The reaction mixture was filtered and the filtrate evaporated to dryness in vacuo. The residue was triturated with HC1 (20 mL) at 250C until pH=2 and stirred 20 min. The solids were collected by filtration to afford the title compound as a yellow solid (22 g, 58%) which was used without further purification.
Step 3. Synthesis of tert-butyl (2-hydroxy-l-(3-nitrophenyl)ethyl)carbamate To a solution of 2-(tert-butoxycarbonylamino)-2-(3-nitrophenyl)acetic acid (10.5 g, 35.mmol) in THE (50 mL) was added BHJ.THF (1 M, 70.9 mL) at 0°C and the mixture stirred at 0°C for 2 h. The reaction quenched by the addition of MeOH (200 mL) at 0°C and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a yellow oil (3.8g, 38%). 1H NMR 113 WO 2024/233900 PCT/US2024/028806 (400MHz, MeOH-d4) 5: 8.28-8.23 (m, 1H), 8.16 (dd, 1H), 7.76 (d, 1H), 7.65-7.55 (m, 1H), 4.77 (s, 1H), 3.82-3.65 (m, 3H), 1.45 (s, 9H).
Step 4. Synthesis of 2-amino-2-(3-nitrophenyl)ethan-l-ol A solution of tert-butyl (2-hydroxy-l-(3-nitrophenyl)ethyl)carbamate (3.8 g, 13.5 mmol) in HCl/EtOAc (40 mL) was stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC (Xtimate C18, 250 x mm, 10 pm; 1-25% MeCN/H2O (0.05% NHOH + lOmM NH4HCO3)) to give the title compound as a white solid (1.83 g, 74%). LCMS m/z = 183 [M+H]+.
Step 5. Synthesis of 2-methoxy-l-(3-nitrophenyl)ethan-l-amine To a solution of 2-amino-2-(3-nitrophenyl)ethanol (1 g, 5.49 mmol) in THF (10 mL) was added NaH (329 mg, 8.23 mmol) at 0°C for 5 min, and Mel (779mg, 5.49 mmol) added and the mixture stirred at 70°C for l h. The reaction mixture was quenched by addition saturated aqueous NH4C1 solution (15 mL) at 0°C. The pH was adjusted to pH=10 with sat.aq.Na2COand then extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2S04), evaporated to dryness in vacuo and the residue purified by MPLC (SiO2, 0-16% MeOH/EtOAc) to give the title compound as a white solid (450 mg, 41.8%). LCMS m/z = 197 [M+H]+.
Step 6. Synthesis of (S)-3-(l-amino-2-methoxyethyl)aniline To a solution of 2-methoxy-l-(3-nitrophenyl)ethan-l-amine (450 mg, 2.29 mmol) in MeOH (5 mL) was added Pd/C (450 mg, 2.29 mmol, 10% purity) and the mixture stirred at 25°C for l h under H2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 3-(l-amino-2-methoxyethyl)aniline as a white solid (340 mg, 89%).
The residue was purified by prep-HPLC (Xtimate Cl8, 250 x 80 mm, 10 pm; 15-45% MeCN/HO (NHOH+NH4HCO3)) followed by SFC (REGIS (s,s) WHELK-01, 250 x 50mm, 10 pm); 50% IP A (+0.1% NH4OH) in CO2) to afford: Peak 1, Intermediate Al,(S)-3-(l-amino-2-methoxyethyl)aniline as a white solid (130 mg, 38%). LCMS m/z = 167 [M+H]+.
Intermediate A2.tert-butyl (R)-(l-(3-aminophenyl)ethyl)(methyl)carbamate 114 WO 2024/233900 PCT/US2024/028806 ^ >־ ، h2nStep 1r .1 step 2 T j) Me'' NH2 Me'''^NHBoc Me'''^NHMe Step 1. Synthesis of tert-butyl (R)-(l-(3-aminophenyl) ethyl) carbamate Na2CO3 (6.23 g, 58.7 mmol) was added to a solution of (R)-3-(l-aminoethyl)aniline (4 g, 29.4 mmol) and di-tert-butyl dicarbonate (6.41 g, 29.4 mmol,) in THE (30 mL) and H20 (mL) and the mixture stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure and the residue diluted with H20 (20 mL) and extracted with EtOAc (3x mL). The combined organics were evaporated to dryness under reduced pressure and the residue purified by MPLC (SiO2, 1-5% EtOAc/PE) to give the title compound as a yellow oil (5.05 g, 73%).
Step 2. Synthesis of (R)-3-(l-(methylamino)ethyl)aniline To a solution of tert-butyl (R)-(l-(3-aminophenyl)ethyl)carbamate (5.05 g, 21.4 mmol) in THE (100 mL) was added LiAlH4 (4.06 g, 107 mmol) at 0°C and the mixture stirred at 50°C for 3 h under N2. The reaction mixture was quenched by addition Na2S04.10H2O (5 g) at 0°C, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (3.4 g, crude). LCMS m/z =151 [M+H]+.
Intermediate A3,tert-butyl (R)-(l-(3-aminophenyl)ethyl)(methyl)carbamate.
Me Me To a solution of (R)-3-(l-(methylamino)ethyl)aniline (3.40 g, 22.6 mmol) in THE (30 mL) was added (Boc)2O (2.96 g, 13.6 mmol) and the mixture stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure and the residue purified by MPLC (SiO2, 1- 5% EtOAc/PE) to give the title compound as a yellow solid (3.5 g, 62%).
Intermediate A4 and A5.tert-butyl (R)-2-(5-aminopyridin-3-yl)piperidine-l-carboxylate and tert-butyl (S)-2-(5-aminopyridin-3-yl)piperidine-l-carboxylate. 115 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-l(2H)- carboxylate.
KHMDS (1 M, 502 mL) in THE (250 mL) was added to a solution of tert-butyl 2- oxopiperidine-1-carboxylate (100 g, 502 mmol) in THE (500 mL) at -78°C and the mixture stirred at -78°C for l h before 1,1,1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl)methanesulfonamide (197 g, 552 mmol) was added to the mixture and the resulting mixture stirred at -78°C for l h. The reaction mixture was slowly poured into H20 (1000 mL) at 0-10°C under nitrogen and extracted with EtOAc (3x 1000 mL). The combined organics were washed with brine (2x 1000 mL), dried (Na2S04) and concentrated to afford the title compound as a yellow oil (220 g, crude) which was used without additional purification. 1HNMR (400 MHz, CDCI3): 5.14 (t, 1H), 3.47-3.42 (m, 2H), 2.11 (dt, 2H), 1.89 (s, 1H), 1.34 (s, 9H), 1.13-1.09 (m, 1H).
Step 2. Synthesis of tert-butyl 5 '-amino-5,6-dihydro-[2,3 '-bipyridine]-1 (4H)-carboxylate.
To a mixture of tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-l(2H)- carboxylate (63.41 g, 191 mmol) and (5-amino-3-pyridyl)boronic acid (33 g, 239 mmol) in dioxane (300 mL) and H20 (100 mL) was added K2CO3 (126.64 g, 916 mmol) and Pd(dppf)C12.CH2C12 (5.86 g, 7.18 mmol,) at 25°C and the mixture stirred at 100°C for l h under N2. The reaction mixture was partitioned between EtOAc (1000 mL) and H20 (10mL) and the aqueous phase extracted with EtOAc (3x 1000 mL). The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO2, 33-100% EtOAc/PE) to give the title compound as a yellow solid (60 g, 91%). LCMS m/z = 276 [M+H]+.
Step 3. Synthesis of tert-butyl (R)-2-(5-aminopyridin-3-yl)piperidine-l-carboxylate and tert- butyl (S)-2-(5-aminopyridin-3-yl)piperidine-l-carboxylate. 116 WO 2024/233900 PCT/US2024/028806 To a mixture of tert-butyl 5'-amino-5,6-dihydro-[2,3'-bipyridine]-l(4H)-carboxylate (15 g, 54.5 mmol) in EtOAc (150 mL) was added Pd/C (15 g, 10% purity) at 25OC and the mixture reaction stirred at 50°C for 2 h under H2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 2-(5-amino-3-pyridyl)piperidine- 1-carboxylate as a white solid (15 g, crude).
The racemate was separated by SFC (Chiralcel C2-3,100 x 4.6 mm, 3 pm; EtOH (0.1%IP Am) in CO2 to afford: Peak 1. Intermediate A4,tert-butyl (R)-2-(5-aminopyridin-3-yl)piperidine-l-carboxylate (23 g, 60%).
Peak 2. Intermediate A5,tert-butyl (S)-2-(5-aminopyridin-3-yl)piperidine-l-carboxylate (23 g, 60%).
Intermediate A6.tert-butyl ((5-aminopyridin-3-yl)methyl)(methyl)carbamate.
Step 1. Synthesis of lf5-bromopyridin-3-yl)-N-methyimethanamine.
A mixture of 5-bromopyridine-3-carbaldehyde (5 g, 26.88 mmol) in methanamine (27.83 g, 269 mmol, 30% purity) was stirred at 25°C for 12 h under N2 and NaBH4 (2.03 g, 53.mmol) added at 0°C. The resulting mixture was stirred at 25°C for 2 h under N2. The reaction mixture was quenched by addition saturated 0.5 M HC1 (10 mL) at 0°C and extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a yellow oil (5.30 g). LCMS m/z = 201 [M+H]+.
Step 2. Synthesis of tert-butyl ((5-bromopyridin-3-yl)methyl)(methyl)carbamate.
To a solution of l-(5-bromopyridin-3-yl)-N-methylmethanamine (5.20 g, 25.9 mmol) and (Boc)2O (5.64 g, 25.9 mmol) in THF (52 mL) and H20 (13 mL) was added Na2CO3 (5.48 g, 51.7 mmol) and the mixture stirred at 25°C for 2 h. The reaction was diluted with H20 ( 117 WO 2024/233900 PCT/US2024/028806 mL) and extracted with EtOAc (3x 50 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, 50% EtOAc/PE) to give the title compound as a yellow oil (4.50 g, 57.8%). LCMS m/z = 3[M+H]+.
Step 3. Synthesis of tert-butyl ((5-((diphenylmethylene)amino)pyridin-3- y !)methyl) (methyl) carbamate.
To a solution of tert-butyl ((5-bromopyridin-3-yl)methyl)(methyl)carbamate (4.40 g, 14.mmol,) and diphenylmethanimine (2.91 g, 16.07 mmol,) in dioxane (70 mL) was added Pd2(dba)3 (1.34 g, 1.46 mmol), Xantphos (1.69 g, 2.92 mmol) and Cs2C03(14.28 g, 43.mmol) and the mixture stirred at 100°C for 3 h under N2. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by MPLC (SiO2, 50% EtOAc/PE) to give the title compound as a yellow oil (3.50 g, 60%). LCMS m/z = 4[M+H]+.
Step 4. Synthesis of tert-butyl ((5-aminopyridin-3-yl)methyl)(methyl)carbamate.
To a solution of tert-butyl ((5-((diphenylmethylene)amino)pyridin-3- yl)methyl)(methyl)carbamate (3.40 g, 8.47 mmol) in MeOH (40 mL) was added NHOH.HCl (1.18 g, 16.94 mmol) and NaOAc (1.39 g, 16.94 mmol) and the mixture stirred at 25°C for h. The reaction mixture was concentrated under reduced pressure and the residue extracted with EtOAc (3x 50 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure to give a residue that was purified by MPLC (SiO2, EtOAc) to give the title compound as a yellow oil (2.00 g, 99.5%). LCMS m/z = 238 [M+H]+.
Intermediate A7.tert-butyl (R)-(l-(5-aminopyridin-3-yl)butyl)carbamate. 118 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of (E)-N-((5-bromopyridin-3-yl)methylene)-2-methylpropane-2- sulfmamide.
To a solution of 5-bromonicotinaldehyde (5 g, 26.88 mmol) and 2-methylpropane-2- sulfmamide (3.58 g, 29.57 mmol) in THE (60 mL) was added Ti(0Et)4 (7.97 g, 34.95 mmol) and the mixture stirred at 40 °C for 12 h. The reaction mixture was added to H20 (50 mL) and then the solids removed by filtration and the filter cake washed with EtOAc (3x 20 mL). The aqueous phase was extracted with additional EtOAc (3x 50mL) and the combined organics were dried (Na2S04) and evaporated to dryness. The residue was purified by MPLC (SiO2, 1-50% EtOAc/PE) to give the title compound as a white solid (6 g, 77%). LCMS m/z = 291 [M+H]+.
Step 2. Synthesis of N-(l-(5-bromopyridin-3-yl)butyl)-2-methylpropane-2-sulfmamide.
To a solution of (E)-N-((5-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulf1namide (Step 1, 3.90 g, 13.49 mmol) in THE (20 mL) was added propylmagnesium chloride (2 M, 10.11 mL) at -78°C and the mixture stirred at 0°C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 0-50% EtOAc) to give the title compound as a yellow solid (5.10 g, crude). LCMS m/z = 335 [M+H]+.
Step 3. Synthesis of tert-butyl (5-(l-((tert-butylsulfmyl)amino)butyl)pyridin-3-yl)carbamate.
To a solution of tert-butyl carbamate (3.51 g, 30 mmol) and N-(l-(5-bromopyridin-3- yl)butyl)-2-methylpropane-2-sulfmamide (5.00 g, 15 mmol) in dioxane (30 mL) was added Cs2CO3 (7.33 g, 22.5 mmol) and Pd2(dba)3 (1.37 g, 1.50 mmol), XPhos (715 mg, 1.50 mmol) and the mixture stirred at 100°C for 2 h under N2. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a white solid (3.00 g, 54%). LCMS m/z = 370 [M+H]+.
Step 4. Synthesis of 5-(l-aminobutyl)pyridin-3-amine.
A solution of tert-butyl (5-(l-((tert-butylsulf1nyl)amino)butyl)pyridin-3-yl)carbamate (3.00 g, 8.12 mmol) HCl/EtOAc (1 mL) was stirred at 25°C for 2 h. The reaction mixture was concentrated under N2 to give the title compound as a yellow solid (2.60 g, crude). LCMS m/z = 166 [M+H]+. 119 WO 2024/233900 PCT/US2024/028806 Step 5. Synthesis of tert-butyl (R)-(l-(5-aminopyridin-3-yl)butyl)carbamate.
To a solution of 5-(l-aminobutyl)pyridin-3-amine (1.10 g, 6.66 mmol) in dioxane (10 mL) and H2O (5 mL) was added NaHCO3 (559 mg, 6.66 mmol) and (Boc)2O (581 mg, 2.mmol) and the mixture stirred at 25OC for 12 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give tert-butyl (l-(5-aminopyridin-3- yl)butyl)carbamate which was further separated by SEC (DAICEL CHIRALPAK AD, 250 x mm, 10 pm); 30% EtOH (0.1% NH4OH) in CO2 to afford: Peak 2. Intermediate A7.tert-butyl (R)-(l-(5-aminopyridin-3-yl)butyl)carbamate (white solid, 210 mg, 11.9%). LCMS m/z = 266 [M+H]+.
Intermediate A8.tert-butyl (S)-(l-(5-aminopyridin-3-yl)propyl)carbamate or tert-butyl (R)- (l-(5-aminopyridin-3-yl)propyl)carbamate.
The title compounds were prepared using an analogous 5-Step method to that described for Intermediate A7.Chiral-SFC (DAICEL CHIRALPAK AD, 250 x 30 mm, 10 pm); 33% EtOH (+ 0.1% NH4OH in CO2)) afforded: Peak 2, Intermediate A8.tert-butyl (S)-(l-(5-aminopyridin-3-yl)propyl)carbamate or tert- butyl (R)-(l-(5-aminopyridin-3-yl)propyl)carbamate (yellow solid: 1.1g, 15%); LCMS m/z = 252 [M+H]+.
Intermediate A9.tert-butyl (S)-((5-aminopyridin-3-yl)(cyclopropyl)methyl)carbamate or tert-butyl (R)-((5-aminopyridin-3-yl)(cyclopropyl)methyl)carbamate. 120 WO 2024/233900 PCT/US2024/028806 The title compound was prepared using an analogous 5-Step method to that described for Intermediate A7.
Chiral-SFC (DAICEL CHIRALPAK AD, 250 x 50 mm, 10 pm); 30% EtOH (+ 0.1%NH40H in CO2)) afforded: Peak 1, Intermediate A9.tert-butyl (S)-((5-aminopyridin-3-yl)(cyclopropyl)methyl)carbamate or tert-butyl (R)-((5-aminopyri din-3-yl)(cyclopropyl)methyl)carbamate (yellow oil: 630 mg, 13%); LCMS m/z = 252 [M+H]+.
Intermediate A10 and All.tert-butyl (R)-(l-(5-aminopyridin-3-yl)-2-ethoxy ethyl) carbamate and tert-butyl (S)-(l-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamate.
Step 1. Synthesis of tert-butyl (5-(2-ethoxyacetyl)pyridin-3-yl)carbamate. 121 WO 2024/233900 PCT/US2024/028806 n-BuLi (2.5 M in hexanes, 14.65 mL) was added dropwise to a solution of tert-butyl N-(5- bromo-3-pyridyl) carbamate (5.00 g, 18.3 mmol) in THE (150 mL) at -60°C. The mixture was stirred at -60°C for 30 min under N2 and ethyl 2-ethoxyacetate (2.90 g, 22 mmol) added and the mixture stirred at 25°C for 2 h under N2. The reaction mixture was quenched by addition of sat aq NH4C1 (20 mL) at 0°C and then diluted with H20 (20 mL) and extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure. The residue was purified by prep-HPLC (Waters Xbridge Prep OBD Cl 8, 150 x 40 mm, 10 pm; 15-45% MeCN/H2O (NHOH + NH4HCO3)) to give the title compound as a yellow oil (1.40 g, 27%). LCMS m/z = 281 [M+H]+.
Step 2. Synthesis of tert-butyl (E)-(5-(2-ethoxy-l-(hydroxyimino)ethyl)pyridin-3- yl)carbamate.
To mixture of tert-butyl (5-(2-ethoxyacetyl)pyridin-3-yl)carbamate (1.28 g, 4.57 mmol) in EtOH (20 mL) was added NHJOH.HCI (381 mg, 5.48 mmol) and NaOAc (749 mg, 9.mmol) and the mixture stirred at 75°C for 2 h. The reaction mixture was quenched by addition sat aq NHCl (20 mL) at 0°C, diluted with H20 (20mL) and extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure to give the title compound (1.30 g, 96%). LCMS m/z = 291 [M+H]+.
Step 3. Synthesis of tert-butyl (5-(l-amino-2-ethoxyethyl)pyridin-3-y l) carbamate.
A mixture of tert-butyl (E)-(5-(2-ethoxy-l-(hydroxyimino)ethyl)pyridin-3-yl)carbamate (1.g, 3.56 mmol), Pd/C (600 mg, 3.56 mmol, 10% purity), NHOH (1 mL) and IP A (10 mL) was degassed and purged with H2 (50psi) for 3 h and then the mixture stirred at 50°C for 16 h under H2 (50psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (960 mg, 96%). LCMS m/z = 282 [M+H]+.
Step 4. Synthesis of 5-(l-amino-2-ethoxyethyl)pyridin-3-amine hydrochloride.
A mixture of tert-butyl (5-(l-amino-2-ethoxyethyl)pyridin-3-yl)carbamate (800 mg, 2.mmol) in EtOAc (6 mL) and HCl/EtOAc (3 mL) was stirred at 25 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (400 mg, 77%). LCMS m/z =182 [M+H]+.
Step 5. Synthesis of tert-butyl (R)-(l-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamate and tert-butyl (S)-(l-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamate.122 WO 2024/233900 PCT/US2024/028806 A mixture of 5-(l-amino-2-ethoxyethyl)pyridin-3-amine hydrochloride (400 mg, 1.84 mmol), B0C20 (160 mg, 0.735 mmol,), NaHCO3 (309 mg, 3.67 mmol) in THF (15 mL) and H20 (mL) was was stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure and the residue diluted with H20 (10 mL) and extracted with EtOAc (3x 10 mL).The combined organics were dried (Na2S04) and concentrated under reduced pressure to give tert-butyl (l-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamate which was separated by chiral SFC (DAICEL CHIRALPAK IC, 250 x 30 mm, 10 pm); 28% EtOH (0.1% NH4OH) in CO2) to afford: Peak 1, Intermediate A10.tert-butyl (R)-(l-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamate or tert-butyl (S)-(l-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamate.
Peak 2, Intermediate All,tert-butyl (R)-(l-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamate or tert-butyl (S)-(l-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamate. LCMS m/z = 2[M+H]+.
Intermediate A12.5-((ethylamino)methyl)pyridin-3-amine.
Step 1. Synthesis of N-ethyl-5-nitronicotinamide.
To a solution of 5-nitronicotinic acid (5 g, 29.7 mmol) in pyridine (10 mL) was added ethanamine; hydrochloride (12.13 g, 148.7 mmol) and EDCI (8.55 g, 44.61 mmol) and the mixture stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure and the residue purified by MPLC (SiO2, 0-100% EtOAc/PE) to give the title compound as a white solid (3.5 g, 60%). LCMS m/z = 196 [M+H]+.
Step 2. Synthesis of 5-amino-N-ethylnicotinamide. 123 WO 2024/233900 PCT/US2024/028806 To a mixture of N-ethyl-5-nitronicotinamide (3.4 g, 17.42 mmol) in MeOH (5 mL) was slowly added Pd/C (4 g, 25.62 mmol, 10% purity) and the mixture was stirred at 25°C for h under H2 (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (2.8 g, 97%). LCMS m/z =1[M+H]+.
Step 3. Synthesis of 5-((ethylamino)methyl)pyridin-3-amine.
To a solution of N-ethyl-5-nitronicotinamide (1.5 g, 9.08 mmol) was added BH3.THF (IM, 45.4 mL,) at 0°C under N2 and the mixture stirred at 50°C for 2 h under N2. The reaction mixture was quenched with 0.1 M HC1 (50 mL) at 0°C, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Xbridge Prep OBD C18, 150 x mm, 10 pm; 1-5% MeCN/H20 (NH4OH+NH4HCO3)) to give the title compound as a yellow oil (550 mg, 40%). LCMS m/z =152 [M+H]+.
Intermediate A13.tert-butyl (S)-2-(5-aminopyridin-3-yl)pyrrolidine-l-carboxylate.
Step 1. Synthesis of tert-butyl 2-(5-aminopyridin-3-yl)-lH-pyrrole-l-carboxylate.
A mixture of 5-bromopyridin-3-amine (1.50 g, 8.67 mmol), tert-butyl 2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrrole-l-carboxylate (2.80 g, 9.54 mmol), Pd(dppf)C12 (634 mg, 0.87 mmol) and K3PO4 (3.68 g, 17.3 mmol) in H20 (15 mL) and THE (40 mL) was stirred at 80oC for 1 h under N2. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a yellow solid (2 g, 89%). LCMS m/z = 2[M+H]+.
Step 2. Synthesis of tert-butyl (S)-2-(5-aminopyridin-3-yl)pyrrolidine-l-carboxylate To a solution of tert-butyl 2-(5-aminopyridin-3-yl)-lH-pyrrole-l-carboxylate (Step 1, 1 g, 3.86 mmol,) in EtOH (20 mL) was added Pd/C (1.00 g, 10% purity) at 25°C. The mixture was stirred at 60°C for 25 h under H2 (15 psi). The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give a residue to give tert-butyl 2-(5- aminopyridin-3-yl)pyrrolidine-l-carboxylate as a yellow solid (700 mg, 69%). The solid 124 WO 2024/233900 PCT/US2024/028806 was further purified by prep-SFC (DAICEL CHIRALPAK IG, 250 x 30 mm, 10 pm); 33% IP A (0.1% NH4OH) in CO2) to afford: Peak 2 Intermediate A13:tert-butyl (S)-2-(5-aminopyridin-3-yl)pyrrolidine-l-carboxylate (yellow solid, 330 mg, 47%). LCMS m/z = 264 [M+H]+.
Intermediate A14 and A15.(S)-5-(l-(methylamino)ethyl)pyridin-3-amine and (R)-5-(l- (methylamino)ethyl)pyri din-3-amine.
/N. O^/tBu .N. CK /tBur n a v n s ״ r^ ־ % s ״ (S).NHMe RLNHMe Step 1. Synthesis of (Z)-N-(l-(5-bromopyridin-3-yl)ethylidene)-2-methylpropane-2- sulfmamide A mixture of l-(5-bromo-3-pyridyl)ethanone (25 g, 125 mmol) in THE (300 mL) was added 2-methylpropane-2-sulf1namide (15.91 g, 131 mmol) and Ti(OEt)4 (37.06 g, 162 mmol) and the mixture stirred at 45°C for 12 h. The reaction mixture was diluted with H20 (300 mL), filtered and extracted with EtOAc (4x 200 mL). The combined organics were concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, 0- 25% EtOAc/PE) to give the title compound as a yellow oil (33 g, 87%). LCMS m/z = 3[M+H]+.
Step 2. Synthesis of N-(l-(5-bromopyridin-3-yl)ethyl)-2-methylpropane-2-sulfmamide NaBH4 (5.75 g, 152 mmol) was added to a solution of (Z)-N-(l-(5-bromopyridin-3- yl)ethylidene)-2-methylpropane-2-sulf1namide (Step 1, 30 g, 99 mmol) in MeOH (200 mL) at 0°C and the mixture stirred at 20°C for l h. The reaction mixture was quenched by addition of NH4C1 aq. (200 ml) at 0°C and Na2CO3 aq. was added until pH=10. The mixture was 125 WO 2024/233900 PCT/US2024/028806 extracted with EtOAc (4x 100 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure. The reaction was purified by column chromatography (SiO2, 0-100% EtOAc/PE) to give the title compound as a white solid (22 g, 73%). LCMS m/z = 307 [M+H]+.
Step 3. Synthesis of N-(l-(5-bromopyridin-3-yl)ethyl)-N, 2-dimethylpropane-2-sulfmamide.
NaH (1.18 g, 29.5 mmol, 60% purity) was added to a solution of iodomethane (4.65 g, 32.mmol) in DMF (40 mL) at -5°C under N2 and the mixture stirred at -5°C for 20 min. To this was added N-(l-(5-bromopyridin-3-yl)ethyl)-2-methylpropane-2-sulf1namide (Step 2, 5 g, 16.4 mmol) and the mixture was stirred at -5°C for 20 min. The reaction was quenched by the addition of NHCl (100mL) at 0°C and the mixture extracted with EtOAc (4x 200 mL). The combined organics were evaporated to dryness and the residue purified by prep-HPLC (Phenomenex C18 250 x 70 mm, 10 pm; 30-55% MeCN/H2O (NHOH + NH4HCO3)) to give the title compound as a brown oil (6.3 g, crude).
Step 4. Synthesis of tert-butyl (5-(l-((tert-butylsulfmyl)(methyl)amino)ethyl)pyridin-3- yl)carbamate.
A mixture N-(l-(5-bromopyridin-3-yl)ethyl)-N,2-dimethylpropane-2-sulf1namide (Step 3, 5.g, 16.3 mmol), tert-butyl carbamate (3.82 g, 32.6 mmol), Cs2CO3 (7.96 g, 24.4 mmol), XPhos (776 mg, 1.63 mmol) and Pd2(dba)3 (1.49 g, 1.63 mmol) in dioxane (40 mL) was degassed and purged with N2 (x3) and the mixture was stirred at 100°C for 2 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a yellow oil (4.5 g, 77%). LCMS m/z = 356 [M+H]+.
Step 5. Synthesis of (S)-5-(l-(methylamino)ethyl)pyridin-3-amine and (R)-5-(l- (methylamino) ethyl)pyridin-3-amine.
HCl/EtOAc (20 mL) was added to a solution of tert-butyl (5-(l-((tert- butylsulf1nyl)(methyl)amino)ethyl)pyridin-3-yl)carbamate (Step 5, 3 g, 8.44 mmol) in EtOAc (10 mL) and the mixture stirred at 25°C for l h. The reaction mixture was filtered and concentrated under reduced pressure to give a 5-(l-(methylamino)ethyl)pyridin-3-amine as a white solid (600 mg, 25%) which was separated by prep-SFC (DAICEL CHIRALPAK IG, 250 x 30 mm, 10 pm); 30% Heptane/EtOH (0.1% NH4OH) in CO2 to afford: 126 WO 2024/233900 PCT/US2024/028806 Peak 1 Intermediate A14(S)-5-(l-(methylamino)ethyl)pyridin-3-amine or (R)-5-(l- (methylamino)ethyl)pyridin-3-amine (brown oil, 240 mg, 18%); LCMS m/z =152 [M+H]+.
Peak 2 Intermediate A15(S)-5-(l-(methylamino)ethyl)pyridin-3-amine or (R)-5-(l- (methylamino)ethyl)pyridin-3-amine (brown oil, 240 mg, 18%); LCMS m/z =152 [M+H]+.
Intermediate A16 and A17.tert-butyl (S)-(l-(5-aminopyridin-3-yl)ethyl)carbamate and tert-butyl (R)-(l-(5-aminopyridin-3-yl)ethyl)carbamate. ,hk O^tBu .N ,NV H S A V H n V 11 । 1 ס*״״ o H Step 3 Ph N Step 1. Synthesis of l-(5-bromopyridin-3-yl)ethan-l-amine.
A mixture of N-(l-(5-bromopyridin-3-yl)ethyl)-2-methylpropane-2-sulf1namide (Intermediate A14 Step 2, 14 g, 45.87 mmol) in EtOAc (1 mL) and HCl/EtOAc (2 mL) was stirred at 25°C for l h. The reaction mixture was concentrated under N2 to give the title compound as a yellow oil (9 g, 97%). LCMS m/z = 201 [M+H]+.
Step 2. Synthesis of tert-butyl (l-(5-bromopyridin-3-yl)ethyl)carbamate.
To mixture of l-(5-bromopyridin-3-yl)ethan-l-amine (Step 1, 8.5 g, 42.3 mmol) in dioxane (80 mL) and H20 (15 mL) was added B0C20 (10.15 g, 46.50 mmol) and NaHCO3 (7.10 g, 84.6 mmol) and the mixture stirred at 25 °C for l h. The solids were removed by filtration and the filtrate extracted with EtOAc (3x 150 mL). The combined organics were dried (Na2S04) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow oil (8.6 g, 67%). LCMS m/z = 301 [M+H]+.
Step 3. Synthesis of tert-butyl (l-(5-((diphenylmethylene)amino)pyridin-3- yl) ethyl) carbamate.
To a mixture of tert-butyl (l-(5-bromopyridin-3-yl)ethyl)carbamate (Step 2, 8.5 g, 28.mmol) and diphenylmethanimine (5.63 g, 31.04 mmol) in dioxane (2 mL) was added Pd2(dba)3 (1.29 g, 1.41 mmol) and Xantphos (1.63 g, 2.82 mmol) and Cs2CO3 (18.39 g, 56. 127 WO 2024/233900 PCT/US2024/028806 mmol) and the mixture stirred at 100°C for l h under N2. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow oil (11 g, 97%).LCMS m/z = 402 [M+H]+.
Step 4. Synthesis of of tert-butyl (S)-( 1-(5-aminopyridin-3-y I) ethyl) carbamate and tert-butyl (R)-(l-(5-aminopyridin-3-yl)ethyl)carbamate.
To the mixture of tert-butyl (l-(5-((diphenylmethylene)amino)pyri din-3-yl)ethyl)carbamate (Step 3, 10 g, 24.9 mmol) in MeOH (100 mL) was added NHOH.HCI (2.60 g, 37.4 mmol) and NaOAc (3.06 g, 37.4 mmol) and the mixture stirred at 25°C for l h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-50% MeOH/DCM) followed by chiral- SEC (DAICEL CHIRALPAK IC, 250 x 30 mm, 10 pm); 40% EtOH (0.1% NH4OH) in COto afford: Peak 1, Intermediate A16.tert-butyl (S)-(l-(5-aminopyridin-3-yl)ethyl)carbamate or tert- butyl (R)-(l-(5-aminopyridin-3-yl)ethyl)carbamate (yellow oil, 1.9 g, 39%); LCMS m/z = 238 [M+H]+.
Peak 2, Intermediate A17.tert-butyl (S)-(l-(5-aminopyridin-3-yl)ethyl)carbamate or tert- butyl (R)-(l-(5-aminopyridin-3-yl)ethyl)carbamate (yellow oil, 1.8 g, 38%); LCMS m/z = 238 [M+H]+.
Intermediate A18.5-(3-aminophenyl)piperazin-2-one.
Step 1. Synthesis of 5-(3-aminophenyl)pyrazin-2 (lH)-one.
To a solution of (3-aminophenyl)boronic acid (1 g, 7.30 mmol, 1 eq) and 5-bromopyrazin- 2(lH)-one (1.28 g, 7.30 mmol) in H20 (5 mL) and EtOH (20 mL) was added K3PO4 (3.10 g, 14.6 mmol) and cataCXiumA Pd G2 (488 mg, 0.73 mmol) and the mixture stirred at 80°C for l h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue was purified by prep-HPLC(Xbridge BEH C18 250 x 128 WO 2024/233900 PCT/US2024/028806 mm, 10 pm; 1-35% MeCN/HO (NH4OH + NH4HCO3)) to give the title compound as a yellow sold (1.18 g, 86%). LCMS m/z =188 [M+H]+.
Step 2. Synthesis of 5-(3-aminopheny !)piperazin-2-one.
To a solution of 5-(3-aminophenyl)pyrazin-2(lH)-one (Step 1, 1 g, 5.34 mmol) in EtOAc (mL) was added Pd/C (1 g, 5.34 mmol, 10% purity) and the mixture stirred at 50°C for 12 h under H2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (268 mg, 26%). LCMS m/z =1[M+H]+.
Intermediate A19.tert-butyl (l-(5-aminopyridin-3-yl)-3-methoxypropyl)carbamate.
OMe Step 1. Synthesis of tert-butyl (5-(methoxy(methyl)carbamoyl)pyridin-3-yl)carbamate.
DIPEA (2.17 g, 16.8 mmol) and HATU (4.79 g, 12.6 mmol) was added to the mixture of 5- ((tert-butoxycarbonyl)amino)nicotinic acid (2 g, 8.39 mmol) and N-methoxymethanamine hydrochloride (1.23 g, 12.59 mmol) in DMSO (10 mL) and the mixture stirred at 25°C for h. The mixture was diluted with H20 (50 mL) and extracted with EtOAc (4x 100 mL). The combined organics were evaporated to dryness in vacuo and the residue purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a white oil (g, 84%). LCMS m/z = 282 [M+H]+.
Step 2. Synthesis of tert-butyl (5-acryloylpyridin-3-y l) carbamate.
To a mixture of tert-butyl (5-(methoxy(methyl)carbamoyl)pyridin-3-yl)carbamate (Step 1, 500 mg, 1.78 mmol) in THE (6 mL) was added bromo(vinyl)magnesium (IM in THE, 6. 129 WO 2024/233900 PCT/US2024/028806 mL) at 0°C and the mixture stirred at 0°C for another 1 min. The mixture was stirred at 25°C for l h under N2. The reaction mixture was quenched with saturated aqueous NH4C1 solution (5 mL) at 0°C and extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a yellow solid (700 mg, 79%).
Step 3. Synthesis of tert-butyl (5-(3-methoxypropanoyl)pyridin-3-y l) car hamate.
NaOMe (152 mg, 2.82 mmol) was added to a solution of tert-butyl (5-acryloylpyridin-3- yl)carbamate (Step 2, 350 mg, 1.41 mmol) in MeOH (6 mL) and the mixture stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-100% EtOAc/PE) to give the title compound as a yellow oil (200 mg, 25%). LCMS m/z = 281 [M+H]+.
Step 4. Synthesis of tert-butyl (Z)-(5-(l-(hydroxyimino)-3-methoxypropyl)pyridin-3- yl)carbamate.
TEA (361 mg, 3.57 mmol) and NHOH.HCl (186 mg, 2.68 mmol) were added to a solution of tert-butyl (5-(3-methoxypropanoyl)pyridin-3-yl)carbamate (Step 3, 250 mg, 0.89 mmol) in EtOH (5 mL) and the mixture stirred at 70°C for 12 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (0-100% EtOAc/PE) to give the title compound as a yellow oil (170 mg, 64%). LCMS m/z = 296 [M+H]+.
Step 5. Synthesis of tert-butyl (5-(l-amino-3-methoxypropyl)pyridin-3-yl)carbamate.
To the mixture of tert-butyl (Z)-(5-(l-(hydroxyimino)-3-methoxypropyl)pyridin-3- yl)carbamate (Step 4, 160 mg, 0.542 mmol) in EtOH (6 mL) was added Ni (160 mg, 2.mmol) and the mixture stirred at 50°C for 2 h under H2. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a yellow oil (150 mg, 98%). LCMS m/z = 282 [M+H]+.
Step 6. Synthesis of 5-(l-amino-3-methoxypropyl)pyridin-3-amine.
A solution of tert-butyl (5-(l-amino-3-methoxypropyl)pyridin-3-yl)carbamate (Step 5, 1mg, 0.533 mmol) in HCl/MeOH (2 mL) and MeOH (0.5 mL) was stirred at 25°C for 30 min. The reaction mixture was concentrated under a stream of N2 to give the title compound of a yellow oil (90 mg, 93%). LCMS m/z =182 [M+H]+. 130 WO 2024/233900 PCT/US2024/028806 Step 7. Synthesis of tert-butyl (l-(5-aminopyridin-3-yl)-3-methoxypropyl)carbamate.
BocO (57.8 mg, 0.265 mmol) and NaHCO3 (74.2 mg, 0.883 mmol) was added to a solution of 5-(l-amino-3-methoxypropyl)pyridin-3-amine (Step 6, 80 mg, 0.441 mmol) in dioxane (mL) and H20 (1 mL) and the mixture stirred at 25°C for l h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue was purified by prep-HPLC-16 (3-35% MeCN) to give the title compound as a yellow oil (100 mg, 80%). LCMS m/z = 282 [M+H]+.
Intermediate A20.tert-butyl (R)-2-(3-aminophenyl )piperi dine-1-carboxylate or tert-butyl (S)-2-(3-aminophenyl)piperidine-l-carboxylate.
Step 1. Synthesis of tert-butyl 6-(3-aminophenyl)-3,4-dihydropyridine-l(2H)-carboxylate To a solution of 3-bromoaniline (556 mg, 3.23 mmol) and tert-butyl 6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-l(2H)-carboxylate (1 g, 3.23 mmol) inH2O (mL) and dioxane (20 mL) was added KzPO4 (1.37 g, 6.47 mmol) and XPHOS-PD-G(254mg, 0.323 umol) and the mixture stirred at 80°C for 12 h under N2. The reaction mixture was concentrated under reduced pressure and the residue was purified by MPLC (SiO2, 1- 25% EtOAc/PE) to give the title compound as a white solid (350 mg, 39%). LCMS m/z = 275 [M+H]+.
Step 2. Synthesis of tert-butyl (R)-2-(3-aminophenyl)piperidine-l-carboxylate or tert-butyl (S)-2-(3-aminophenyl)piperidine-l-carboxylate.
To a solution of tert-butyl 6-(3-aminophenyl)-3,4-dihydropyridine-l(2H)-carboxylate (Step 1, 330 mg, 1.20 mmol) in MeOH (10 mL) was added Pd/C (330 mg, 1.20 mmol, 10% purity) and the mixture stirred at 50 °C for 1 h under H2 (50 psi). The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by prep-HPLC- 131 WO 2024/233900 PCT/US2024/028806 17 (15-45% MeCN) followed by chiral-SFC (REGIS (s,s) WHELK-01, 250 x 50 mm, pm); 50% IP A (0.1% NHOH) in CO2) to afford: Peak 2, Intermediate A20.tert-butyl (R)-2-(3-aminophenyl)piperidine-l-carboxylate or tert- butyl (S)-2-(3-aminophenyl)piperidine-l-carboxylate (yellow oil, 120 mg, 37%); LCMS m/z = 277 [M+H]+.
Intermediate A21.tert-butyl (R)-2-(5-amino-2-fluoropyridin-3-yl)piperidine-l-carboxylate or tert-butyl (S)-2-(5-amino-2-fluoropyridin-3-yl)piperidine-l-carboxylate.
The title compounds were prepared from 5-bromo-6-fluoropyridin-3-amine and tert-butyl 6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-l(2H)-carboxylate usingan analogous 2-step method as described for Intermediate A20.Prep-SFC (Diacel Chiralpak IC, 250 x 30 mm, 10 pm; 55% MeOH (0.1% NH4OH) in CO2 Peak 1, Intermediate A21.tert-butyl (R)-2-(5-amino-2-fluoropyridin-3-yl)piperidine-l- carboxylate or tert-butyl (S)-2-(5-amino-2-fluoropyridin-3-yl)piperidine-l-carboxylate (whitesolid, 200 mg, 42%). LCMS m/z = 296 [M+H]+.
Intermediate A22.tert-butyl (R)-(l-(5-aminopyridin-3-yl)-2-methoxyethyl)carbamate or tert-butyl (S)-(l-(5-aminopyridin-3-yl)-2-methoxyethyl)carbamate. 132 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of 2-amino-2-(5-bromopyridin-3-yl)acetonitrile.
The reaction was carried out in triplicate.
Ti (O؛Pr)4 (31.17 g, 110 mmol) and NH3 (5 M, 235 mL) were added to a solution of 5- bromonicotinaldehyde (17 g, 91.39 mmol) in MeOH (100 mL) and the mixture stirred at 25°C for 1 h and a solution of trimethylsilanecarbonitrile (10.88 g, 110 mmol) in MeOH (mL) added. The resulting mixture stirred at 25°C for 12 h and poured into ice-water (2mL) with stirring. The mixture was filtered and the foltrate extracted with EtOAc (3x 2mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow solid. The 3 batches were combined to afford (28.6 g, 49%). LCMS m/z = 212 [M+H]+.
Step 2. Synthesis of methyl 2-(5-bromopyridin-3-yl)-2-((tert-butoxycarbonyl)amino)acetate.
A solution of 2-amino-2-(5-bromopyridin-3-yl)acetonitrile (Step 1, 11.64 g, 54.9 mmol) in HCl/MeOH (50 mL) was stirred at 25°C for 12 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give methyl 2-amino-2-(5-bromopyridin-3- yl)acetate hydrochloride as a yellow solid (80.8 g, crude) which used without further purification. To a solution of methyl 2-amino-2-(5-bromopyridin-3-yl)acetate hydrochloride (80.8 g, 287 mmol) and B0C20 (62.6 g, 287 mmol) in THE (450 mL) and H20 (150 mL) was added NaHCO3 (48.22 g, 574 mmol) and the mixture was stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure and the residue diluted with H(200 mL) and extracted with EtOAc (3x 200 mL). The combined extracts were dried (Na2SO4) and concentrated under reduced pressure and the residue was purified by column 133 WO 2024/233900 PCT/US2024/028806 chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow oil (48 g, 48%). LCMS m/z = 345 [M+H]+.
Step 3. Synthesis of tert-butyl (l-(5-bromopyridin-3-yl)-2-hydroxyethyl)carbamate.
LiCl (1.72 g, 40.7 mmol) was added to the mixture of NaBH4 (1.54 g, 40.7 mmol) in EtOH (50 mL) and the mixture stirred at 0°C for 10 min. To this was added a solution of methyl 2- (5-bromopyridin-3-yl)-2-((tert-butoxycarbonyl)amino)acetate (Step 2, 5.40 g, 15.64 mmol) in THE (50 mL) dropwise over 20 mins at 0°C and the mixture stirred at 25°C for 2 h. The reaction mixture was quenched by addition of H2O (20 mL) at 0°C and extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow oil (3.50 g, 70%). LCMS m/z = 317 [M+H]+.
Step 4. Synthesis of tert-butyl (l-(5-bromopyridin-3-yl)-2-methoxyethyl)carbamate.
To a solution of tert-butyl (l-(5-bromopyri din-3-yl)-2-hydroxyethyl)carbamate (Step 3, 1.g, 5.04 mmol) in THE (15 mL) was added Mel (573 mg, 4.04 mmol) at 0°C and the mixture stirred at 25°C for 15 min. To this was added NaH (403.5 mg, 10.09 mmol, 60% purity) at 0°C and stirred at 25°C for 2 h. The mixture was quenched by addition of H20 (10 mL) at 0°C and extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (1-50% EtOAc/PE) to give the title compound as a yellow oil (1.40 g, 42%). LCMS m/z = 331 [M+H]+.
Step 5. Synthesis of tert-butyl (l-(5-((tert-butoxycarbonyl)amino)pyridin-3-yl)-2- methoxyethyl) carbamate.
To a solution of tert-butyl (l-(5-bromopyri din-3-yl)-2-methoxyethyl)carbamate (Step 4, 3mg, 1.01 mmol) and tert-butyl carbamate (178 mg, 1.52 mmol) in dioxane (5 mL) was added Cs2CO3 (494 mg, 1.52 mmol), XPhos (48.22 mg, 0.101 mmol) and Pd2(dba)3 (92.6 mg, 0.1mmol) and the mixture was stirred at 100°C for 2 h under N2. The mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (1-50% EtOAc/PE) to give the title compound as a yellow oil (1.10 g, 99%). LCMS m/z = 368 [M+H]+.
Step 6. Synthesis of 5-(l-amino-2-methoxyethyl)pyridin-3-amine hydrochloride. 134 WO 2024/233900 PCT/US2024/028806 A solution of tert-butyl (l-(5-((tert-butoxycarbonyl)amino)pyridin-3-yl)-2- methoxyethyl)carbamate (Step 5, 1.05 g, 2.86 mmol) in HCl/EtOAc (10 mL) was stirred at 25°C for l h. The mixture was concentrated under reduced pressure to give the title compound as a yellow oil (500 mg, 86%). LCMS m/z =168 [M+H]+.
Step 7. Synthesis of tert-butyl (R)-(l-(5-aminopyridin-3-yl)-2-methoxyethyl)carbamate or tert-butyl (S)-(l-(5-aminopyridin-3-yl)-2-methoxyethyl)carbamate.
To a solution of 5-(l-amino-2-methoxyethyl)pyridin-3-amine hydrochloride (450 mg, 2.mmol) and (Boc)2O (241.1 mg, 1.10 mmol) in H20 (3 mL) and THF (15 mL) was added NaHCO3 (371 mg, 4.42 mmol) and the mixture stirred at 25°C for l h. The mixture was quenched with H20 (10 mL) at 0°C and extracted with EtOAc (3x 10 mL). The combined extracts were evaporated to dryness and the residue purified by column chromatography on silica gel (1-33% EtOAc/PE) followed by chiral-SFC (Diacel Chiralpak IC, 250 x 30 mm, pm; 10-50% EtOH (+ 0.1% NH4OH) in CO2) to afford: Peak 1, Intermediate A22;tert-butyl (R)-(l-(5-aminopyridin-3-yl)-2- methoxyethyl)carbamate or tert-butyl (S)-(l-(5-aminopyridin-3-yl)-2- methoxyethyl)carbamate. LCMS m/z = 268 [M+H]+.
Intermediate A23.tert-butyl (R)-(l-(5-aminopyridin-3-yl)-2-methoxyethyl)(methyl)carbamate or tert-butyl (S)-(l-(5-aminopyridin-3-yl)-2- methoxyethyl)(methyl)carbamate.
Step 1. Synthesis of tert-butyl (l-(5-bromopyridin-3-yl)-2-methoxyethyl)(methyl)carbamate.
To a solution of tert-butyl (l-(5-bromopyri din-3-yl)-2-hydroxyethyl)carbamate (Intermediate A22 Step 3, 5 g, 15.76 mmol) in THF (30 mL) was added NaH (2.52 g, 63 mmol, 60% purity) at 0°C for 10 min followed by Mel (17.9 g, 126 mmol) and the mixture stirred at 25°C 135 WO 2024/233900 PCT/US2024/028806 for 2 h. The reaction mixture was quenched with sat.aq. NH4C1 (20 ml) at 0°C. The mixture was diluted with H20 (20 mL) and extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure and the residue purified by column chromatography on silica gel ( 0-25% EtOAc/PE) to give the title compound as a yellow oil (3 g, 55%). LCMS m/z = 347 [M+H]+.
Step 2. Synthesis of tert-butyl (l-(5-((diphenylmethylene)amino)pyridin-3-yl)-2- methoxyethyl)(methyl) carbamate.
To a solution of tert-butyl (l-(5-bromopyridin-3 -yl)-2-methoxyethyl)(methyl)carbamate (Step 1, 2.98 g, 8.63 mmol) and diphenylmethanimine (1.88 g, 10.4 mmol) in dioxane (30 mL) was added Cs2C03 (5.62 g, 17.3 mmol), Xantphos (999 mg, 1.73 mmol) and Pd(dba)2 (248 mg, 0.43 mmol) and the mixture stirred at 100°C for 2 h under N2. The reaction mixture was filtered and the filtrate evaporated to dryness under reduced pressure and extracted with EtOAc (3x 30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, 0-25% EtOAc/PE) to give the title compound as a yellow oil (2.40 g, 62%). LCMS m/z = 446 [M+H]+.
Step 3. tert-butyl (R)-(l-(5-aminopyridin-3-yl)-2-methoxyethyl)(methyl)carbamate and tert- butyl (S)-( 1-(5-aminopyridin-3-y I)-2-methoxy ethyl) (me thy I) carbamate.
To a solution of tert-butyl (l-(5-((diphenylmethylene)amino)pyridin-3-yl)-2- methoxyethyl)(methyl)carbamate (Step 2, 2.30 g, 5.16 mmol) in MeOH (25 mL) was added NHOH.HCl (430 mg, 6.19 mmol) and NaOAc (508 mg, 6.19 mmol) and the mixture stirred at 25°C for 1 h. The reaction was concentrated under reduced pressure and the residue was extracted with EtOAc (3x 30 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-100% EtOAc/PE) followed by prep-SFC (Phenomenex-Cellulose-2, 250 x mm, 10 pm); 45% MeOH (0.1% NHOH) to afford: Peak 1, Intermediate A23 .tert-butyl (R)-(l-(5-aminopyridin-3-yl)-2- methoxyethyl)(methyl)carbamate or tert-butyl (S)-(l-(5-aminopyridin-3-yl)-2- methoxyethyl)(methyl)carbamate (yellow oil, 575 mg, 40%). LCMS m/z = 282 [M+H]+.
Intermediate A24.tert-butyl ((5-aminopyridin-3-yl)methyl)(ethyl)carbamate. 136 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of N-ethyl-5-nitronicotinamide.
To a mixture of 5-nitronicotinic acid (7 g, 41.6 mmol) and ethylamine hydrochloride (17 g, 208 mmol) in pyridine (60 mL) was added EDCI (12 g, 62.5 mmol) in one portion and the mixture was stirred at 25°C for 4 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the reaction purified by column chromatography (SiO2, 50% PE/EtOAc) to give the title compound as a yellow solid (6.11 g, 75%). LCMS m/z = 196 [M+H]+.
Step 2. Synthesis of 5-amino-N-ethylnicotinamide.
To a solution of N-ethyl-5-nitronicotinamide (6 g, 30.74 mmol) in MeOH (100 mL) was slowly added Pd/C (6 g, 25.62 mmol, 10% purity) and the mixture stirred at 25°C for 12 h under H2 (15 psi). The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a yellow solid (5 g, 98%). LCMS m/z =1[M+H]+.
Step 3. Synthesis of 5-((ethylamino)methyl)pyridin-3-amine.
To 5-amino-N-ethylnicotinamide (4.5 g, 27.24 mmol, 1 eq) was added BH3.THF (IM, 136.mL) at 0°C under N2 in one portion and the mixture stirred at 60°C for 12 h. The reaction mixture was quenched by 0.1 N HCI (50 mL) at 0°C and stirred at 80°C for 1 h. The pH was adjusted to pH 6-7 by the addition of IN NH4OH to pH 6-7 and the solids removed by filtration. The filtrate wasevaporated to dryness to afford the title compound as a yellow oil (5.1 g, crude). LCMS m/z = 152 [M+H]+.
Step 4. Synthesis of tert-butyl ((5-aminopyridin-3-yl)methyl)(ethyl)carbamate. 137 WO 2024/233900 PCT/US2024/028806 The mixture of 5-((ethylamino)methyl)pyridin-3-amine (5 g, 33 mmol) and di-tert-butyl dicarbonate in THE (15 mL) and H20 (5 mL) was added NaHCO3 (5.56 g, 66.1 mmol) and the mixture was stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure and mixture diluted with H20 (20 mL) and extracted with EtOAc (3x mL). The combined organics were dried (Na2S04), evaporated to dryness under reduced pressure and the residue purified by column chromatography (SiO2, 50% PE/EtOAc) to give the title compound as a yellow oil (3 g, 36%). LCMS m/z = 252 [M+H]+.
Intermediate A25.5-((isopropylamino)methyl)pyridin-3-amine.
Step 1. Synthesis ofN-isopropyl-5-nitronicotinamide.
To a mixture of 5-nitronicotinic acid (2 g, 11.9 mmol) and propan-2-amine (4.92 g, 83.mmol,) in DMF (15 mL) was added HATU (6.79 g, 17.6 mmol) and DIPEA (2.31 g, 17.mmol) at 0°C and the mixture stirred at 0°C for 10 min and at 25°C for 30 min. The solids were removed be filtration, the filtrate concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow solid (1.8 g, 72%). LCMS m/z = 210 [M+H]+.
Step 2. Synthesis of 5-amino-N-isopropylnicotinamide.
To a solution of N-isopropyl-5-nitronicotinamide (Step 1, 1.5 g, 7.17 mmol) in MeOH (mL) was added Pd/C (1 g, 10% purity) and the mixture stirred under H2 at 25°C for l h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a white solid (1 g, 78%). LCMS m/z =180 [M+H]+.
Step 3. Synthesis of 5-((isopropylamino)methyl)pyridin-3-amine. 138 WO 2024/233900 PCT/US2024/028806 To a solution of 5-amino-N-isopropylnicotinamide (Step 2, 800 mg, 4.46 mmol) was added BH3.THF (IM, 22.32 mL) at 0°C under N2 and the mixture stirred at 60°C for 2 h under N2. The reaction mixture was quenched by 0.1 M HCI (50 mL) at 0°C, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC-11 (1-10% MeCN) to give the title compound as a yellow oil (100 mg, 13%). LCMS m/z = 166 [M+H]+.
Intermediate A26.(R)-5-(2-amino-l-methoxypropan-2-yl)pyridin-3-amine or (S)-5-(2- amino-1-m ethoxypropan-2-yl )pyri din-3-amine.
Step 1. Synthesis of 2-amino-2-(5-bromopyridin-3-yl)propanenitrile.
To a solution of l-(5-bromopyridin-3-yl)ethan-l-one (10 g, 50 mmol) in MeOH (20 mL) was added tetraisopropoxytitanium (17.05 g, 60 mmol) and NH3 (5M, 140 mL) and stirred at 25°C for 1 h. To this was added then a solution of trimethylsilanecarbonitrile (5.95 g, mmol) in MeOH (20 mL) and the mixture stirred at 25°C for 12 h. The reaction mixture was poured into ice-water (50 mL) and the resulting mixture filtered through celite. The filtrate was extracted with EtOAc (3x 50 mL) and the combined organics dried (Na2S04) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (15-50% EtOAc/PE) to give the title compound as a yellow solid (4.40 g, 39%). LCMS m/z = 228 [M+H]+.
Step 2. Synthesis of methyl 2-amino-2-(5-bromopyridin-3-yl)propanoate.
A mixture of 2-amino-2-(5-bromopyridin-3-yl)propanenitrile (Step 1, 4.40 g, 19.5 mmol) inHCl/MeOH (50 mL) was stirred at 25°C for 12 h. The reaction mixture was concentrated 139 WO 2024/233900 PCT/US2024/028806 under reduced pressure to give the title compound as a brown oil (5.50 g, crude, HC1). LCMS m/z = 259 [M+H]+.
Step 3. Synthesis of 2-amino-2-(5-bromopyridin-3-yl)propan-l-ol.
To a solution of NaBH4 (759 mg, 20 mmol) in EtOH (50 mL) was added LiCl (851 mg, mmol) and the mixture stirred at 0°C for 10 min. A solution methyl 2-amino-2-(5- bromopyridin-3-yl)propanoate (Step 2, 2.00 g, 7.72 mmol) in THE (50 mL) was added dropwise over 20 min at 0°C and the mixture warmed to 25°C for 2 h. The reaction mixture was quenched by addition of H20 (50 mL) at 0°C and extracted with EtOAc (3x 50 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20% MeOH/EtOAc) to give the title compound as a yellow oil (1.50 g, 84%). LCMS m/z = 231 [M+H]+.
Step 4. Synthesis of 2-(5-bromopyridin-3-yl)-l-methoxypropan-2-amine.
NaH (929 mg, 23.2 mmol, 60% purity) was added to a solution of 2-amino-2-(5- bromopyridin-3-yl)propan-l-ol (Part 3, 1.79 g, 7.75 mmol) in THE (20 mL) at 0°C. The mixture was stirred at 25°C for 15 mins and Mel (880 mg, 6.20 mmol) added at 0°C. The mixture was stirred at 25°C for 2 h, quenched by addition saturated aqueous NH4C1 (10 mL) at 0°C and extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue purified by column chromatography on silica gel (100% EtOAc) to give the title compound as a yellow oil (970 mg, 51%).LCMS m/z = 245 [M+H]+.
Step 5. Synthesis of tert-butyl (5-(2-amino-l-methoxypropan-2-yl)pyridin-3-yl)carbamate.
To a solution of 2-(5-bromopyridin-3-yl)-l-methoxypropan-2-amine (Step 4, 940 mg, 3.mmol) and tert-butyl carbamate (674 mg, 5.75 mmol) in dioxane (10 mL) was added Cs2C(1.87 g, 5.75 mmol,) and Pd2(dba)3 (351 mg, 0.38 mmol) and XPhos (183 mg, 0.38 mmol) and the mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by column chromatography on silica gel (100% EtOAc) to give the title compound as a yellow oil (9mg, 83%). LCMS m/z = 282 [M+H]+.
Step 6. Synthesis of (R)-5-(2-amino-l-methoxypropan-2-yl)pyridin-3-amine and (S)-5-(2- amino-l-methoxypropan-2-yl)pyridin-3-amine. 140 WO 2024/233900 PCT/US2024/028806 A solution of tert-butyl (5-(2-amino-l-methoxypropan-2-yl)pyri din-3-yl)carbamate (Step 5, 880 mg, 3.13 mmol) in HCl/MeOH (5 mL) was stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure and the pH of the residue adjusted pH=8 and purified by prep-SFC (DAICEL CHIRALPAK IC, 250 x 30 mm, 10 pm; 50% IP A (0.1% NH4OH) in CO2) to afford: Peak 1, Intermediate A26.(R)-5-(2-amino-l-methoxypropan-2-yl)pyridin-3-amine or (S)-5- (2-amino-l-methoxypropan-2-yl)pyridin-3-amine (200 mg, 35%); LCMS m/z =182 [M+H]+.
Intermediate A27.tert-butyl (R)-3-(5-aminopyridin-3-yl)-l,4-oxazepane-4-carboxylate or tert-butyl (S)-3-(5-aminopyridin-3-yl)-l,4-oxazepane-4-carboxylate.
Step 1. Synthesis of tert-butyl 3-oxo-1,4-oxazepane-4-carboxylate.
To a solution of l,4-oxazepan-3-one (1.94 g, 16.9 mmol) and (Boc)2O (11 g, 50.6 mmol) in DCM (30 mL) was added DMAP (206 mg, 1.69 mmol) and TEA (2.56 g, 25.3 mmol) and the mixture stirred at 40°C for 12 h under N2. The reaction mixture was diluted with H20 (mL) and extracted with EtOAc (3x 40mL). The combined organics were washed with brine (2x 30 mL), dried (Na2S04) and concentrated under reduced pressure and the residue purified by MPLC (SiO2, 0-25% EtOAc/PE) to give the title compound as a brown oil (2.52 g, 69%). LCMS m/z = 216 [M+H]+.
Step 2. Synthesis of tert-butyl 3-((diphenoxyphosphoryl)oxy)-6,7-dihydro-l,4-oxazepine- 4(5H)-carboxylate. 141 WO 2024/233900 PCT/US2024/028806 To a solution of tert-butyl 3-oxo-l,4-oxazepane-4-carboxylate (Step 1, 1.5 g, 6.97 mmol) in THE (25 mL) was added KHMDS (IM, 10.45 mL) at -78°C for 1.5 h and diphenyl phosphorochloridate (2.81 g, 10.45 mmol) added. The mixture was stirred at 0°C for l h under N2. The reaction mixture was diluted with H20 (80 mL) and extracted with EtOAc (3x 50mL). The combined organics were washed with brine (2x 30 mL), dried (Na2S04) and concentrated under reduced pressure and the residue purified by MPLC (SiO2, 0-25% EtOAc/PE) to give the title compound as a yellow oil (1.46 g, 46%). LCMS m/z = 4[M+H]+.
Step 3. Synthesis of tert-butyl 3-(5-aminopyridin-3-yl)-6,7-dihydro-l,4-oxazepine-4(5H)- carboxylate.
To a solution of tert-butyl 3-((diphenoxyphosphoryl)oxy)-6,7-dihydro-l,4-oxazepine-4(5H)- carboxylate (Step 2, 1.32 g, 2.94 mmol) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-3-amine (970 mg, 4.41 mmol) in DME (15 mL) was added Pd(PPh3)4 (170 mg, 0.147 mmol) and Na2CO3 (2M, 2.94 mL) and the mixture stirred at 90°C for 2 h under N2. The reaction mixture was concentrated under reduced pressure and the residue purified by MPLC (SiO2, 0-50% EtOA/PE) to give the title compound as a brown solid (340 mg, 40%). LCMS m/z = 292 [M+H]+.
Step 4. Synthesis of tert-butyl (R)-3-(5-aminopyridin-3-yl)-l,4-oxazepane-4-carboxylate or tert-butyl (S)-3-(5-aminopyridin-3-yl)-l,4-oxazepane-4-carboxylate.
A mixture of tert-butyl 3-(5-aminopyridin-3-yl)-6,7-dihydro-l,4-oxazepine-4(5H)- carboxylate (Step 3, 320 mg, 1.10 mmol) and Pd/C (400 mg, 10% purity) in MeOH (5 mL) was stirred at 50°C for 2 h under H2 (50 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 3-(5-aminopyridin-3-yl)- l,4-oxazepane-4-carboxylate as a white solid (190 mg), tert-butyl 3-(5-aminopyridin-3-yl)- l,4-oxazepane-4-carboxylate was separated by chiral-SEC (DAICEL CHIRALPAK AD, 2x 30 mm, 10 pm); 20% MeOH (0.1%NH4OH) in CO2) to afford: Peak 1, Intermediate A27.tert-butyl (R)-3-(5-aminopyridin-3-yl)-l,4-oxazepane-4- carboxylate or tert-butyl (S)-3-(5-aminopyridin-3-yl)-l,4-oxazepane-4-carboxylate (brown oil, 92 mg, 28%); LCMS m/z = 294 [M+H]+.
Intermediate A28.tert-butyl 5-(5-aminopyridin-3-yl)-l,4-oxazepane-4-carboxylate. 142 WO 2024/233900 PCT/US2024/028806 The title compound was prepared from l,4-oxazepan-5-one using an analogous 4-Step method to that described for Intermediate A27without chiral-SFC purification. LCMS m/z = 294 [M+H]+.
Intermediate A29 and A30.tert-butyl (R)-2-(5-aminopyridin-3-yl)azepane-l-carboxylate and tert-butyl (S)-2-(5-aminopyridin-3-yl)azepane-l-carboxylate.
Step 4،and The title compounds were prepared from azepan-2-one using an analogous 4 Step method as described for Intermediate A27. Chiral-SFC (REGIS (s, s) WHELK-01, 250 x 50 mm, 10pm); 40% EtOH (0.1% NH4OH) in CO.) afforded: Peak 1, Intermediate A29.tert-butyl (R)-2-(5-aminopyridin-3-yl)azepane-l-carboxylate or tert-butyl (S)-2-(5-aminopyridin-3-yl)azepane-l-carboxylate (white solid, 1.35 g, 42%);LCMS m/z = 292 [M+H]+. 143 WO 2024/233900 PCT/US2024/028806 Peak 2, Intermediate A30.tert-butyl (R)-2-(5-aminopyridin-3-yl)azepane-l-carboxylate or tert-butyl (S)-2-(5-aminopyridin-3-yl)azepane-l-carboxylate (white solid, 1.5 g, 46%); LCMS m/z = 292 [M+H]+.
Intermediate A31, A32, A33 and A34.tert-butyl (2S,6R)-2-(5-aminopyridin-3-yl)-6- methylpiperidine-1-carboxylate and tert-butyl (2S,6S)-2-(5-aminopyridin-3-yl)-6- methylpiperidine-1-carboxylate and tert-butyl (2R,6S)-2-(5-aminopyridin-3-yl)-6- methylpiperidine-1-carboxylate and tert-butyl (2R,6R)-2-(5-aminopyridin-3-yl)-6- methylpiperidine-1 -carboxylate.
Step 1. Synthesis of tert-butyl 2-methyl-6-oxopiperidine-l-carboxylate.
LDA (2M, 33.1 mL) was added to a solution of 6-methylpiperidin-2-one (6.8 g, 60.1 mmol) in THF (60 mL) at -78°C for 30 min. To this was added (Boc)2O (14.43 g, 66.1 mmol) and the mixture mixture stirred at -78°C for 2 h under N2. The reaction mixture was quenched by addition saturated aqueous NH4C1 solution (100 mL) at 0°C and extracted with EtOAc (3x 100 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure to give the title compound as a yellow oil (12 g, 93%).
Step 2. Synthesis of tert-butyl 2-methyl-6-((trifluoromethyl)sulfonyl)oxy)-3,4- dihydropyridine-l(2H)-carboxylate.
LDA (2M, 35.17 mL) was added to a solution of tert-butyl 2-methyl-6-oxopiperidine-l- carboxylate (Step 1, 10g, 46.9 mmol) in THF (50 mL) at -78°C under N2 and the mixture stirred at -78°C for 0.5 h. To this was added dropwise a solution of N-(5-chloro-2-pyridyl)- l,l,l-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (20.25 g, 51.6 mmol) in THF and the mixture stirred at 25°C for 2 h under N2. The reaction mixture was quenched by 144 WO 2024/233900 PCT/US2024/028806 addition saturated aqueous NH4Cl solution (100 mL) at 0°C, and then extracted with EtOAc (3x 100 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 0-5% EtOAc/PE) to give the title compound as a yellow oil (11 g, 68%).
Step 3. Synthesis of tert-butyl 5 '-amino-6-methyl-5,6-dihydro-[2,3 '-bipyridine]-1 (4H)- carboxylate.
To a mixture of tert-butyl 2-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine- l(2H)-carboxylate (Step 2, 10.5 g, 30.41 mmol) and 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-3-amine (7.03 g, 31.93 mmol) in dioxane (100 mL) and H20 (mL) was added Pd(PPh3)4 (1.05 g, 0.912 mmol) and Cs2C03 (19.81 g, 60.81 mmol) and the mixture stirred at 110°C for 1 h under N2. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 10-100% EtOAc/PE) to give the title compound as a yellow oil (5.5 g, 62%). LCMS m/z = 290 [M+H]+.
Step 4. Synthesis of tert-butyl (2S,6R)-2-(5-aminopyridin-3-yl)-6-methylpiperidine-l- carboxylate and tert-butyl (2S,6S)-2-(5-aminopyridin-3-yl)-6-methylpiperidine-l-carboxylate and tert-butyl (2R,6S)-2-(5-aminopyridin-3-yl)-6-methylpiperidine-l-carboxylate and tert- butyl (2R,6R)-2-(5-aminopyridin-3-yl)-6-methylpiperidine-l-carboxylate.
To a solution of tert-butyl 5'-amino-6-methyl-5,6-dihydro-[2,3'-bipyridine]-1(4H)- carboxylate (Step 3, 2 g, 6.91 mmol) in MeOH (40 mL) was added Pd/C (2 g, 6.91 mmol, 10% purity) and the mixture stirred under H2 at 50°C for l h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give tert-butyl 2-(5- aminopyridin-3-yl)-6-methylpiperidine-l-carboxylate as a white solid (1.3 g, 64%) which was purified by chiral-SFC (REGIS(S, S) WHELK-01, 250 x 25 mm, 10 pm); 30% IP A (0.1% NH4OH) in CO2) to afford: Peak 1, Intermediate A31.tert-butyl (2S,6R)-2-(5-aminopyridin-3-yl)-6-methylpiperidine- 1-carboxylate or tert-butyl (2S,6S)-2-(5-aminopyridin-3-yl)-6-methylpiperidine-l- carboxylate or tert-butyl (2R,6S)-2-(5-aminopyridin-3-yl)-6-methylpiperidine-l-carboxylate or tert-butyl (2R,6R)-2-(5-aminopyridin-3-yl)-6-methylpiperidine-l-carboxylate (white solid, 580 mg). LCMS m/z = 292 [M+H]+. 145 WO 2024/233900 PCT/US2024/028806 Peak 2, Intermediate A32.tert-butyl (2S,6R)-2-(5-aminopyridin-3-yl)-6-methylpiperidine- 1-carboxylate or tert-butyl (2S,6S)-2-(5-aminopyridin-3-yl)-6-methylpiperidine-l- carboxylate or tert-butyl (2R,6S)-2-(5-aminopyridin-3-yl)-6-methylpiperidine-l-carboxylate or tert-butyl (2R,6R)-2-(5-aminopyridin-3-yl)-6-methylpiperidine-l-carboxylate (white solid, 280 mg). LCMS m/z = 292 [M+H]+.
Peak 3, Intermediate A33.tert-butyl (2S,6R)-2-(5-aminopyridin-3-yl)-6-methylpiperidine- 1-carboxylate or tert-butyl (2S,6S)-2-(5-aminopyridin-3-yl)-6-methylpiperidine-l- carboxylate or tert-butyl (2R,6S)-2-(5-aminopyridin-3-yl)-6-methylpiperidine-l-carboxylate or tert-butyl (2R,6R)-2-(5-aminopyridin-3-yl)-6-methylpiperidine-l-carboxylate (yellow oil, 600 mg). LCMS m/z = 292 [M+H]+.
Peak 4, Intermediate A34.tert-butyl (2S,6R)-2-(5-aminopyridin-3-yl)-6-methylpiperidine- 1-carboxylate or tert-butyl (2S,6S)-2-(5-aminopyridin-3-yl)-6-methylpiperidine-l- carboxylate or tert-butyl (2R,6S)-2-(5-aminopyridin-3-yl)-6-methylpiperidine-l-carboxylate or tert-butyl (2R,6R)-2-(5-aminopyridin-3-yl)-6-methylpiperidine-l-carboxylate (yellow oil, 300 mg). LCMS m/z = 292 [M+H]+.
Intermediate A35, A36, A37 and A38.tert-butyl (2R,5R)-2-(5-aminopyridin-3-yl)-5- methylpyrrolidine-1-carboxylate and tert-butyl (2S,5S)-2-(5-aminopyridin-3-yl)-5- methylpyrrolidine-1-carboxylate and tert-butyl (2R,5S)-2-(5-aminopyridin-3-yl)-5- methylpyrrolidine-1-carboxylate and tert-butyl (2S,5R)-2-(5-aminopyridin-3-yl)-5- methylpyrrolidine-1 -carboxylate. and Me Me Step 1. Synthesis of 2-methyl-5-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)-lH-pyrrole. 146 WO 2024/233900 PCT/US2024/028806 A mixture of 2-methylpyrrole (8.00 g, 98.6 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (12.52 g, 49.3 mmol), 4,4'-di-tert- butyl-2,2'-bipyridine (1.06 g, 3.94 mmol) and (l,5-Cyclooctadiene)(methoxy)iridium(I) dimer (1.31 g, 1.97 mmol) in hexane (80 mL) was degassed and purged with N2 (x3) and stirred at 30°C for 2 h under N2. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 0-10% EtOAc/PE) to give the title compound as a yellow solid (8.1 g, 40%). LCMS m/z = 208 [M+H]+.
Step 2. Synthesis of 3-(5-methyl-lH-pyrrol-2-yl)-5-nitropyridine.
To a solution of 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrole (Part 1, 8.08 g, 39 mmol) in dioxane (40 mL) and H20 (4 mL) was added 3-bromo-5-nitro-pyridine (5.50 g, 27.1 mmol), K2CO3 (7.49 g, 54.2 mmol) and Pd(PPh3)4 (3.13 g, 2.71 mmol) and the mixture stirred at 110°C for 3 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue diluted with H20 (50 mL) and extracted with EtOAc (3x 40 mL). The combined organics were washed with brine (2x 30 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-50% EtOAc/PE/EtOAc) to give the title compound as a yellow solid (8.40 g). LCMS m/z = 204 [M+H]+.
Step 3. Synthesis of tert-butyl 2-methyl-5-(5-nitropyridin-3-yl)-lH-pyrrole-l-carboxylate.
To a solution of 3-(5-methyl-lH-pyrrol-2-yl)-5-nitropyridine (Part 2, 8.2 g, 40.4 mmol) in DCM (50 mL) was added DMAP (245 mg, 2.02 mmol) and di-tert-butyl dicarbonate (9.26 g, 42.42 mmol) and the mixture stirred at 40°C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with H20 (50 mLO and extracted with EtOAc (3x 40 mL). The combined organics were washed with brine (2x 30 mL), dried (Na2S04) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-20% EtOAc/PE) to give the title compound as a yellow solid (7.50 g, 61%). LCMS m/z = 304 [M+H]+.
Step 4. Synthesis of tert-butyl (2R,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l- carboxylate and tert-butyl (2S,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l- carboxylate and tert-butyl (2R,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l- carboxylate and tert-butyl (2S,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l- carboxylate. 147 WO 2024/233900 PCT/US2024/028806 To a solution of tert-butyl 2-methyl-5-(5-nitropyridin-3-yl)-lH-pyrrole-l-carboxylate (Step 3, g, 23.1 mmol) in EtOH (100 mL) was added Pd/C (7 g, 10% purity) and the mixture stirred under H2 at 60°C for 16 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give tert-butyl 2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l- carboxylate as a white solid (6 g) which was purified by chiral-SFC (REGIS(S, S) WHELK- 01, 250 x 25 mm, 10 pm); 30% IP A (0.1% NHOH) in CO2) to afford: Peak 1, Intermediate A35.tert-butyl (2R,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine- 1-carboxylate or tert-butyl (2S,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l- carboxylate or tert-butyl (2R,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l-carboxylate or tert-butyl (2S,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l-carboxylate (white solid, 1.35 g). LCMS m/z = 278 [M+H]+.
Peak 2, Intermediate A36.tert-butyl (2R,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine- 1-carboxylate or tert-butyl (2S,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l- carboxylate or tert-butyl (2R,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l-carboxylate or tert-butyl (2S,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l-carboxylate (white solid, 1.5 g). LCMS m/z = 278 [M+H]+.
Peak 3, Intermediate A37.tert-butyl (2R,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine- 1-carboxylate or tert-butyl (2S,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l- carboxylate or tert-butyl (2R,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l-carboxylate or tert-butyl (2S,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l-carboxylate (white solid, 1.5 g). LCMS m/z = 278 [M+H]+.
Peak 4, Intermediate A38.tert-butyl (2R,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine- 1-carboxylate or tert-butyl (2S,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l- carboxylate or tert-butyl (2R,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l-carboxylate or tert-butyl (2S,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-l-carboxylate (white solid, 1.35 g). LCMS m/z = 278 [M+H]+.
Intermediate A39.5-(l-aminocyclopentyl)pyridin-3-amine. 148 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of methyl 2-(5-bromopyridin-3-yl)acetate.
To a solution of 2-(5-bromopyridin-3-yl)acetic acid (5 g, 23.14 mmol) in MeOH (40 mL) was added SOC12 (4 mL) and the mixture stirred at 60 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with H20 (10mL) and extracted with EtOAc (3x 10mL). The combined organics were concentrated under reduced pressure and the residue purified by MPLC (SiO2, 1-5% EtOAc/PE) to give the title compound as a white oil (5.26 g, 98%). LCMS m/z = 230 [M+H]+.
Step 2. Synthesis of methyl l-(5-bromopyridin-3-yl)cyclopentane-l-carboxylate.
To a solution of methyl 2-(5-bromopyridin-3-yl)acetate (Step 1, 1.5 g, 6.52 mmol) and 1,4- diiodobutane (2.02 g, 6.52 mmol) in THE (5 mL) was added LiHMDS (IM, 8.15 mL) at 0°C and the mixture stirred at 25°C for 2 h under N2. To this was added LiHMDS (IM, 8.15 mL) at 0°C and the mixture stirred at 25°C for 2 h under N2. The reaction mixture was quenched by addition saturated aqueous NH4C1 (2 mL) at 0°C and diluted with H20 (2mL) and extracted with EtOAc (3x 2 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, 1-5% EtOAc/PE) to give the title compound as a brown oil (1.32 g, 71%) as. LCMS m/z = 2[M+H]+.
Step 3. Synthesis of l-(5-bromopyridin-3-yl)cyclopentane-l-carboxylic acid.
To a solution of methyl l-(5-bromopyridin-3-yl)cyclopentane-l-carboxylate (Step 2, 1.32 g, 4.65 mmol) in THE (10 mL) and H20 (5 mL) was added LiOH (222 mg, 9.29 mmol) and the mixture stirred at 40°C for 4 h. The reaction mixture was concentrated under reduced pressure and the pH adjusted with IM HC1 to pH 4-5, diluted with H20 (20mL) and extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure to give the title compound as a red solid (1.09 g, 87%). LCMS m/z = 2[M+H]+.149 WO 2024/233900 PCT/US2024/028806 Step 4. Synthesis of l-(5-bromopyridin-3-yl)-N-hydroxycyclopentane-l-carboxamide.
To a solution of l-(5-bromopyridin-3-yl)cyclopentane-l-carboxylic acid (Step 3, 1.36 g, 5.mmol) and hydroxylamine hydrochloride (420 mg, 6.04 mmol) and DIPEA (1.95 g, 15.mmol) in DMF (1 mL) was added BOP reagent (3.34 g, 7.55 mmol) and the mixture stirred at 25°C for 0.5 h. The reaction mixture was quenched by addition H20 (3 mL) at 0°C and extracted with EtOAc (3x 5 mL). The combined organics were dried (Na2S04), concentrated under reduced pressure and the residue purified by prep-HPLC-15 (5-35% MeCN) to give the title compound as a white solid (216 mg, 15%). LCMS m/z = 285 [M+H]+.
Step 5. Synthesis of l-(5-bromopyridin-3-yl)cyclopentan-l-amine.
To a solution of l-(5-bromopyridin-3-yl)-N-hydroxycyclopentane-l-carboxamide (Step 4, 195 mg, 0.684 mmol) in DMSO (3 mL) was added K2CO3 (472 mg, 3.42 mmol) and the mixture stirred at 80oC for 12 h. The reaction mixture was extracted with H20 (10mL) and EtOAc (3x 10 mL). The combined organics were concentrated under reduced pressure and the residue purified by prep-TLC (SiO2, 10% MeOH/EtOAc) to give the title compound as a yellow oil (113 mg, 68%).LCMS m/z = 241 [M+H]+.
Step 6. Synthesis of tert-butyl (5-(l-aminocyclopentyl)pyridin-3-yl)carbamate.
To a solution of l-(5-bromopyridin-3-yl)cyclopentan-l-amine (Step 5, 100 mg, 0.415 mmol) and tert-butyl carbamate (72.9 mg, 0.622 mmol) in dioxane (5 mL) was added Pd2(dba)3 (mg, 0.415 mmol), XPhos (19.77 mg, 0. 415 mmol) and Cs2CO3 (203 mg, 0.622 mmol) and the mixture was stirred at 100°C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to give a residue and the residue purified by prep-TLC (EtOAc) to give the title compound as a yellow solid (105 mg, 91%). LCMS m/z = 278 [M+H]+.
Step 7. Synthesis of 5-(l-aminocyclopentyl)pyridin-3-amine.
To a solution of tert-butyl (5-(l-aminocyclopentyl)pyridin-3-yl)carbamate (Part 6, 105 mg, 0.378 mmol) in HCl/EtOAc (2 mL) and the mixture stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure and the residue adjusted with DIPEA to pH 8-9 and purified by prep-HPLC-13 (1-15% MeCN) to give the title compound as a white solid (43 mg, 64%). LCMS m/z = 178 [M+H]+.
Intermediate A40.tert-butyl (l-(5-aminopyridin-3-yl)cyclopropyl)carbamate. 150 WO 2024/233900 PCT/US2024/028806 Step 1-3. Synthesis of l-(5-bromopyridin-3-yl)cyclopropane-l-carboxylic acid.
The title compound was prepared using an analogous 3-Step method as described for l-(5- bromopyridin-3-yl)cyclopentane-l-carboxylic acid (Intermediate A39 Steps 1-3). LCMS: m/z =242 [M+H]+.
Step 4. Synthesis of tert-butyl (l-(5-bromopyridin-3-yl)cyclopropyl)carbamate.
To a solution of l-(5-bromopyridin-3-yl)cyclopropane-l-carboxylic acid (Step 3, 600 mg, 2.48 mmol) in t-BuOH (24 mL) was added DPP A (1.02 g, 3.72 mmol), 4A molecular sieve (600 mg) and triethylamine (376 mg, 3.72 mmol). The reaction mixture was stirred at 25°C for l h and at 100°C for 3 h. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (3x 50 mL). The combined organics were dried (Na2S04), concentrated under reduced pressure and the residue purified by silica gel chromatography (0-25% EtOAc/PE) to afford the title compound as an off-white solid (730 mg, 94%).LCMS: m/z =313 [M+H]+.
Step 5. Synthesis of tert-butyl (l-(5-((diphenylmethylene)amino)pyridin-3- yl)cyclopropyl)carbamate.
A mixture of tert-butyl (l-(5-bromopyridin-3-yl)cyclopropyl)carbamate (Step 4, 365 mg, 2.mmol), diphenylmethanimine (600 mg, 1.92 mmol), caesium carbonate (1.87 g, 5.75 mmol), XantPhos (222 mg, 0.38 mmol) and Pd2(dba)3 (175 mg, 0.19 mmol) in dioxane (15 mL) was degassed and purged with N2 (3x) and stirred at 100°C for 3 h under N2. The reaction mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography (0-25% EtOAc/PE) to afford the title compound as a yellow oil (590 mg, 74%). LCMS: m/z =414 [M+H]+.
Step 6. Synthesis of tert-butyl (l-(5-aminopyridin-3-yl)cyclopropyl)carbamate.
To a solution of tert-butyl (l-(5-((diphenylmethylene)amino)pyridin-3- yl)cyclopropyl)carbamate (Step 5, 590 mg, 1.43 mmol) in MeOH (20 mL) was added 151 WO 2024/233900 PCT/US2024/028806 hydroxylamine hydrochloride (3.80 g, 54.7 mmol) and sodium acetate (5.80 g, 70.7 mmol) and the reaction mixture stirred at 25°C for 2 h. The reaction mixture was added to saturated aqueous sodium bicarbonate (100 mL) concentrated under reduced pressure to remove MeOH and the residue extracted with EtOAc (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc/PE) to afford the title compound as an off-white solid (3mg, 93%). LCMS: m/z =198 [M+H]+.
Intermediate A41.3-((ethylamino)methyl)aniline.
Step 1. Synthesis of N-(3-nitrobenzyl)ethanamine.
To a solution of 3-nitrobenzaldehyde (3 g, 19.85 mmol) in EtOH (40 mL) was added dropwise ethanamine (984 mg, 21.84 mmol) and the mixture stirred 25°C for 5 h under N2. NaBH4 (1.55 g, 41 mmol) was added at 0°C and the resulting mixture stirred at 25°C for 2 h under N2. The reaction mixture was quenched by addition saturated aqueous NH4C1 solution (30 mL) at 0°C and extracted with DCM (3x 30 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a brown oil (2.4 g, 67%). LCMS m/z = 181 [M+H]+.
Step 2. Synthesis of 3-((ethylamino)methyl)aniline.
To a solution of N-(3-nitrobenzyl)ethanamine (2.4 g, 13.32 mmol) in MeOH (30 mL) was added Pd/C (3 g, 10% purity) and the mixture stirred at 25°C for 2 h under H2 (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by prep-HPLC-18 (5-35% MeCN) to give the title compound as a brown oil (1.08 g, 54%). LCMS m/z = 151 [M+H]+.
Intermediate A42.5,6-dihydrospiro[cyclopenta[c]pyridine-7,2'-pyrrolidin]-4-amine. 152 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of 3,5-dibromo-4-(but-3-en-l-yl)pyridine To a solution of 3,5-dibromo-4-methyl-pyridine (25 g, 99.63 mmol) in THF (200 mL) was added LDA (2M, 64.76 mL) at -78°C under N2 and after 45 mins, 3-bromoprop-l-ene (18.g, 149 mmol) in THF (30 mL) was added and the mixture was stirred at -78°C for 2 h under N2. The reaction mixture was quenched by addition saturated aqueous NH4C1 solution (2mL) at 0°C and extracted with EtOAc (3x 100 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue purified by MPLC (SiO2, 1-10% EtOAc/PE) to give the title compound as a brown oil (27.8 g, 96%). LCMS m/z = 292 [M+H]+.
Step 2. Synthesis of 4-bromo-7-methylene-6,7-dihydro-5H-cyclopenta[c]pyridine To a solution of 3,5-dibromo-4-(but-3-en-l-yl)pyridine (Step 1, 26.8 g, 92.1 mmol) in MeCN (200 mL) was added TEA (18.64 g, 184 mmol), Pd(OAc)2 (1.03 g, 4.61 mmol) and PPh(2.42 g, 9.21 mmol) and the mixture stirred at 80oC for 24 h under N2. The reaction mixture was concentrated under reduced pressure and the residue purified by MPLC (SiO2, 1-16% EtOAc/PE) to give the title compound as a white solid (12.5 g, 65%). LCMS m/z = 2[M+H]+.
Step 3. Synthesis of ethyl 3-(7-azido-4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7- yl)propanoate To a solution of 4-bromo-7-methylene-6,7-dihydro-5H-cyclopenta[c]pyridine (3.1 g, 14.mmol) and ethyl 2-diazoacetate (3.37 g, 29.51 mmol) in i-PrOH (50 mL) was added diacetoxyiron (257 mg, 1.48 mmol), TEA (2.99 g, 29.51 mmol), TMSN3 (3.40 g, 29.mmol) and TBHP (5.5 M, 8.05 mL) and the mixture stirred at 50°C for 2 h under N2. The 153 WO 2024/233900 PCT/US2024/028806 reaction mixture was quenched by addition saturated aqueous Na2S03 solution (50 mL) at 0°C and then extracted with EtOAc (3x 80 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a brown oil (1.98 g, 39%). LCMS m/z = 339 [M+H]+.
Step 4. Synthesis of 4-bromo-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2 '-pyrrolidin]-5 '-one To a solution of ethyl 3-(7-azido-4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7- yl)propanoate (Step 3, 1.52 g, 4.48 mmol) in THE (20 mL), i-PrOH (4 mL), AcOH (4 mL) was added Zn (2.91 g, 44.5 mmol) and the mixture stirred at 40°C for 2 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give a residue which was diluted with H20 (70 mL), extracted with EtOAc (40 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, 1-100% EtOAc/PE) to give the title compound as a white solid (573 mg, 48%). LCMS m/z = 2[M+H]+.
Step 5. Synthesis of tert-butyl (5 '-oxo-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2 - pyrrolidin]-4-yl)carbamate A mixture of 4-bromo-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2'-pyrrolidin]-5'-one (Step 4, 553 mg, 2.07 mmol), tert-butyl carbamate (970 mg, 8.28 mmol), Pd2(dba)3 (190 mg, 0.2mmol), XPhos (98.7 mg, 0.207 mmol) and Cs2CO3 (1.01 g, 3.11 mmol) in dioxane (10 mL) and the mixture stirred at 100°C for 4 h under N2. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by MPLC (SiO2, 1- 100% EtOAc/PE) to give the title compound as a brown solid (360 mg, 57%). LCMS m/z = 304 [M+H]+.
Step 6. Synthesis of 4-amino-5,6-dihydrospiro[cyclopenta[c]pyridine- 7,2 '-pyrrolidin]-5 '-one A mixture of tert-butyl (5'-oxo-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2'-pyrrolidin]-4- yl)carbamate (116 mg, 0.382 mmol) in HCl/EtOAc (2 mL) was stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (112 mg,). LCMS m/z = 204 [M+H]+.
Step 7. Synthesis of 5,6-dihydrospiro[cyclopenta[c]pyridine-7,2 '-pyrrolidin]-4-amine To a solution of 4-amino-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2'-pyrrolidin]-5'-one (Step 6, 137 mg, 0.674 mmol) in THE (2 mL) was added borane dimethylsulphide complex 154 WO 2024/233900 PCT/US2024/028806 (10 M, 0.674 mL) at 0°C and the mixture stirred at 60°C for 2 h under N2. The reaction mixture was quenched by addition IM HC1 (2 mL) at 0°C and then concentrated under reduced pressure. The residue was purified by prep-HPLC-16 (1-30% MeCN) to give the title compound as a yellow oil (45 mg, 35%). LCMS m/z =190 [M+H]+.
Intermediate A43.(R)-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4,7-diamine or (S)- 7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4,7-diamine.
Step 1. Synthesis of 4-bromo-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol.
To a mixture of 4-bromo-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one (100 mg, 0.472 mmol) in THF (2.5 mL) was added MeMgBr (3M, 471 pL) in THF at -78°C and the mixture was stirred at 25°C for 18 h under N2 and then stirred at 80°C for 1 h under N2. The reaction mixture was quenched by addition of saturated aqueous NH4C1 solution (10 mL) at 0°C and then extracted with EtOAc (3x 15 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to give a residue that was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a white solid (400 mg, 53%). LCMS m/z = 228 [M+H]+.
Step 2. Synthesis of 7-azido-4-bromo-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine.
To a solution of 4-bromo-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Step 1, 1mg, 0.526 mmol) in DCM (2 mL) was added TMSN3 (182 mg, 1.58 mmol) under N2. Indium tribromide (373 mg, 1.05 mmol) was added and the mixture stirred at 0°C and at 25°C for h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure.The residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow oil (250 mg, 62%). LCMS m/z = 253 [M+H]+ Step 3. Synthesis of 4-bromo-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-7-amine.
Zn (310 mg, 4.74 mmol) was added to a solution of 7-azido-4-bromo-7-methyl-6,7-dihydro- 5H-cyclopenta[c]pyridine (Part 2, 200 mg, 0.79 mmol) in THF (4 mL), IP A (1 mL) and 155 WO 2024/233900 PCT/US2024/028806 AcOH (1 mL) under N2 and the mixture stirred at 20°C for 8 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by prep- HPLC-15 (5-45% MeCN) to give the title compound as a yellow solid (150 mg, 83%).LCMS m/z = 227 [M+H]+ Step 4. Synthesis of tert-butyl (7-amino-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-4- yl)carbamate.
To the mixture of 4-bromo-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-7-amine (Step 3, 100 mg, 0.44 mmol) and tert-butyl carbamate (103 mg, 0.88 mmol) in dioxane (4 mL) was added Pd2(dba)3 (40.3 mg, 0.044 mmol) and XPhos (21 mg, 0.044 mmol) and Cs2CO3 (2mg, 0.88 mmol) and the mixture stirred at 100°C for2 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (100 mg, 86%). LCMS m/z = 264 [M+H]+ Step 5. Synthesis of (R)-7-methy 1-6,7-dihydro-5H-cyclopenta[c]pyridine-4,7-diamine and (S)-7-methy 1-6,7-dihydro-5H-cyclopenta[c]pyridine-4,7-diamine.
A mixture of tert-butyl (7-amino-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-4- yl)carbamate (Step 4) in EtOAc (1 mL) and HCl/EtOAc (1 mL) was stirred at 25°C for 1 h. The reaction mixture was concentrated under N2 and the residue purified by prep-HPLC (Phenomenex Luna Cl 8 200 x 40 mm, 10 pm; 1-15% MeCN/H2O (HCO2H)) followed by prep-SFC (Diacel Chiralpak AD, 250 x 30 mm, 10 pm; 25% MeOH (+ 0.1% NH4OH) in CO2) to afford: Peak 2, Intermediate A43.(R)-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4,7-diamine or (S)-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4,7-diamine (yellow oil, 30 mg, 50%); LCMS m/z = 164 [M+H]+ Intermediate A44 and A45.tert-butyl (S)-(l-(5-aminopyridin-3-yl)-3,3- difluoropropyl)carbamate and tert-butyl (R)-(l-(5-aminopyridin-3-yl)-3,3- difluoropropyl)carbamate. 156 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of methyl 2-(5-bromopyridin-3-yl)acetate A mixture of 2-(5-bromo-3-pyridyl) acetonitrile (10 g, 50.75 mmol) in HCl/MeOH (30 mL) was stirred at 25°C for 12 h. The mixture was treated with saturated aqueous Na2CO3 untilpH = 8, diluted with H20 (50 mL) and extracted with EtOAc (3x 50 mL). The combined organics were washed with brine (3x 50 ml), dried (Na2S04) and concentrated under reduced pressure to give the title compound as a yellow oil (11.63 g, 99%). LCMS m/z = 2[M+H]+ Step 2. Synthesis of methyl 2-(5-bromopyridin-3-yl)-4,4-difluorobutanoate To a solution of methyl 2-(5-bromopyridin-3-yl)acetate (Part 1, 11.0 g, 47.8 mmol) in THE (250 mL) was added LDA (2M, 35.86 mL) at -78°C over 30 min. To this was added a solution of 2,2-difluoroethyl trifluoromethanesulfonate (15.36 g, 71.72 mmol) in THE (mL) and the mixture stirred at 25°C for 1 h under N2. The reaction mixture was quenched by addition H20 (50 mL) at 0°C, and extracted with EtOAc (3x 50 mL). The combined organicswere dried (Na2SO4), concentrated under reduced pressure and the residue purified by 157 WO 2024/233900 PCT/US2024/028806 column chromatography on silica gel (0-25% EtOAc/PE) to give the title compound as a yellow oil (10.6 g, 75%). LCMS m/z = 294 [M+H]+ Step 3. Synthesis of 2-(5-bromopyridin-3-yl)-4,4-difluorobutanoic acid To a solution of methyl 2-(5-bromopyridin-3-yl)-4,4-difluorobutanoate (Step 2, 10.60 g, 36.04 mmol) in THE (20 mL) and H20 (5 mL) was added LiOH (2.59 g, 108 mmol) and the mixture stirred at 25°C for l h. The mixture was acidified to pH 2 with 1M HC1 and extracted with EtOAc (3x 50 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a yellow solid (8.08 g, 80%). LCMS m/z = 280 [M+H]+ Step 4. Synthesis of 2-(5-bromopyridin-3-yl)-4,4-difluoro-N-hydroxybutanamide To a solution of 2-(5-bromopyridin-3-yl)-4,4-difluorobutanoic acid (Step 3, 8.08 g, 28.mmol) and hydroxylamine hydrochloride (2.41 g, 34.62 mmol) in DMF (20 mL) was added DIPEA (11.2 g, 86.6 mmol) and BOP (16.59 g, 37.5 mmol) and the mixture stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure and residue was diluted with H20 (100 mL) and extracted with EtOAc (3x 100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% EtOAc/PE) to give the title compound as a yellow oil (7.60 g, crude). LCMS m/z = 295 [M+H]+ Step 5. Synthesis of l-(5-bromopyridin-3-yl)-3,3-difluoropropan-l-amine K2CO3 (7.10 g, 51.38 mmol) was added to a solution of 2-(5-bromopyridin-3-yl)-4,4- difluoro-N-hydroxybutanamide (Part 4, 7.58 g, 25.69 mmol) in DMSO (50 mL) and the mixture stirred at 80°C for l h. The reaction mixture was concentrated under reduced pressure and the residue diluted with H20 (100 mL) and extracted with EtOAc (3x 100 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a yellow oil (4.00 g, crude). LCMS m/z = 251 [M+H]+ Step 6. Synthesis of tert-butyl (l-(5-bromopyridin-3-yl)-3,3-difluoropropyl)carbamate To a solution of -(5-bromopyridin-3-yl)-3,3-difluoropropan-l-amine (Step 5, 4 g, 15.9 mmol) in dioxane (20 mL) and H20 (4 mL) was added NaHCO3 (2.68 g, 31.9 mmol) and Boc2O (3.48 g, 15.9 mmol) and the mixture stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure, diluted with H20 (50 mL) and extracted with EtOAc 158 WO 2024/233900 PCT/US2024/028806 (3x 50mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (0-25% EtOAc/PE) to give the title compound as a white solid (3.70 g, 66%). LCMS m/z = 3[M+H]+ Step 7. Synthesis of tert-butyl (l-(5-((diphenylmethylene)amino)pyridin-3-yl)-3,3- difluoropropyl)carbamate To a solution of tert-butyl (l-(5-bromopyridin-3-yl)-3,3-difluoropropyl)carbamate (Step 6, 3.70 g, 10.54 mmol) and diphenylmethanimine (2.10 g, 11.59 mmol, 1.94 mL, 1.10 eq) in dioxane (30 mL) was added C82CO3 (10.3 g, 31.61 mmol), Xantphos (1.22 g, 2.11 mmol) and Pd2(dba)3 (965 mg, 1.05 mmol) and the mixture stirred at 100°C for 3 h under N2. The reaction mixture was concentrated under reduced pressure and the residue diluted with H(100 mL) and extracted with EtOAc (3x 100 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-25% EtOAc/PE) to give the title compound as a yellow oil (3.45 g, 72%). LCMS m/z = 452 [M+H]+ Step 8. Synthesis of tert-butyl (S)-(l-(5-aminopyridin-3-yl)-3,3-difluoropropyl)carbamate and tert-butyl (R)-(l-(5-aminopyridin-3-yl)-3,3-difluoropropyl)carbamate To a solution of tert-butyl (l-(5-((diphenylmethylene)amino)pyridin-3-yl)-3,3- difluoropropyl)carbamate (Step 7, 3.45 g, 7.64 mmol) in MeOH (30 mL) was added NH2OH.HC1 (1.06 g, 15.28 mmol) and NaOAc (1.25 g, 15.28 mmol) and the mixture stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H20 (100 mL) and extracted with EtOAc (3x 100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% EtOAc/PE) followed by chiral SEC (DAICEL CHIRALPAK AD, 2x 50 mm, 10 pm); 25% EtOH (+ 0.1%NH4OH) in CO2) to afford: Peak 1, Intermediate A44.tert-butyl (S)-(l-(5-aminopyridin-3-yl)-3,3- difluoropropyl)carbamate or tert-butyl (R)-(l-(5-aminopyridin-3-yl)-3,3- difluoropropyl)carbamate (yellow solid, 800 mg, 36%); LCMS m/z = 288 [M+H]+ Peak 2, Intermediate A45.tert-butyl (S)-(l-(5-aminopyridin-3-yl)-3,3- difluoropropyl)carbamate or tert-butyl (R)-(l-(5-aminopyridin-3-yl)-3,3- difluoropropyl)carbamate (yellow solid, 880 mg, 40%); LCMS m/z = 288 [M+H]+ 159 WO 2024/233900 PCT/US2024/028806 Intermediate A46.(1 S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-l- carboxylic acid.
A mixture of ethyl (lS,3aR,6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylate hydrochloride (4.60 g, 20.94 mmol) and LiOH.H2O (5.27 g, 126 mmol) in MeOH (20 mL), THF (mL)and H20 (20 mL) was stirred at 25°C for 12 h. (Boc)2O (9.14 g, 41.87 mmol) was added and the mixture stirred at 25°C for 8 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue was treated with EtOAc (30 mL) and stirred at 20°C for 0.5 h. The mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a white solid (4.20 g, 78%). LCMS m/z = 2[M+H]+.
Intermediate A47.5-((3aS,6aR)-octahydrocyclopenta[c]pyrrol-l-yl)pyridin-3-amine.
Step 1. Synthesis of tert-butyl (5-iodopyridin-3-yl)carbamate.
A mixture of tert-butyl N-(5-bromopyridin-3-yl)carbamate (5 g, 18.31 mmol), Cui (349 mg, 1.83 mmol), Nai (5.49 g, 36.6 mmol) and N',N'-dimethylethane-l,2-diamine (2.42 g, 27.mmol) in dioxane (30 mL) was stirred at 110°C for 24 h under N2. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 0-50% EtOAc/PE/) to give the title compound as a white solid (4 g, 68%). LCMS m/z = 321 [M+H]+.
Step 2. Synthesis of tert-butyl (3aS,6aR)-l-(5-((tert-butoxycarbonyl)amino)pyridin-3- yl)hexahydrocyclopenta[c]pyrrole-2 (lH)-carboxylate. 160 WO 2024/233900 PCT/US2024/028806 To a solution of tert-butyl (5-iodopyri din-3-yl)carbamate (Step 1, 163 mg, 0.51 mmol) and (lS,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid (Intermediate 46, 100 mg, 0.392 mmol) in DMF (3 mL) was added (Ir[dF(CF3)ppy]2(dtbpy))PF6 (4.39 mg, 3.92 umol), dichloronickel;l,2-dimethoxyethane (8.61 mg, 39.2 umol), Cs2C03 (383 mg, 1.18 mmol) and 4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine (15.8 mg, 59 umol) and the mixture stirred at 25°C for 12 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by prep-HPLC-11 (40-75% MeCN) to give the title compound as a yellow oil (1mg, 47%). LCMS m/z = 402 [M+H]+.
Step 3. Synthesis of 5-((3aS, 6aR)-octahydrocyclopenta[c]pyrrol-l-yl)pyridin-3-amine. tert-butyl (3aS,6aR)-l-(5-((tert-butoxycarbonyl)amino)pyridin-3- yl)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (Step 2, 150 mg, 0.372 mmol) in HCl/EtOAc (1 mL) and EtOAc (0.5 mL) was stirred at 25°C for 6 h. The reaction mixture concentrated under reduced pressure and the residue was diluted with EtOAc (10 mL) and treated with NH4OH (0.5 mL) and concentrated under reduced pressure. The residue was purified by prep-HPLC-15 (1-30% MeCN) to give the title compound as a white solid (mg, 66%). LCMS m/z = 204 [M+H]+.
Intermediate A48.(R)-2-(l-(5-aminopyridin-3-yl)-2,2-difluoroethyl)isoindoline-l,3-dione or (S)-2-(l-(5-aminopyridin-3-yl)-2,2-difluoroethyl)isoindoline-l,3-dione.
Step 1. Synthesis of l-(5-bromopyridin-3-yl)-2,2-difluoroethan-l-ol.
To a solution of 5-bromopyridine-3-carbaldehyde (5 g, 26.88 mmol) and difluoromethyl(trimethyl)silane (5.01 g, 40.32 mmol) in DMF (50 mL) was added CsF (8mg, 5.38 mmol) and the mixture stirred at 25°C for 12 h under N2. TBAF (IM, 40.32 mL) 161 WO 2024/233900 PCT/US2024/028806 was added and the mixture stirred at 25°C for 1 h under N2. The reaction mixture was concentrated under reduced pressure and the residue diluted with H20 (70 mL) and extracted with EtOAc (3x 50 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, 50% PE/EtOAc) to give the title compound as a yellow oil (1.3 g, 20% yield). LCMS m/z = 238 [M+H]+.
Step 2. Synthesis of 2-(l-(5-bromopyridin-3-yl)-2,2-difluoroethyl)isoindoline-l,3-dione.
To a solution of l-(5-bromopyridin-3-yl)-2,2-difluoroethan-l-ol (Step 1, 1.2 g, 5.04 mmol) and isoindoline-1,3-dione (816 mg, 5.55 mmol) in THE (30 mL) was added PPh3 (1.45 g, 5.55 mmol) and DEAD (1.05 g, 6.05 mmol) and the mixture stirred at 25°C for 2 h under N2. The reaction mixture was concentrated under reduced and the residue purified by MPLC (SiO2, 50% PE/EtOAc) to give the title compound as a yellow oil (950 mg, 51%). LCMS m/z = 367 [M+H]+.
Step 3. Synthesis of tert-butyl (5-(l-(l,3-dioxoisoindolin-2-yl)-2,2-difluoroethyl)pyridin-3- yl)carbamate.
To the mixture of 2-(l-(5-bromopyridin-3-yl)-2,2-difluoroethyl)isoindoline-l,3-dione (Step 2, 900 mg, 2.45 mmol) and tert-butyl carbamate (431 mg, 3.68 mmol) in dioxane (15 mL) was added XPhos (117 mg, 0.245 mmol), Cs2CO3 (1.20 g, 3.68 mmol) and Pd2(dba)3 (2mg, 0.245 mmol) and the mixture stirred at 100°C for 2 h under N2. The mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residue was purified by MPLC (SiO2, 0-33% EtOAc/PE) to give the title compound as a yellow solid (500 mg, 50%).LCMS m/z = 404 [M+H]+.
Step 4. Synthesis of (R)-2-(l-(5-aminopyridin-3-yl)-2,2-difluoroethyl)isoindoline-l, 3-dione or (S)-2-(l-(5-aminopyridin-3-yl)-2,2-difluoroethyl)isoindoline-l, 3-dione. tert-Butyl (5-(l-(l,3-dioxoisoindolin-2-yl)-2,2-difluoroethyl)pyridin-3-yl)carbamate (Step 3, 470 mg, 1.17 mmol) was dissolved into HCl/EtOAc (5 mL) and the mixture stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc and the pH adjusted with NH4OH to pH = 9-10. The reaction mixture was extracted with EtOAc (3x 30 mL) and the combined organics dried and concentrated under reduced pressure. The residue was separated by SFC (DAICEL CHIRALCEL OJ, 2x 30 mm, 10 pm); 26% MeOH (0.1% NH4OH) in CO2) to afford: 162 WO 2024/233900 PCT/US2024/028806 Peak 1, Intermediate A48.(R)-2-(l-(5-am1nopyr1d1n-3-yl)-2,2-d1fluoroethyl)1so1ndol1ne- 1,3-dione or (S)-2-(l-(5-aminopyridin-3-yl)-2,2-difluoroethyl)isoindoline-l,3-dione (yellow oil, 150 mg, 42%); LCMS m/z = 304 [M+H]+.
Intermediate A49.2-(((5-aminopyridin-3-yl)methyl)amino)ethan-l-ol.
BocN، Step 1. Synthesis ofN-((5-bromopyridin-3-yl)methyl)-2-((tert-butyldimethylsilyl)oxy)ethan-l- amine.
To a solution of 5-bromopyridine-3-carbaldehyde (5 g, 26.9 mmol) in EtOH (20 mL) was added 2-((tert-butyldimethylsilyl)oxy)ethan-l-amine (5.18 g, 29.6 mmol) at 25°C and the mixture stirred at 25°C for 12 h under N2. To this was added NaBH4 (2.03 g, 53.8 mmol) was added at 0°C and the resulting mixture stirred at 25°C for 2 h under N2. The reaction mixture was quenched by addition saturated NH4C1 (25 mL) at 0°C and extracted with EtOAc (3x 20 mL). The combined organics were dried over (Na2S04) and concentrated under reduced pressure to give the title compound as a yellow solid (8.7 g, 93%). LCMS m/z = 347 [M+H]+.
Step 2. Synthesis of tert-butyl ((5-bromopyridin-3-yl)methyl)(2-((tert- butyldimethylsilyl)oxy)ethyl)carbamate.
A mixture of N-((5-bromopyridin-3-yl)methyl)-2-((tert-butyldimethylsilyl)oxy)ethan-l- amine (Step 1, 8.5 g, 24.6 mmol), Na2CO3 (5.22 g, 49.2 mmol) in THE (30 mL) and H2O (mL) was added di-tert-butyl dicarbonate (5.37 g, 24.6 mmol) and the mixture stirred at 25°C for l h. The reaction mixture was filtered. The filtrate was diluted with H20 (30 mL) and extracted with EtOAc (3x 30mL). The combined organics were washed with brine (2x 20mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-100% EtOAc/PE) to give the title compound as a yellow solid (9.5 g, 86%). LCMS m/z = 447 [M+H]+.163 BocN، WO 2024/233900 PCT/US2024/028806 Step 3. Synthesis of tert-butyl ((5-((tert-butoxycarbonyl)amino)pyridin-3-yl)methyl)(2-((tert- butyldimethylsilyl)oxy)ethyl)carbamate.
A mixture of tert-butyl ((5-bromopyridin-3-yl)methyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)- carbamate (Step 2, 9.3 g, 20.88 mmol), tert-butyl carbamate (4.89 g, 41.75 mmol), Pd2(dba)(1.91 g, 2.09 mmol), XPhos (995.24 mg, 2.09 mmol) and Cs2C03 (10.20 g, 31.32 mmol) in dioxane (80 mL) was degassed and purged with N2 (3x) and the mixture stirred at 100°C for h under N2. The reaction mixture was filtered and the filtrate diluted with H20 (60 mL) and extracted with EtOAc (3x 50mL). The combined organics were washed with brine (2x mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-100% EtOAc/PE) to give the title compound as a yellow solid (9.5 g, 94%). LCMS m/z = 482 [M+H]+.
Step 4. Synthesis of 2-(((5-aminopyridin-3-yl)methyl)amino)ethan-l-ol.
A solution of tert-butyl ((5-((tert-butoxycarbonyl)amino)pyridin-3-yl)methyl)(2-((tert- butyldimethylsilyl)oxy)ethyl)carbamate (Step 3, 1.5 g, 3.11 mmol) in HCl/EtOAc (20 mL) was stirred at 25°C for 12 h. The reaction mixture was concentrated under N2 and the residue diluted with EtOAc (30 mL) and the pH adjusted to pH >7 with NHOH at 0°C. The mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by prep-HPLC-1 1 (1-15% MeCN) to give the title compound as a yellow solid (150 mg, 28%). LCMS m/z = 168 [M+H]+.
Intermediate ASO.tert-butyl ((5-aminopyridin-3-yl)methyl)carbamate.
To a solution of 5-aminonicotinonitrile (500 mg, 4.20 mmol) in EtOH (15 mL) was added NiC12 (544 mg, 4.20 mmol) and NaBH4 (635 mg, 16.8 mmol) at 0°C and the mixture stirred at 25°C for 8h. To this was added di-tert-butyl dicarbonate (1.37 g, 6.30 mmol) and the mixture stirred for 1 hr. The reaction mixture was quenched by addition saturated aqueous NH4C1 at 0°C and then extracted with EtOAc (3x 30 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-100% EtOAc/PE) to give the title compound as a yellow solid (5mg, 58%). LCMS m/z = 224 [M+H]+.164 WO 2024/233900 PCT/US2024/028806 Intermediate A51.tert-butyl (l-(5-aminopyridin-3-yl)cyclobutyl)carbamate.
Step 1. Synthesis of l-(5-bromopyridin-3-yl)cyclobutane-l-carboxylic acid.
To a solution of methyl 2-(5-bromopyridin-3-yl)acetate (500 mg, 2.17 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (57.5 mg, 0.217 mmol) in DMF (6 mL) was added NaH (261 mg, 6.52 mmol, 60% purity) at 0°C and the mixture was stirred at 0°C for 0.5 h. To this was added 1,3-dibromopropane (483 mg, 2.39 mmol) in DMF (1 mL) and the mixture stirred at 25°C for 5 h. The reaction mixture was quenched by addition water (30 mL) and extracted with ethyl acetate (3x 30 mL) and the combined organics discarded. The aqueous phase was acidified by addition 6 M HC1 to pH = 2-3 and extracted with EtOAc (3x 60 mL). The combined organics were washed with brine (2x 30 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a pale yellow oil (540 mg, crude). LCMS m/z = 256 [M+H]+.
Step 2. Synthesis of tert-butyl (l-(5-bromopyridin-3-yl)cyclobutyl)carbamate.
A mixture of l-(5-bromopyridin-3-yl)cyclobutane-l-carboxylic acid (Part 1, 500 mg, 1.mmol) in t-BuOH (15 mL) was added DPP A (806 mg, 2.93 mmol) , TEA (296 mg, 2.mmol) and 4A molecular sieves (500 mg) and the mixture was stirred at 25°C for l h and then at 100°C for l h . The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3x 30 mL). The combined organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a white solid (2mg, 31%). LCMS m/z = 327 [M+H]+.
Step 3. Synthesis of tert-butyl (l-(5-((diphenylmethylene)amino)pyridin-3- yl)cyclobutyl)carbamate. 165 WO 2024/233900 PCT/US2024/028806 The title compound was prepared as a yellow oil (120 mg, 92%) from tert-butyl (l-(5- bromopyridin-3-yl)cyclobutyl)carbamate (Step 2) using an analogous method to that described for Intermediate Al6, Step 3. LCMS m/z = 428 [M+H]+.
Step 4. Synthesis of tert-butyl (l-(5-aminopyridin-3-yl)cyclobutyl)carbamate.
The title compound was prepared from tert-butyl (l-(5-((diphenylmethylene)amino)pyridin- 3-yl)cyclobutyl)carbamate (Step 3) using an analogous method to that described for Intermediate Al6, Step 4. LCMS m/z = 264 [M+H]+.
Intermediate A52.5-(2-aminopropan-2-yl)pyridin-3-amine.
Step 1. Synthesis of tert-butyl (tert-butoxycarbonyl)(5-cyanopyridin-3-yl)carbamate.
To the mixture of 5-aminopyridine-3-carbonitrile (5 g, 42 mmol) in DCM (50 mL) was added DMAP (2.56 g, 21 mmol) and TEA (6.37 g, 63 mmol, 8.76 mL) and B0C20 (13.74 g, mmol) and the mixture stirred at 25°C for 12 h. The mixture was diluted with H20 (30 mL) and extracted with EtOAc (3x 40 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow oil (9.2 g, 68%). LCMS m/z = 264 [M+H]+.
Step 2. Synthesis of tert-butyl (5-(2-aminopropan-2-yl)pyridin-3-yl)carbamate. tert-Butyl (tert-butoxycarbonyl)(5-cyanopyridin-3-yl)carbamate (Step 1, 2 g, 6.26 mmol) in THE (25 mL) was stirred with methylmagnesium bromide (3M, 16.70 mL) at 0°C for 30 min. To this was added Ti(O‘Pr)4 (1.78 g, 6.26 mmol) was added at 0°C and the mixture stirred at 70°C for 2 h under N2. To the mixture was quenched with H20 (30 mL) and the mixture filtered and the filter cake was washed with EtOAc (3x 40 mL). The aqueous was extracted with EtOAc (3x 30 mL) and the combined organics dried (Na2SO4) and concentrated. The 166 WO 2024/233900 PCT/US2024/028806 residue was purified by prep-HPLC-11 (5-45% MeCN) to give the title compound as a yellow oil (500 mg, 31%). LCMS m/z = 252 [M+H]+.
Step 3. Synthesis of 5-(2-aminopropan-2-yl)pyridin-3-amine.
A solution of tert-butyl (5-(2-aminopropan-2-yl)pyridin-3-yl)carbamate (Step 2, 400 mg, 1.mmol) in EtOAc (1 mL) and HCl/EtOAc (5 mL) was stirred at 25°C for 0.5 h. The reaction mixture was concentrated under N2 and the pH of the residue adjusted to pH 6-7 with IM NH40H. The residue was purified by prep-HPLC-11 (1-20% MeCN) to give the title compound as a yellow oil (70 mg, 29%). LCMS m/z =152 [M+H]+.
Intermediate A53.tert-butyl ((5-aminopyridin-3-yl)methyl)(ethyl-d5)carbamate.
Step 1. Synthesis of tert-butyl ((5-bromopyridin-3-yl)methyl)carbamate.
To the mixture of (5-bromo-3-pyridyl)methanamine (4.9 g, 26.20 mmol) in THE (40 mL) and H2O (4 mL) was added NaHCO3 (4.40 g, 52.4 mmol) and di-tert-butyl dicarbonate (6.29 g, 28.8 mmol) and the mixture stirred at 20°C for 0.5 h. The reaction mixture was partitioned between EtOAc (20 mL) and H20 (15 mL) and the water phase extracted with EtOAc (3x mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, 0-50% EtOAc/PE) to give the title compound as a white solid (6.5 g, 86%). LCMS m/z = 289 [M+H]+.
Step 2. Synthesis of tert-butyl ((5-bromopyridin-3-yl)methyl)(ethyl-d5)carbamate.
To a solution of tert-butyl ((5-bromopyridin-3-yl)methyl)carbamate (Step 1, 450 mg, 1.mmol) in DMF (3 mL) was added NaH (125 mg, 3.13 mmol, 60% purity) at 0°C and the mixture stirred at 0°C for 0.5 h. To this was added a solution of 1-iodoethane-1,1,2,2,2-d(378 mg, 2.35 mmol) in DMF (0.5 mL) and the mixture was stirred at 0°C for 0.5 h. NaCI (sat aq, 5 mL) was added and the reaction mixture partitioned between EtOAc (10 mL) and H20 (5 mL). The aqueous phase was extracted with EtOAc (3x 10 mL). The combined 167 WO 2024/233900 PCT/US2024/028806 organics were dried (Na2S04) and concentrated under reduced pressure and the residue purified by MPLC (SiO2, 0-25% EtOAc/PE) to give the title compound as a white oil (4mg, 95%). LCMS m/z = 322 [M+H]+.
Step 3. Synthesis of tert-butyl ((5-((diphenylmethylene)amino)pyridin-3-yl)methyl)(ethyl- d5)carbamate.
The title compound was prepared as a yellow oil (480 mg, 87%) from tert-butyl ((5- bromopyridin-3-yl)methyl)(ethyl-d5)carbamate (Step 2) using an analogous method to that described for Intermediate Al6 (Step 3). LCMS m/z = 421 [M+H]+.
Step 4. Synthesis of tert-butyl ((5-aminopyridin-3-yl)methyl)(ethyl-d5)carbamate.
The title compound was prepared from tert-butyl (l-(5-((diphenylmethylene)amino)pyridin- 3-yl)cyclobutyl)carbamate (Step 3) using an analogous method to that described for Intermediate Al6. LCMS m/z = 257 [M+H]+.
Intermediate A54.(S)-5-(l-((methyl-d3)amino)ethyl)pyridin-3-amine or (R)-5-(l-((methyl- d3)amino)ethyl)pyri din-3-amine.
The title compounds were prepared from l-(5-bromopyridin-3-yl)ethan-l-one using an analogous 5 Step method as described for Intermediate A14 and A15. Chiral-SFC (DAICEL CHIRALPAK IG, 250 x 30 mm, 10 pm); 30% Heptane/EtOH (+ 0.1% NH4OH) in CO2) afforded: Peak 1, Intermediate A54:(S)-5-(l-((methyl-d3)amino)ethyl)pyridin-3-amine or (R)-5-(l- ((methyl-d3)amino)ethyl)pyridin-3-amine (yellow solid, 600 mg, 40%). LCMS m/z = 1[M+H]+.
Intermediate A55.5-(3-aminotetrahydro-2H-pyran-3-yl)pyridin-3-amine.168 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of (Z)-N-(dihydro-2H-pyran-3(4H)-ylidene)-2-methylpropane-2- sulfmamide.
Ti(0Et)4 (29.62 g, 130 mmol) was added to a mixture of tetrahydropyran-3-one (10 g, 1mmol) and 2-methylpropane-2-sulf1namide (12.11 g, 100 mmol) in THE (100 mL) and the mixture stirred at 25°C for 12 h. The reaction mixture was quenched by addition saturated aqueous NaHCO3 solution (100 mL) and H20 (100 mL) at 0°C. Then the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (1-50% EtOAc/PE) to give the title compound as a yellow solid (4 g, 20%). LCMS m/z = 204 [M+H]+.
Step 2. Synthesis of tert-butyl (5-(3-((tert-butylsulfmyl)amino)tetrahydro-2H-pyran-3- yl)pyridin-3-yl)carbamate. n-BuLi (2.5 M, 9.15 mL) was added to a solution of tert-butyl N-(5-bromo-3- pyridyl)carbamate (2.5 g, 9.15 mmol) in THE (60 mL) at -78°C and the mixture stirred at - 78°C for 0.5 h under N2. A solution of (Z)-N-(dihydro-2H-pyran-3(4H)-ylidene)-2- methylpropane-2-sulfinamide (Step 1, 4.65 g, 22.9 mmol) in THE (40 mL) was added to the mixture and stirred at -78°C for 0.5 h under N2. The reaction mixture was added to saturated aq.NH4Cl (100 mL) at 0 °C and extracted with EtOAc (3x 100 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, 0-100% EtOAc/PE) to give the title compound as a yellow solid (1.5 g, crude). LCMS m/z = 398 [M+H]+.
Step 3. Synthesis of 5-(3-aminotetrahydro-2H-pyran-3-yl)pyridin-3-amine.
To a solution of tert-butyl (5-(3-((tert-butylsulf1nyl)amino)tetrahydro-2H-pyran-3-yl)pyridin- 3-yl)carbamate (Step 2, 1.4 g, 3.52 mmol) in HCl/EtOAc (15 mL) was stirred at 25°C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC-18 (1-25% MeCN) to give the title compound as a yellow solid (50 mg, 7%). LCMS m/z =194 [M+H]+.
Intermediate A56.tert-butyl ((5-aminopyridin-3-yl)methyl)(methyl)carbamate. 169 WO 2024/233900 PCT/US2024/028806 Ph Step 1. Synthesis of lf5-bromopyridin-3-yl)-N-methyimethanamine.
The title compound was prepared from 5-bromonicotinaldehyde using an analogous method to that described for Intermediate A41 (Step 1). LCMS m/z = 201 [M+H]+.
Step 2. Synthesis of tert-butyl ((5-bromopyridin-3-yl)methyl)(methyl)carbamate.
To a solution of l-(5-bromopyridin-3-yl)-N-methylmethanamine (Ste pl, 5.20 g, 25.9 mmol) and (Boc)2O (5.64 g, 25.9 mmol) in THE (52 mL) and H20 (13 mL) was added Na2CO(5.48 g, 51.7 mmol) and the mixture stirred at 25°C for 2 h. The reaction was diluted with H20 (80 mL) and extracted with EtOAc (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue was purified by MPLC (SiO2, 50% EtOAc/PE) to give the title compound as a yellow oil (4.5 g, 58%). LCMS m/z = 301 [M+H]+.
Step 3. Synthesis of tert-butyl ((5-((diphenylmethylene)amino)pyridin-3- y I) methyl) (methyl) carbamate.
To a solution of tert-butyl ((5-bromopyridin-3-yl)methyl)(methyl)carbamate (Step 2, 4.40 g, 14.61 mmol) and diphenylmethanimine (2.91 g, 16.07 mmol) in dioxane (70 mL) was added Pd2(dba)3 (1.34 g, 1.46 mmol), Xantphos (1.69 g, 2.92 mmol) and Cs2CO3 (14.28 g, 43.mmol) and the mixture stirred at 100°C for 3 h under N2. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by MPLC (SiO2, 50% EtOAc/PE) to give the title compound was a yellow oil (3.50 g, 59%). LCMS m/z = 402 [M+H]+.
Step 4. Synthesis of tert-butyl ((5-aminopyridin-3-yl)methyl)(methyl)carbamate.
To a solution of tert-butyl ((5-((diphenylmethylene)amino)pyridin-3- yl)methyl)(methyl)carbamate (Step 3, 3.40 g, 8.47 mmol) in MeOH (40 mL) was added NHOH.HCl (1.18 g, 16.94 mmol) and NaOAc (1.39 g, 16.94 mmol) and the mixture stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure to remove 170 WO 2024/233900 PCT/US2024/028806 solvent and extracted with EtOAc (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced and the residue purified by MPLC (SiO2, EtOAc) to give the title compound as a yellow oil (2.00 g, 99%). LCMS m/z = 402 [M+H]+.
Intermediate A57A and A57B.tert-butyl (S)-(l-(5-aminopyridin-3-yl)but-3-yn-l-yl)carbamate and tert-butyl (R)-(l-(5-aminopyridin-3-yl)but-3-yn-l-yl)carbamate.
Step 1. Synthesis ofN-(l-(5-bromopyridin-3-yl)-4-(trimethylsilyl)but-3-yn-l-yl)-2- methylpropane-2-sulfmamide.
Indigane (397 mg, 3.46 mmol) and 3-bromoprop-l-ynyl(trimethyl)silane (1.65 g, 8.64 mmol) were added to a solution of (E)-N-((5-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (Intermediate A7, Step 1 500 mg, 1.73 mmol) in THE (16 mL) and the mixture stirred at 60°C for 7 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by prep-HPLC-19 (45-75% MeCN) to give the title compound as a brown solid (930 mg, 33%). LCMS m/z = 403 [M+H]+.
Step 2. Synthesis of N-(l-(5-((diphenylmethylene)amino)pyridin-3-yl)-4-(trimethylsilyl)but-3- yn-l-yl)-2-methylpropane-2-sulfmamide.
A mixture of N-(l-(5-bromopyridin-3-yl)-4-(trimethylsilyl)but-3-yn-l-yl)-2-methylpropane- 2-sulfinamide (Step 1, 880 mg, 2.19 mmol), diphenylmethanimine (795 mg, 4.38 mmol), Cs2CO3 (1.43 g, 4.38 mmol), Xantphos (507 mg, 0.88 mmol) and Xantphos Pd G4 (422 mg, 171 WO 2024/233900 PCT/US2024/028806 0.44 mmol) in dioxane (10 mL) was degassed and purged with N2 (x3) and the mixture stirred at 100°C for 2 h under N2. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 0-25% EtOAc/PE) to afford the title compound as a yellow oil (1.5 g, crude). LCMS m/z = 502 [M+H]+.
Step 3. Synthesis ofN-(l-(5-aminopyridin-3-yl)-4-(trimethylsilyl)but-3-yn-l-yl)-2- methylpropane-2-sulfmamide.
To a solution of N-(l-(5-((diphenylmethylene)amino)pyridin-3-yl)-4-(trimethylsilyl)but-3- yn-l-yl)-2-methylpropane-2-sulfmamide (Step 2, 1.3 g, 2.59 mmol) in MeOH (10 mL) was added NHOH.HCl (270 mg, 3.89 mmol) and NaOAc (319 mg, 3.89 mmol) and the mixture stirred at 25°C for 1 h. The residue was diluted with H20 (50 mL) and extracted with EtOAc (3x 40 mL). The combined organics were washed with brine (2x 30 mL), dried (Na2S04) and concentrated under reduced pressure to give the title compound as a white solid (1.1 g, crude). LCMS m/z = 338 [M+H]+.
Step 4. Synthesis of 5-(l-amino-4-(trimethylsilyl)but-3-yn-l-yl)pyridin-3-amine.
A mixture of N-( 1 -(5 -aminopyridin-3 -yl)-4-(trimethyl silyl)but-3 -yn-1 -yl)-2-methylpropane- 2-sulfinamide (Step 3, 1 g, 2.96 mmol) in HCl/EtOAc (7 mL) was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (650 mg, 94%). LCMS m/z = 234 [M+H]+.
Step 5. Synthesis of 5-(l-aminobut-3-yn-l-yl)pyridin-3-amine.
To a solution of 5-(l-amino-4-(trimethylsilyl)but-3-yn-l-yl)pyridin-3-amine (600 mg, 2.mmol) in MeOH (2 mL) was added K2CO3 (1.07 g, 7.71 mmol) and the mixture stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (500 mg, crude). LCMS m/z =162 [M+H]+.
Step 6. Synthesis of tert-butyl (S)-(l-(5-aminopyridin-3-yl)but-3-yn-l-yl)carbamate and tert- butyl (R)-(l-(5-aminopyridin-3-yl)but-3-yn-l-yl)carbamate.
Na2CO3 (657 mg, 6.20 mmol) was added to a solution of 5-(l-aminobut-3-yn-l-yl)pyridin-3- amine (Step 5, 500 mg, 3.10 mmol) and (Boc)2 (677 mg, 3.1 mmol) in H20 (3 mL) and MeOH (10 mL) and the mixture stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography 172 WO 2024/233900 PCT/US2024/028806 (SiO2, 0-100% EtOAc/PE) followed by chiral SEC (DAICEL CHIRALPAK AD, 250 x mm, 10 pm); 30% EtOH (0.1% NH4OH) in CO2) to afford: Peak 1, Intermediate A57A:tert-butyl (S)-(l-(5-aminopyridin-3-yl)but-3-yn-l-yl)carbamate or tert-butyl (R)-(l-(5-aminopyridin-3-yl)but-3-yn-l-yl)carbamate (yellow solid, 70 mg, 8.6%). LCMS m/z = 262 [M+H]+.
Peak 2, Intermediate A57B:tert-butyl (S)-(l-(5-aminopyridin-3-yl)but-3-yn-l-yl)carbamate or tert-butyl (R)-(l-(5-aminopyridin-3-yl)but-3-yn-l-yl)carbamate (yellow solid, 90 mg, 11%). LCMS m/z = 262 [M+H]+.
Intermediate A58.(1 S,3R)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexan-l-amine or (lR,3S)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexan-l-amine.
Step 1. Synthesis of 3-((tert-butoxycarbonyl)amino)cyclohexane-l-carboxylic acid.
To the mixture of 3-aminocyclohexanecarboxylic acid (10 g, 69.8 mmol) and NaOH (4.19 g, 105 mmol) in dioxane (80 mL) and H20 (30 mL) was added di-tert-butyl dicarbonate (22.g, 105 mmol,) at 0°C and the mixture stirred at 20°C for 12 h. The mixture was concentrated under reduced pressure and the residue partitioned between EtOAc (100 mL) and H20 (1mL). The aqueous phase was washed with EtOAc (3x 100 mL). The pH of the aqueous phase was adjusted to pH 5 with 1 M HC1. The solids were collected by filtration to afford the title compound as a white solid (14 g, 82%). LCMS m/z = 243 [M+H]+.
Step 2. Synthesis of tert-butyl (3-((2,4-dimethoxybenzyl)carbamoyl)cyclohexyl)carbamate. 173 WO 2024/233900 PCT/US2024/028806 To a mixture of 3-((tert-b utoxycarbonyl)amino)cyclohexane-1 -carboxylic acid (Step 1, 10 g, 41.10 mmol) and (2,4-dimethoxyphenyl)methanamine (7.56 g, 45.21 mmol) in DMF (50 mL) was added DIPEA (10.62 g, 82.20 mmol) and HATU (23.44 g, 61.65 mmol) and the mixture stirred at 20°C for 2 h. The reaction mixture was partitioned between EtOAc (20 mL) and H20 (15 mL) and the aqueous phase extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure and the residue purified by MPLC (SiO2, 0-100% EtOAc/PE) to give the title compound was a white solid (13 g, crude). 1HNMR (400MHz, CDCI3) 8; 7.07 (d, 1H), 6.38-6.33 (m, 2H), 5.87 (br s, 1H), 4.26 (d, 2H), 3.76 (s, 3H), 3.72 (s, 3H), 2.06-2.00 (m, 2H), 1.86 (br d, 1H), 1.77-1.69 (m, 2H), 1.35 (s, 9H), 1.32-1.24 (m, 2H), 1.04-0.95 (m, 1H).
Step 3. Synthesis of 3-amino-N-(2,4-dimethoxybenzyl)cyclohexane-l-carboxamide.
To a solution of tert-butyl (3-((2,4-dimethoxybenzyl)carbamoyl)cyclohexyl)carbamate (Step 2, 13 g, 33.1 mmol) in HCl/EtOAc (100 mL) was stirred at 25°C for 1 h. The mixture was washed with saturated aqueous Na2CO3 (5 ml) until pH = 9 and concentrated under reduced pressure. The residue was diluted with H20 (20 mL) and extracted with DCM (3x 20 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a white solid (7.5 g, 77%). LCMS m/z = 294 [M+H]+.
Step 4. Synthesis of (lS,3R)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexan-l-amine or (lR,3S)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexan-l-amine.
BH3-DMS (10 M, 23.26 mL) was added to a solution of 3-amino-N-(2,4- dimethoxybenzyl)cyclohexane-l-carboxamide (Step 3, 6.8 g, 23.26 mmol) in THE (10 mL) at 0°C and the mixture stirred at 60°C for 2 h under N2. The reaction mixture was quenched by addition of H20 (5 mL) at 0°C and concentrated under reduced pressure. The residue was purified by prep-HPLC-20 (1-13% MeCN) and prep-SFC (ChiralPak IH, 250 x 30 mm, pm; 25% EtOH (+ 0.1% IP Am) in CO2 to afford: Peak 1, Intermediate A58:(lS,3R)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexan-l- amine or (lR,3S)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexan-l-amine (yellow oil, g, 15%). LCMS m/z = 280 [M+H]+.
Intermediate A59.5-aminopyridazine-3-carboxamide. 174 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of tert-butyl (6-chloropyridazin-4-yl)carbamate.
To a solution of 6-chloropyridazin-4-amine (5 g, 38.6 mmol) in DCM (50 mL) was added (Boc)2O (29.5 g, 135 mmol), DMAP (7.07 g, 57.9 mmol) and TEA (13.7 g, 135 mmol) and the mixture stirred at 25°C for l h. The reaction mixture was diluted with H20 (80 mL) and extracted with DCM (3x 80 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure and the residue purified by MPLC (SiO2, 50% PE:EtOAc) to give the title compound as a yellow solid (6.40 g, crude). LCMS m/z = 2[M+H]+.
Step 2. Synthesis of tert-butyl (6-cyanopyridazin-4-yl)carbamate.
To a solution of tert-butyl (6-chloropyridazin-4-yl)carbamate (Step 1, 6.30 g, 27.4 mmol) in DMF (70 mL) was added BrettPhos Pd G3 (2.49 g, 2.74 mmol), Zn(CN)2 (16.11 g, 1mmol) and BRETTPHOS (1.47 g, 2.74 mmol) and the mixture stirred at 80°C for 2 h under N2. The mixture was diluted with H20 (80 mL) and extracted with EtOAc (3x 80 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, 50% EtOAc/PE) to give the title compound as a yellow oil (4.00 g, crude). LCMS m/z = 221 [M+H]+.
Step 3. Synthesis of tert-butyl (6-carbamoylpyridazin-4-yl)carbamate.
To a solution of tert-butyl (6-cyanopyridazin-4-yl)carbamate (Part 2, 4 g, 18.2 mmol) in DMSO (40 mL) was added K2CO3 (5.02 g, 36.3 mmol) and the mixture stirred at 20°C for mins. To this was added HO2 (20.6 g, 182 mmol) and stirred at 20°C for 2 h. KOH (2.04 g, 36.3 mmol) was added and the resulting mixture stirred at 20°C for 2 h. The reaction mixture was quenched by addition saturated aqueous Na2S03 (5 mL) at 0°C, diluted with H20 (mL) and extracted with EtOAc (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue was purified by MPLC (SiO2, 50% 175 WO 2024/233900 PCT/US2024/028806 EtOAc/PE) to give the title compound as a white solid (350 mg, 8%). LCMS m/z = 2[M+H]+.
Step 4. Synthesis of 5-aminopyridazine-3-carboxamide.
A solution of tert-butyl (6-carbamoylpyridazin-4-yl)carbamate (330 mg, 1.39 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at 25°C for l h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a yellow solid (160 mg, crude). LCMS m/z =139 [M+H]+.
Intermediate A60.tert-butyl (S)-(l-(5-aminopyridin-3-yl)propyl)carbamate and tert-butyl (R)-(l-(5-aminopyri din-3-yl)propyl)carbamate.
Step 1. Synthesis of l-(5-bromopyridin-3-yl)propan-l-amine hydrochloride.
To a solution of (E)-N-((5-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulf1namide (Intermediate A7 Step 1, 116 g, 401 mmol) in THE (1.2 L) was added EtMgBr (3 M, 1mL) at -78°C under N2 and the mixture stirred at 0°C for 2 h under N2. The reaction mixture was quenched by addition saturated aqueous NH4C1 solution (I L) at 0°C, diluted with water (1 L) and extracted with EtOAc (4x 1 L). The combined organics were dried (Na2SO4) and concentrated to give N-(l-(5-bromopyridin-3-yl)propyl)-2-methylpropane-2-sulf1namide as a yellow solid (500 g, crude). The solid was dissolved in EtOAc/HCl (1.2 L) and stirred for h at 250C. The reaction mixture was evaporated to dryness to afford the title compound as a yellow solid (560 g). LCMS m/z = 215 [M+H]+.
Step 2. Synthesis of tert-butyl (l-(5-bromopyridin-3-yl)propyl)carbamate.
To a mixture of l-(5-bromopyridin-3-yl)propan-l-amine hydrochloride (Step 1, 560 g, 2.mol) and (Boc)2O (625 g, 2.86 mol) in THE (1.2 L) and H20 (0.3 L) was added NaOH (1 M, L) and the mixture stirred at 25°C for 3 h. The reaction mixture was partitioned between 176 WO 2024/233900 PCT/US2024/028806 EtOAc (I L) and H20 (1 L). The aqueous phase was extracted with EtOAc (3x 1 E). The combined organics was dried (Na2S04) and evaporated to dryness. The residue was purified by column chromatography on silica gel (25-33% EtOAc/PE) to give the title compound as a yellow solid (151g, 18%). 1HNMR (400 MHz, CDCI3) 6: 8.60 (s, 1H), 8.49 (br s, 1H), 7.(s, 1H), 4.89 (d, 1H), 4.58 (br s, 1H), 1.87-1.75 (m, 2H), 1.45 (br s, 9H), 0.96 (t, 3H).
Step 3. Synthesis of tert-butyl (l-(5-((diphenylmethylene)amino)pyridin-3- yl)propyl)carbamate.
To the mixture of tert-butyl (l-(5-bromopyridin-3-yl)propyl)carbamate (Step 2, 130 g, 4mmol) and diphenylmethanimine (82.22 g, 454 mmol) in dioxane (1500 mL) was added Pd2(dba)3 (37.77 g, 41.24 mmol) , Xantphos (47.73 g, 82.5 mmol) and Cs2CO3 (268.76 g, 8mmol) and the mixture stirred at 100°C for 3 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (15-33% EtOAc/PE) to give the title compound as a brown oil (150 g, 87%). LCMS m/z = 416 [M+H]+.
Step 4. Synthesis of tert-butyl (S)-(l-(5-aminopyridin-3-yl)propyl)carbamate and tert-butyl (R)-(l-(5-aminopyridin-3-yl)propyl)carbamate.
To the mixture of tert-butyl (l-(5-((diphenylmethylene)amino)pyri din-3-yl)propyl)carbamate (Step 3, 68 g, 164 mmol) in MeOH (800 mL) was added NHOH.HCI (22.74 g, 327 mmol) and NaOAc (33.56 g, 409 mmol) and the mixture stirred at 20°C for 1 h. The reaction mixture was partitioned between EtOAc (1000 mL) and H20 (800 mL) and the aqueous phase extracted with EtOAc (3x 1000 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure and the residue purified by MPLC (SiO2, 0-100% EtOAc/PE) followed by chiral-SFC (DAICEL CHIRALPAK AD, 250 x 30 mm, 10 pm); 35% EtOH (0.1% NH4OH) in CO2) to afford.
Peak 2, Intermediate A60,tert-butyl (S)-(l-(5-aminopyridin-3-yl)propyl)carbamate or tert- butyl (R)-(l-(5-aminopyridin-3-yl)propyl)carbamate as a white solid (22 g, 53%). LCMS m/z = 252 [M+H]+.
Intermediate A61.tert-butyl (S)-2-(3-aminophenyl)pyrrolidine-l-carboxylate. 177 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of tert-butyl 2-(3-nitrophenyl)-lH-pyrrole-l-carboxylate.
To a solution of 1-bromo-3-nitrobenzene (4.4 g, 21.8 mmol) and tert-butyl 2-(4,4,5,5- tetram ethyl-1,3,2-dioxaborolan-2-yl)pyrrole-l-carboxylate (6.39 g, 21.8 mmol) in DME (mL)/H2O (4 mL) was added Pd(PPh3)4 (2.52 g, 2.18 mmol) and Na2CO3 (4.62 g, 43.6 mmol) and the mixture stirred at 90°C for 2 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by flash column chromatography (SiO2, 0-16% EtOAc/PE) to give the title compound as a yellow oil (5.8 g, 92%).
Step 2. Synthesis of tert-butyl (S)-2-(3-aminophenyl)pyrrolidine-l-carboxylate and tert-butyl (R)-2-(3-aminophenyl)pyrrolidine-1-carboxylate.
To a mixture of tert-butyl 2-(3-nitrophenyl)-lH-pyrrole-l-carboxylate (5.8 g, 20.12 mmol) in MeOH (50 mL) was added Pd/C (4.7 g, 10% purity) slowly and the mixture stirred at 60°C for 8 h under H2 (50 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by chiral SEC (Lux Cellulose-2, 250 x mm; 10 pm; 25% EtOH (+0.1% NHOH) in CO2) to afford: Peak 1, Intermediate A61:tert-butyl (S)-2-(3-aminophenyl)pyrrolidine-l-carboxylate or tert- butyl (R)-2-(3-aminophenyl)pyrrolidine-1 -carboxylate as a white solid (1.3 g, 24%). LCMS m/z = 163 [M-Boc+H]+.
Intermediate A62.tert-butyl (l-(5-aminopyridin-3-yl)cyclopropyl)carbamate. 178 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of l-(5-bromopyridin-3-yl)cyclopropane-l-carboxylic acid.
The title compound was prepared from 2-(5-bromopyridin-3-yl)acetic acid using an analogous 3-Step method as described for Intermediate A39, Steps 1-3. LCMS m/z = 2[M+H]+.
Step 2. Synthesis of tert-butyl (l-(5-bromopyridin-3-yl)cyclopropyl)carbamate.
To a solution of l-(5-bromopyridin-3-yl)cyclopropane-l-carboxylic acid (Step 1, 600 mg, 2.48 mmol) in t-BuOH (24 mL) was added DPP A (1.02 g, 3.72 mmol), 4A molecular sieve (600 mg) and triethylamine (376 mg, 3.72 mmol) and the mixture stirred at 25°C for l h and at 100°C for 3 h. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (3x 50 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure and the residue purified by silica gel chromatography (0-25% EtOAc/PE) to afford the title compound as an off-white solid (730 mg, 94%). LCMS m/z = 313 [M+H]+.
Step 3. Synthesis of tert-butyl (l-(5-((diphenylmethylene)amino)pyridin-3- yl)cyclopropyl)carbamate.
A mixture of tert-butyl (l-(5-bromopyridin-3-yl)cyclopropyl)carbamate (Step 2, 365 mg, 2.mmol,), diphenylmethanimine (600 mg, 1.92 mmol), C82CO3 (1.87 g, 5.75 mmol), XantPhos (222 mg, 383 umol) and Pd2(dba)3 (175 mg, 192 umol) in dioxane (15 mL) was degassed and purged with nitrogen (3x) and the mixture stirred at 100°C for 3 h under N2. The reaction mixture was concentrated under reduced and the residue purified by chromatography column 0-25% EtOAc/PE) to afford the title compound as a yellow oil (590 mg, 74%). LCMS m/z = 414 [M+H]+.
Step 4. Synthesis of tert-butyl (l-(5-aminopyridin-3-yl)cyclopropyl)carbamate.
To a solution of tert-butyl (l-(5-((diphenylmethylene)amino)pyridin-3- yl)cyclopropyl)carbamate (Step 3, 590 mg, 1.43 mmol) in MeOH (20 mL) was added hydroxylamine hydrochloride (3.80 g, 54.7 mmol) and sodium acetate (5.80 g, 70.7 mmol) and the mixture stirred at 25°C for 2 h. The reaction mixture was added to saturated aqueous sodium bicarbonate (100 mL) and concentrated under reduced pressure to remove MeOH and the residue extracted with EtOAc (3x 50 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by silica gel chromatography 179 WO 2024/233900 PCT/US2024/028806 column (0-100% EtOAc/PE) to afford the title compound as an off-white solid (330 mg, 93%). LCMS m/z = 250 [M+H]+.
Intermediate A63.tert-butyl (4-(5-aminopyridin-3-yl)tetrahydro-2H-pyran-4-yl)carbamate.
The title compound was prepared in an analogous 4-Step method as described for Intermediate A62. LCMS m/z = 294 [M+H]+.
Intermediate A64.tert-butyl (2-amino-6-methoxyphenethyl)(methyl)carbamate.
Step 1. Synthesis of 2-(bromomethyl)-l-methoxy-3-nitrobenzene.
To a solution of l-methoxy-2-methyl-3-nitrobenzene (3 g, 17.95 mmol) in tetrachloromethane (60 mL) was added N-bromosuccinimide (3.51 g, 19.74 mmol) and benzoyl peroxide (435 mg, 1.79 mmol) and the mixture stirred at 80oC for 12 h. The reaction mixture was diluted with water (50 mL) and was extracted with ethyl acetate (3x 60 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure andthe residue purified by silica gel chromatography (0-20% EtOAc/PE) to afford the title compound as a yellow solid (4.3 g, 97%). 1H NMR (400 MHz, CDCI): 7.55 (d, 1H), 7.43 (t, 1H), 7.16 (d, 1H), 4.84 (s, 2H), 3.99 (s, 3H).
Step 2. Synthesis of 2-(2-methoxy-6-nitrophenyl)acetonitrile.180 WO 2024/233900 PCT/US2024/028806 To a solution of 2-(bromomethyl)-l-methoxy-3-nitrobenzene (Step 1, 4.3 g, 17.48 mmol) in acetonitrile (60 mL) was added lithium hydroxide monohydrate (880 mg, 20.97 mmol) at 0°C followed by trimethyl silyl cyanide (2.60 g, 26.21 mmol) and the mixture stirred at 25°C for h. The reaction mixture was diluted with water (50 mL) and was extracted with EtOAc (3x 60mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-60% EtOAc/PE) to afford the title compound as a yellow solid (3.1 g, 92%).
Step 3. Synthesis of tert-butyl (2-methoxy-6-nitrophenethyl)carbamate.
To a solution of 2-(2-methoxy-6-nitrophenyl)acetonitrile (Step 2, 1.5 g, 7.81 mmol) in THE (80 mL) was added borane-THF complex (1 M, 23.42 mL) at 25 °C under N2 and the mixture was heated at 60°C for 16 h. The reaction mixture was quenched by addition MeOH (5 mL) and stirred for 0.5 hour. To this was added HC1 (IM, 10 mL) and the mixture was heated to 60°C and stirred for 0.5 h. The mixture was diluted with H20 (100 mL) and extracted with EtOAc (3x 80 mL). The combined organics were discarded. The aqueous phase was basified by addition saturated aqueous sodium bicarbonate to pH = 8-9 and used directly. To this was added di-tert-butyl di carbonate (1.90 g, 8.71 mmol) and the mixture was stirred at 25°C for h. The reaction mixture was extracted with EtOAc (3x 60 mL) and the combined organics dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-16% EtOAc/PE) to afford the title compound as a yellow solid (1.5 g, 66%). 1HNMR (400 MHz, CDCI3): 7.39 (d, 1H), 7.32 (t, 1H), 7.08 (d, 1H), 4.79 (s, 1H), 3.92 (s, 3H), 3.44 (t, 2H), 3.01 (t, 2H), 1.41 (s, 9H).
Step 4. Synthesis of tert-butyl (2-methoxy-6-nitrophenethyl)(methyl)carbamate.
To a solution of tert-butyl (2-methoxy-6-nitrophenethyl)carbamate (Step 3, 500 mg, 1.mmol) in THE (20 mL) was added NaH (135 mg, 3.37 mmol, 60% purity) at 25 °C and the mixture stirred at 25°C for 0.5 h and Mel (479 mg, 3.37 mmol) added. The resulting mixture was stirred at 40°C for 15.5 h. Additional NaH (135 mg, 3.37 mmol, 60% purity) was added to the reaction mixture at 25OC, and then heated to 40 °C and stirred for another 15.5 h. The reaction mixture was quenched with H20 (30 mL) and extracted with EtOAc (3x 20mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue purified by chromatography (SiO2, 0-70% MeCN/H2O (0.1% HCI)) to afford the title compound as a yellow oil (210 mg, 40%). 1H NMR (400 MHz, CDCI3): 7.40 (d, 1H), 7.32 (t, 1H), 7.06 (d, 1H), 3.90 (s, 3H), 3.49 (t, 2H), 3.03 (t, 2H), 2.90 (s, 3H), 1.39 (s, 9H). 181 WO 2024/233900 PCT/US2024/028806 Step 5. Synthesis of tert-butyl (2-amino-6-methoxyphenethyl)(methyl)carbamate.
To a solution of tert-butyl (2-methoxy-6-nitrophenethyl)(methyl)carbamate (Step 4, 210 mg, 0.677 mmol) in EtOH (9 mL) and H20 (3 mL) was added iron (189 mg, 3.38 mmol) and ammonium chloride (189 mg, 3.38 mmol) and the mixture stirred at 70°C for 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was diluted with H20 (20 mL) and extracted with EtOAc (3x 20 mL). The combined organics were washed with brine (60 mL), dried (Na2S04) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 33-50% EtOAc/PE) to afford the title compound as a colourless oil (170 mg, 75%). 1H NMR (400 MHz, DMSO-d6): 6.86 (t, 1H), 6.29 (d, 1H), 6.20 (d, 1H), 5.32-4.59 (m, 2H), 3.67 (s, 3H), 3.25-3.08 (m, 2H), 2.83-2.73 (m, 3H), 2.70-2.59 (m, 2H), 1.42-1.29 (m, 9H).
Intermediate A65.tert-butyl 2-(3-aminophenyl)-5-(hydroxymethyl)pyrrolidine-l- Step 1. Synthesis of 1-(tert-butyl) 2-methyl 5-(3-nitrophenyl)-lH-pyrrole-l,2-dicarboxylate A solution of (l-(tert-butoxycarbonyl)-5-(methoxycarbonyl)-lH-pyrrol-2-yl)boronic acid (1.004 g, 3.96 mmol), 1-bromo-3-nitrobenzene (667 mg, 3.30 mmol), PdC12(dppf)-DCM adduct (139 mg, 0.165 mmol), and tBuXPhos (107 mg, 0.248 mmol) in dioxane (18 mL) and saturated aqueous Na2CO3 (4.5 mL) was purged with N2 for 10 min and heated to 80°C for h. The reaction was cooled, filtered through Celite and washed with 75 mL EtOAc. The filtrate was concentrated by rotary evaporation and the residue purified by flash chromatography (SiO2, 0-70% EtOAc/Hex) to afford the title compound as a yellow oil (3mg, 28%). LCMS m/z = 369 [M+Na]+.
Step 2. 1-(tert-butyl) 2-methyl 5-(3-aminophenyl)pyrrolidine-l,2-dicarboxylate. 182 WO 2024/233900 PCT/US2024/028806 To a solution of 1-(tert-butyl) 2-methyl 5-(3-nitrophenyl)-lH-pyrrole-l,2-dicarboxylate (Step 1,719 mg, 2.07 mmol) in MeOH (10 mL), added Pt/C (5 wt %, 661 mg, 0.17 mmol). The flask was sparged with H2 for 10 min and then stirred at RT under a balloon atmosphere of Hfor 19 h. The reaction mixture was then filtered through Celite and washed with EtOAc (mL) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO, 24g silica, 0-70% EtOAc/Hex) provided the title compound as viscous yellow oil that partially solidified under vacuum (504 mg, 76%). LCMS m/z = 3[M+Na]+.
Step 3. tert-butyl 2-(3-aminophenyl)-5-(hydroxymethyl)pyrrolidine-l-carboxylate.
LiBH4 (160 mg, 7.8 mmol) was added to 1-(tert-butyl) 2-methyl 5-(3- aminophenyl)pyrrolidine-l,2-dicarboxylate (Step 2, 417 mg, 1.3 mmol) in MeOH (13 mL) at RT and stirred for 15 min and then 50°C for 3 days. Additional LiBH4 (166 mg, 7.8 mmol) was added and heating continued at 50°C for 19 h. The reaction mixture was poured into aqueous ammonium chloride and extracted with EtOAc (3x 30 mL). The combined organics were washed twice with water, brine, dried (MgSO4) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO, 24g silica, 0-100% EtOAc/Hex) to afford the title compound as a white solid (112 mg, 29%). LCMS m/z = 315 [M+Na]+. 1H- NMR analysis showed a single diastereomer, but the identity could not be determined due to peak broadening. The trans isomer is most likely based on literature precedent for the synthetic route employed (see: Kaiser and Muchowski, J. Org. Chem, 1984, 49 (22), 4203- 4209).
Intermediate A66.tert-butyl ((5-aminopyridin-3-yl)methyl)(2- (methyl sul fonyl)ethyl) carb am ate.
BocT Step 1. Synthesis of tert-butyl ((5-bromopyridin-3-yl)methyl)(2- (methylsulfonyl) ethyl) carbamate.
To a suspension of 5-bromonicotinaldehyde (563 mg, 3.0 mmol) and 2- (methylsulfonyl)ethan-l-amine hydrochloride (492 mg, 3.0 mmol) in DCE (10 mL) were added sequentially DIPEA (0.630 mL, 3.6 mmol) and NaBH(OAc)3 (899 mg, 4.2 mmol) and 183 Boc N.
WO 2024/233900 PCT/US2024/028806 the resulting mixture stirred at RT for 7 h. The reaction was poured into saturated aqueous sodium bicarbonate and extracted with EtOAc (3x 30 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated by rotary evaporation to afford N-((5- bromopyridin-3-yl)methyl)-2-(methylsulfonyl)ethan-l-amine. The crude amine was dissolved in THE (12 mL) and B0C20 (722 mg, 3.15 mmol) added and the reaction stirred at RT for 2 h. The reaction was poured into aqueous sodium bicarbonate and extracted with EtOAc (3x 30 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO, 24g silica, 0-100% EtOAc/hex) to afford the title compound as a clear yellow oil (4mg, 36% yield over 2 steps). LCMS m/z = 393 [M+H]+.
Step 2. Synthesis of tert-Butyl ((5-aminopyridin-3-yl)methyl)(2- (methylsulfonyl) ethyl) carbamate.
To a suspension of tert-butyl ((5-bromopyridin-3-yl)methyl)(2- (methylsulfonyl)ethyl)carbamate (Part 1, 414 mg, 1.05 mmol) and cuprous oxide (68 mg, 0.42 mmol) in NMP (4 mL) was added aqueous ammonium hydroxide (28-30%, 1.5 mL, 10.5 mmol). The flask was sealed and heated to 100°C for 21 h. The reaction was cooled to RT, poured into water and extracted EtOAc (4x 10 mL). The combined organics were washed with water (x2), brine, dried (MgSO4) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO 12g silica, 0-100% EtOAc/hex then 10% MeOH/DCM) to afford the title compound as a highly viscous, clear yellow oil (2mg, 67%). 1H-NMR analysis showed a roughly 40:60 mixture of rotamers. LCMS m/z = 330 [M+H]+.
Intermediate A67.(R)-3-fluoro-5-(l-(methylamino)ethyl)aniline. 184 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of (S,E)-N-(3-bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfmamide.
To a solution of (S)-2-methylpropane-2-sulf1namide (4.41 g, 37.5 mmol) and 3-bromo-5- fluorobenzaldehyde (2.538 g, 12.5 mmol) in DCM (25 mL) at RT was added sequentially PPTS (315 mg, 1.25 mmol) and MgSO4 (7.31 g, 67.5 mmol) and the reaction mixture stirred at RT for 17 h. The reaction was filtered through a 1-inch pad of silica gel and Celite, washing with 100 mL DCM and 20 mL 10% MeOH/DCM. The combined organics were evaporated to dryness and the residue purified by flash chromatography (ISCO, 80g silica, 0- 70% EtOAc/hex) to afford the title compound as a white solid (3.094 g, 81%). LCMS m/z = 306 [M+H]+.
Step 2. Synthesis of (S)-N-((R)-l-(3-bromo-5-fluorophenyl)ethyl)-2-methylpropane-2- sulfmamide.
To a dry flask under N2 atmosphere was added a solution of (S,E)-N-(3-bromo-5- fluorobenzylidene)-2-methylpropane-2-sulf1namide (Step 1, 1.256 g, 4.0 mmol) in anhydrous DCM (25 mL). The solution was cooled to -78°C and MeMgBr solution (3 M in Et20, 3.mL, 9.0 mmol) was added dropwise over 4 mim and the reaction left in the cold bath to warm to RT overnight. The reaction was quenched with saturated aqueous ammonium chloride (mL), diluted with DCM (100 mL) and poured into water (100 mL). The aqueous phase was extracted with DCM (2x 50 mL). The combined organics were washed with brine, dried 185 WO 2024/233900 PCT/US2024/028806 (MgSO4) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO, 40g silica, 0-100% EtOAc/hex) to provide the title compound as a clear, colourless oil (1.003 g, 77%). LCMS m/z = 322 [M+H]+.
Step 3. Synthesis of (R)-1-(3-bromo-5-fluorophenyl)ethan-l-amine hydrochloride. 4M HC1 dioxane solution (1.55 mL, 6.2 mmol) was added to a solution of (S)-N-((R)-l-(3- bromo-5-fluorophenyl)ethyl)-2-methylpropane-2-sulf1namide (Step 2, 1.003 g, 3.11 mmol) in MeOH (6.5 mL) at RT and the reaction was stirred at RT for 45 min. The mixture was concentrated under reduced pressure until the material was just fully soluble and then poured into Et20 (100 mL). A white ppt crashed out and the mixture left to stand for 15 min. The precipitate was collected by filtration, washing with 100 mL diethyl ether and dried to provide the title compound as a white solid (701 mg, 88%). LCMS m/z = 218 [M+H]+.
Step 4. Synthesis of tert-butyl (R)-(l-(3-bromo-5-fluorophenyl)ethyl)carbamate.
To a suspension of (R)-1-(3-bromo-5-fluorophenyl)ethan-l-amine hydrochloride (Step 3, 6mg, 2.70 mmol) in DCM (20 mL) was added TEA (0.60 mL, 4.32 mmol). The reaction mixture was stirred at RT for 30 min and B0C20 (568 mg, 2.65 mmol) added in a single portion and the reaction stirred at RT for 3 h. The reaction was then diluted with DCM (mL) and washed successively with dilute aqueous HC1, saturated aqueous sodium bicarbonate, water, and brine. The organics was dried (MgSO4) and concentrated by rotary evaporation. Flash chromatography (ISCO, 12g silica, 0-80% EtOAc/hexanes) provided the title compound as a white solid (731 mg, 85%). LCMS m/z = 340 [M+Na]+.
Step 5. Synthesis of tert-butyl (R)-(l-(3-amino-5-fluorophenyl)ethyl)carbamate.
To a suspension of tert-butyl (R)-(l-(3-bromo-5-fluorophenyl)ethyl)carbamate (Step 4, 1mg, 0.51 mmol), Cs2CO3 (240 mg, 0.71 mmol), Pd2(dba)3 (34.5 mg, 0.026 mmol), and BINAP (32.2 mg, 0.51 mmol) in anhydrous toluene (2 mL) was added benzophenone imine (0.110 mL, 0.61 mmol) and the mixture was purged with nitrogen for 10 min and then heated to 80°C for 15 h. The reaction was cooled to RT and filtered through Celite and washed with EtOAc. Flash chromatography (ISCO, 12g silica, 0-50% EtOAc/Hex) afford the intermediate tert-butyl (R)-(l-(3-((diphenylmethylene)amino)-5-fluorophenyl)ethyl)carbamate (130 mg) enriched to -90% purity. A solution of tert-butyl (R)-(l-(3-((diphenylmethylene)amino)-5- fluorophenyl)ethyl)carbamate (130 mg, 0.31 mmol) in MeOH (5 mL) was cooled on ice and hdroxylamine hydrochloride (64.8 mg, 0.93 mmol) and sodium acetate (126 mg, 1.55 mmol) 186 WO 2024/233900 PCT/US2024/028806 added sequentially. The reaction was removed from ice and stirred at RT for 4 h. The reaction was poured into aqueous ammonium chloride and extracted with EtOAc (3x 20 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO, 4g silica, 0-100% EtOAc/hex) to afford the title compound as a clear yellow oil (72.1 mg, 55% yield over steps). LCMS m/z = 255 [M+H]+.
Step 6. Synthesis of (R)-3-fluoro-5-(l-(methylamino)ethyl)aniline.
A solution of tert-butyl (R)-(l-(3-amino-5-fluorophenyl)ethyl)carbamate (Step 5, 69.1 mg, 0.27 mmol) in anhydrous THE (5 mL) was cooled on ice. LiAlH4 (54 mg, 1.35 mmol) was added in several portions. The reaction was removed from the ice bath and heated to 65°C for 4 h. The reaction was cooled to RT diluted with EtOAc (5 mL) and cautiously quenched with water (200 uL). 1 M aqueous NaOH (1 mL) was added and the mixture was stirred at RT for 5 min. Excess MgSO4 was added and the mixture filtered through a 1-inch pad of MgSO4, washing with EtOAc (50 mL). The filtrate was concentrated to provide the title compound as a clear yellow oil (40.3 mg, 89%). 1H NMR (500 MHz, CDCI3): 6.47-6.37 (m, 2H), 6.26 (dt, 1H), 3.93-3.59 (m, 2H), 3.53 (q, 1H), 2.31 (s, 3H), 1.32 (d, 3H).
Intermediate A68.tert-butyl 3-(5-aminopyridin-3-yl)morpholine-4-carboxylate.
BocN، Step 1. Synthesis of 3-(5-bromopyridin-3-y!)morpholine To a solution of the 2-((tributylstannyl)methoxy)ethan-l-amine (1092 mg, 3.00 mmol) in DCM (15 mL) was added 5-bromonicotinaldehyde (558 mg, 3.0 mmol) and 4A molecular sieves (350 mg) under an inert atmosphere at ambient temperature. The reaction mixture was stirred for 2 h and filtered through a pad of Celite rinsing with dichloromethane (50 mL).The filtrate was concentrated under reduced pressure to afford l-(5-bromopyridin-3 -yl)-N-(2- ((tributylstannyl)methoxy)ethyl)methanimine.
Separately, anhydrous copper(II) trifluoromethanesulfonate (1085 mg, 3.0 mmol) was added to a solution of 2,6-lutidine (0.35 mL) in l,l,l,3,3,3-hexafluoropropan-2-ol (12 mL) and stirred at RT for 1 h. A solution of l-(5-bromopyridin-3-yl)-N-(2- 187 Boc step 3 WO 2024/233900 PCT/US2024/028806 ((tributylstannyl)methoxy)ethyl)methanimine in dry DCM (48 mL) was added in one portion and the resulting mixture stirred at RT for 36 h. The reaction was quenched with a mixture of NaHCO3 (24 mL) and 10% aqueous NH4OH (12 mL) and stirred vigorously for 15 min. The layers were then separated and the aqueous layer extracted with DCM (3x 10 mL). The combined organics were then washed with water (3x 10 mL), brine (5 mL), dried (Na2S04) and evaporated to dryness. The residue was purified by flash chromatography (ISCO, 24 g silica, 0-15% MeOH (w/ 5% NH4OH) in DCM) provided the title compound as a yellow solid (351 mg, 48%). LCMS m/z = 244 [M+H]+.
Step 2. Synthesis of tert-butyl 3-(5-bromopyridin-3-yl)morpholine-4-carboxylate To a solution of 3-(5-bromopyridin-3-yl)morpholine (Step 1, 350 mg, 1.44 mmol) in DCM (2.9 mL) was added (Boc)2O (368 pl, 1.58 mmol), DMAP (8.8 mg, 0.066 mmol) and TEA (301 pl, 2.16 mmol) and the mixture stirred at ambient temperature for a 4 h. The mixture was poured into water (10 mL) and the aqueous layer extracted with DCM (3x 10 mL). The combined organics were washed sat aq NH4C1 (10 mL), brine (10 mL), dried (Na2S04) and evaporated to dryness. The residue was purified by flash chromatography (ISCO, 24 g silica, 10-50% EtOAc/Hex) to afford the title compound as a white solid (481 mg, 97%). LCMS m/z = 344 [M+H]+.
Step 3. Synthesis of tert-butyl 3-(5-aminopyridin-3-yl)morpholine-4-carboxylate.
To a suspension of tert-butyl 3-(5-bromopyridin-3-yl)morpholine-4-carboxylate (Step 2, 4mg, 1.399 mmol), Cs2CO3 (683 mg, 2.098 mmol), Pd2(dba)3 (64 mg, 0.070 mmol) and BINAP (87 mg, 0.140 mmol) in anhydrous toluene (5.6 mL) was added benzophenone imine (290 pL, 1.68 mmol). The mixture was sparged with N2 for 10 min and then heated to 80°C for 15 h. The reaction was cooled to it and filtered through Celite and washed with EtOAc. The residue was purified by flash chromatography (ISCO, 24 g silica, 0-40% EtOAc/Hex) provided tert-butyl 3-(5-((diphenylmethylene)amino)pyridin-3-yl)morpholine-4-carboxylate as a light yellow solid (236 mg, 49%). A solution of tert-butyl 3-(5- ((diphenylmethylene)amino)pyridin-3-yl)morpholine-4-carboxylate (184 mg, 0.415 mmol) in MeOH (6.9 mL) was cooled to 0° C and hydroxylamine hydrochloride (86 mg, 1.245 mmol) and sodium acetate (170 mg, 2.0 mmol) were added sequentially. The reaction was removed from ice and stirred at it for 2 h. The reaction mixture was poured into aqueous NH4C1 and extracted with EtOAc (3x 50 mL). The combined organics were washed with brine, dried (Na2S04) and concentrated in vacuo. The residue was purified by flash chromatography 188 WO 2024/233900 PCT/US2024/028806 (ISCO, 24g silica, 0-15% MeOH (w/ 5% NH4OH) in DCM) provided the title compound as a light beige solid (90 mg, 78%). LCMS m/z = 280 [M+H]+.
Intermediate A69.r el-tert-butyl (2S,5S)-2-(3-aminophenyl)-5-methylpyrrolidine- carboxylate.
Step 1. Synthesis of l-(3-nitrophenyl)pentane-l,4-dione.
A solution of levulinic acid (1.749 g, 15.0 mmol), H20 (0.70 mL, 37.5 mmol) and pivalic anhydride (4.6 mL, 22.5 mmol) in THE (40 mL) was added to Pd(OAc)2 (109 mg, 0.mmol), tris(4-methoxyphenyl)phosphine (377 mg, 1.05 mmol), (3-nitrophenyl)boronic acid (3.061 g, 18.0 mmol) in THE (50 mL). The flask was purged vigorously with N2 for 10 min, sealed and heated to 60°C for 42 h. The mixture was filtered through Celite, washed with EtOAc (100 mL). The filtrate was evaporated to remove THE, diluted with EtOAc (150 mL), washed with sat aq NaHCO3 (3x), brine, dried (MgSO4) and evaporated to dryness. The residue was purified by flash chromatography (ISCO, silica, 0-10% MeOH/DCM) to afford a residue that was dissolved in EtOAc (50 mL) and washed with (3x, 1M NaOH), H20 (2x), brine, dried (MgSO4) and concentrated by rotary evaporation to provide the title compound as a yellow solid (473 mg, 14%). LCMS m/z = 222 [M+H]+.
Step 2. Synthesis of 2-methyl-5-(3-nitrophenyl)-lH-pyrrole.
MgSO4 (511 mg, 4.25 mmol, 2.1 equiv) was added to a solution of 1-(3-nitrophenyl)pentane- 1,4-dione (Step 1, 461 mg, 2.05 mmol) and ammonium acetate (483 mg, 6.15 mmol) in MeOH (40 mL). Glacial acetic acid (0.12 mL, 2.05 mmol) was added with stirring at it and the mixture stirred at it for 4 days. The reaction mixture was evaporated to dryness in vacuo and the residue dissolved in EtOAc (50 mL), washed with water (2x), saturated aqueous sodium bicarbonate, brine, dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by flash chromatography (ISCO 24 g silica, 0-10% MeOH/DCM) to afford the title compound as a red-orange solid (298 mg, 72%). LCMS m/z = 203 [M+H]+. 189 WO 2024/233900 PCT/US2024/028806 Step 3. Synthesis of tert-butyl 2-methyl-5-(3-nitrophenyl)-lH-pyrrole-l-carboxylate.
To a solution of 2-methyl-5-(3-nitrophenyl)-lH-pyrrole (Step 2, 376 mg, 1.85 mmol) in MeCN (8 mL) were added DMAP (46.4 mg, 0.36 mmol) and BocO (786 mg, 3.60 mmol) and the mixture heated to 80°C for 22 h. The mixture was poured into dilute aqueous HCI and extracted with EtOAc (3x 50 mL). The combined organics were washed with sat aq NaHCO3, water (2x), brine, dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by flash chromatography (ISCO, 24 g silica, 0-75% EtOAc/hex) provided the title compound as a red-orange solid (434 mg, 80%). LCMS m/z = 303 [M+H]+.
Step 4. Synthesis of rel-tert-butyl (2S,5S)-2-(3-aminophenyl)-5-methylpyrrolidine-l- carboxylate.
To a solution of tert-butyl 2-methyl-5-(3-nitrophenyl)-lH-pyrrole-l-carboxylate (Step 3, 4mg, 1.50 mmol) in MeOH (15 mL) was added Pt/C (5 wt %, 616 mg, 0.15 mmol) and the reaction flask sparged with H2 for 10 min and stirred at it overnight under a balloon atmosphere of H2. The reaction was filtered through Celite and washed with MeOH. The combined organics were evaporated to dryness and the residue purified using 2 rounds of flash chromatography (ISCO, 24 g silica, 0-80% EtOAc/hex; followed by ISCO, 12 g silica, 20-90% EtOAc/hex) to afford the title compound as a highly viscous colourless oil (293 mg, 70%). LCMS m/z = 277 [M+H]+.
Intermediate A70.tert-butyl (l-(3-aminophenyl)cyclobutyl)carbamate.
Step 1. Synthesis of tert-butyl (l-(3-((diphenylmethylene)amino)phenyl)cyclobutyl)carbamate.
To a solution of tert-butyl (l-(3-bromophenyl)cyclobutyl)carbamate (500 mg, 1.53 mmol) and diphenylmethanimine (306 mg, 1.69 mmol) in dioxane (10 mL) was added Pd2(dba)(140 mg, 0.153 mmol, 0.1 eq), Xantphos (177 mg, 0.306 mmol) and Cs2CO3 (1.50 g, 4.mmol) and the mixture stirred at 100°C for 3 h under N2. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by MPLC (SiO2, 20% EtOAc/PE) to give the title compound as a green oil (700 mg, crude). LCMS m/z = 4[M+H]+.190 WO 2024/233900 PCT/US2024/028806 Step 2. Synthesis of tert-butyl (l-(3-aminophenyl)cyclobutyl)carbamate.
To a solution of tert-butyl (l-(3-((diphenylmethylene)amino)phenyl)cyclobutyl)carbamate (Step 1, 650 mg, 1.52 mmol) in MeOH (10 mL) was added hydroxylamine hydrochloride (2.54 g, 36.6 mmol) and NaOAc (5.63 g, 68.6 mmol) and the mixture stirred at 25°C for 2 h. The reaction mixture was added to saturated aqueous NaHCO3 solution (10 mL) and concentrated under reduced pressure to remove solvent. The residue was extracted with EtOAc (3x 50 mL) and the combined organics dried (Na2S04) and concentrated under reduced pressure and the residue purified by MPLC (SiO2, 50% EtOAc/PE) to give the title compound as a yellow solid (330 mg, 82%). LCMS m/z = 207 [M+H]+.
Intermediate A71.2-(((5 -aminopyridin-3 -yl)methyl)amino)ethan-1 -01.
Step 1. Synthesis ofN-((5-bromopyridin-3-yl)methyl)-2-((tert-butyldimethylsilyl)oxy)ethan-l- amine.
To a solution of 5-bromopyridine-3-carbaldehyde (5 g, 26.9 mmol) in EtOH (20 mL) was added 2-((tert-butyldimethylsilyl)oxy)ethan-l-amine (5.18 g, 29.6 mmol) at 25°C and the mixture stirred at 25°C for 12 h under N2. To this was added NaBH4 (2.03 g, 53.8 mmol) was added at 0°C and the resulting mixture stirred at 25°C for 2 h under N2. The reaction mixture was quenched by addition saturated NH4C1 (25 mL) at 0°C and extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure to give the title compound as a yellow solid (8.7 g, 94%). LCMS m/z = 3[M+H]+.
Step 2. Synthesis of tert-butyl ((5-bromopyridin-3-yl)methyl)(2-((tert- butyldimethylsilyl)oxy)ethyl)carbamate.
(Boc)2O (5.37 g, 24.61 mmol) was added to mixture of N-((5-bromopyridin-3-yl)methyl)-2- ((tert-butyldimethylsilyl)oxy)ethan-l-amine (Step 1, 8.5 g, 24.6 mmol), Na2CO3 (5.22 g, 49.mmol) in THE (30 mL) and H20 (10 mL) and the mixture stirred at 25°C for l h. The 191 WO 2024/233900 PCT/US2024/028806 reaction mixture was filtered and the filtrate diluted with H20 (30 mL) and extracted with EtOAc (3x 30mL). The combined organics were washed with brine 40 mL (2x 20mL), dried (Na2SO4) and concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, 0-100% EtOAc/PE) to give the title compound as a yellow solid (9.g, 86%). LCMS m/z = 447 [M+H]+.
Step 3. Synthesis of tert-butyl ((5-((tert-butoxycarbonyl)amino)pyridin-3-yl)methyl)(2-((tert- butyldimethylsilyl)oxy)ethyl)carbamate.
A mixture of tert-butyl ((5-bromopyridin-3-yl)methyl)(2-((tert- butyldimethylsilyl)oxy)ethyl)carbamate (Step 2, 9.3 g, 20.9 mmol), (Boc)2O (4.89 g, 41.mmol), Pd2(dba)3 (1.91 g, 2.09 mmol), XPhos (995 mg, 2.09 mmol) and Cs2C03 (10.20 g, 31.32 mmol) in dioxane (80 mL) was degassed and purged with N2 (3x) and stirred at 100°C for 2 h under N2. The reaction mixture was filtered and the filtrate diluted with H20 (60 mL) and extracted with EtOAc (3x 50 mL). The combined organics were washed with brine (2x mL), dried (Na2SO4), concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, 0-100% EtOAc/PE) to give the title compound as a yellow solid (9.5 g, 94%). LCMS m/z = 482 [M+H]+.
Step 4. Synthesis of 2-(((5-aminopyridin-3-yl)methyl)amino)ethan-l-ol.
A mixture of tert-butyl ((5-((tert-butoxycarbonyl)amino)pyridin-3-yl)methyl)(2-((tert- butyldimethylsilyl)oxy)ethyl)carbamate (Step 3, 1.5 g, 3.11 mmol) in HCl/EtOAc (20 mL) was stirred at 25°C for 12 h. The reaction mixture was concentrated under N2 and the residue diluted with EtOAc (30 mL) and the pH adjusted to pH >7 with NHOH at 0°C. The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by prep-HPLC-1 1 (1-15% MeCN) to give the title compound as a yellow solid (150 mg, 29%). LCMS m/z = 168 [M+H]+.
Intermediate A72.r el-tert-butyl (2S,5S)-2-(3-aminophenyl)-5-methylpyrrolidine-l- carboxylate. 192 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of l-(3-nitrophenyl)pentane-l,4-dione.
To a mixture of Pd(OAc)2 (109 mg, 0.45 mmol), tris(4-methoxyphenyl)phosphine (377 mg, 1.05 mmol) and (3-nitrophenyl )boronic acid (3.061 g, 18.0 mmol) in THE (50 mL) was added a solution of levulinic acid (1.749 g, 15.0 mmol), water (0.70 mL, 37.5 mmol, 2.5 equiv) and pivalic anhydride (4.6 mL, 22.5 mmol) in THF (40 mL) and the mixture purged vigorously with N2 for 10 min and then sealed and heated to 60°C for 42 h. The mixture was filtered through Celite, washed with EtOAc (100 mL). The filtrate was concentrated by rotary evaporation diluted with EtOAc (150 mL) and washed with sat aq sodium bicarbonate (3x), brine, dried (MgSO4) and evaporated to dryness. The residue was purified by flash chromatography (ISCO, 80 silica, 0-10% MeOH/DCM) to afford a mixture of the title compound and pivalic acid. The mixed fractions were dissolved in EtOAc (50 mL) and washed three times with 1 M aqueous sodium hydroxide, twice with water, and once with brine, dried over MgSO4, filtered, and concentrated by rotary evaporation to provide the title compound as a yellow solid (473 mg, 14%). LCMS m/z = 221 [M+H]+.
Step 2. Synthesis of 2-methyl-5-(3-nitrophenyl)-lH-pyrrole.
MgSO4 (511 mg, 4.25 mmol) was added to a solution of 1-(3-nitrophenyl)pentane-1,4-dione (Step 1, 461 mg, 2.05 mmol) and ammonium acetate (483 mg, 6.15 mmol) in MeOH (40 mL) and whilst stirring at it was added glacial acetic acid (0.12 mL, 2.05 mmol) and the mixture stirred at it for 4 days. The reaction mixture was evaporated to dryness and the residue dissolved in EtOAc (50 mL), washed with H20 (x2), sat aq sodium bicarbonate, brine, dried (MgSO4) evaporated to dryness in vacuo. The residue was purified by flash chromatography (ISCO 24 g silica, 0-0% MeOH/DCM) provided the title compound as a red-orange solid (298 mg, 72%). LCMS m/z = 203 [M+H]+.
Step 3. tert-butyl 2-methyl-5-(3-nitr ophenyl)-lH-pyrr ole-1-carboxylate. 193 WO 2024/233900 PCT/US2024/028806 To a solution of 2-methyl-5-(3-nitrophenyl)-lH-pyrrole (Step 2, 376 mg, 1.85 mmol) in MeCN (8.0 mL) were added DMAP (46.4 mg, 0.36 mmol) and B0C20 (786 mg, 3.60 mmol) and the reaction mixture heated to 80°C for 22 h. The reaction mixture was poured into dilute aqueous HCI and extracted with EtOAc (3x 50 mL). The combined organics were washed with sat aq sodium bicarbonate, H20 (2x), brine, dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by flash chromatography (ISCO, 24 g silica, 0- 75% EtOAc/hex) to afford the title compound as a red-orange solid (434 mg, 80%). LCMS m/z = 303 [M+H]+.
Step 4. rel-tert-butyl (2S,5S)-2-(3-aminophenyl)-5-methylpyrrolidine-l-carboxylate To a solution of tert-butyl 2-methyl-5-(3-nitrophenyl)-lH-pyrrole-l-carboxylate (Step 4, 4mg, 1.50 mmol) in MeOH (15 mL) was added Pt/C (5 wt %, 616 mg, 0.15 mmol) and the reaction flask purged with H2 for 10 min and then stirred at it overnight with a balloon atmosphere of H2. The reaction mixture was filtered through Celite, washed with MeOH and the filtrate evaporated to dryness. The residue was purified by two rounds of flash chromatography (ISCO, 24 g silica, 0-80% EtOAc/hex, followed by ISCO, 12 g silica, 20- 90% EtOAc/hex) to afford the title compound as a clear, colorless, highly viscous oil (2mg, 70%). NMR analysis was unable to confirm the relative stereochemistry due to signal broadening; however, the relative stereochemistry is presumed to be cis- given literature precedent. LCMS m/z = 277 [M+H]+.
Intermediate A73.5-(((2-methoxyethyl)amino)methyl)pyri din-3-amine The title compound was prepared using an analogous 4-Step method as described for Intermediate A71. LCMS m/z = 182 [M+H]+.
Intermediate A74.tert-butyl (R)-2-(5-aminopyridin-3-yl)-5-oxopiperazine-l-carboxylate or tert-butyl (S)-2-(5-aminopyri din-3 -yl)-5-oxopiperazine-1 -carboxylate. 194 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of 5-(5-aminopyridin-3-yl)pyrazin-2(lH)-one.
To a solution of (5-amino-3-pyridyl)boronic acid (78.83 mg, 0.57 mmmol) and 5- bromopyrazin-2-ol (50 mg, 0.285 mmol) in H20 (0.5 mL) and EtOH (2 mL) was added K3PO4 (121.31 mg, 0.57 mmol) and cataCXium® A Pd G2 (19.11 mg, 0.028 mmol) and the mixture stirred at 80°C for 1 hr under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (2.1 g, 39%). LCMS m/z = 189 [M+H]+.
Step 2. Synthesis of 5-(5-aminopyridin-3-yl)piperazin-2-one.
To a solution of 5-(5-amino-3-pyridyl)-lH-pyrazin-2-one (Step 2, 1.9 g, 10.10 mmol) in MeOH (10 mL) and DMF (30 mL) was added Pd/C (1.9 g, 10.10 mmol, 10% purity) under N2 and the suspension degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 25°C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (3 g, crude). LCMS m/z =193 [M+H]+.
Step 3. Synthesis of tert-butyl (R)-2-(5-aminopyridin-3-yl)-5-oxopiperazine-l-carboxylate or tert-butyl (S)-2-(5-aminopyridin-3-yl)-5-oxopiperazine-l-carboxylate.
A solution of 5-(5-amino-3-pyridyl)piperazin-2-one (Step 2, 2 g, 10.40 mmol) and (Boc)2O (2.27 g, 10.40 mmol) in MeOH (10 mL) was stirred at 25°C for l h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure 5-(5-amino-3-pyridyl) piperazin-2-one as yellow solid. The residue was separated by SFC (DAICEL CHIRALPAK IG, 250 x 30 mm, 10 pm); 50% MeOH (0.1% NH4OH) in CO2) to afford: 195 WO 2024/233900 PCT/US2024/028806 Peak 1,Intermediate A74. tert-butyl (R)-2-(5-aminopyridin-3-yl)-5-oxopiperazine-l- carboxylate or tert-butyl (S)-2-(5-aminopyridin-3-yl)-5-oxopiperazine-l-carboxylate (white solid; 75 mg, 2.5%). LCMS m/z = 293 [M+H]+.
Intermediate A75.Synthesis of tert-butyl (S)-2-(3-amino-2-morpholinophenyl)pyrrolidine- 1-carboxylate and tert-butyl (R)-2-(3-amino-2-morpholinophenyl)pyrrolidine-l-carboxylate.
Step 1. Synthesis of 4-(2-bromo-6-nitrophenyl)morpholine.
To a solution of l-bromo-2-fluoro-3-nitro-benzene (2 g, 9.09 mmol) and morpholine (7mg, 9.09 mmol) in DMSO (5 mL) was added DIPEA (3.52 g, 27.3 mmol) at 25 °C and the reaction mixture stirred at 100 °C for 16 h. Water (5 ml) was added and the reaction mixture filtered and filtrate concentrated under reduced pressure to give the title compound as a yellow solid (2.5 g, crude). 1H NMR (400MHz, CDCI3) 8; 7.79 (d, 1H), 7.57 (d, 1H), 7.10 (t, 1H), 3.90-3.77 (m, 4H), 3.21-3.07 (m, 4H).
Step 2. Synthesis of tert-butyl 2-(2-morpholino-3-nitrophenyl)-lH-pyrrole-l-carboxylate.
To a solution of 4-(2-bromo-6-nitro-phenyl)morpholine (Step 11, 2.40 g, 8.36 mmol) and tert-butyl 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrole-l-carboxylate (5.88 g, 20.mmol) in DME (35 mL) and H20 (7 mL) was added Na2CO3 (1.77 g, 16.7 mmol) and Pd(PPh3)4 (1.45 g, 0.418 mmol) at 25 °C and the reaction mixture stirred at 90 °C for 2 h under N2. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by MPLC (SiO2, 10% EtOAc/PE) to give the title compound as a yellow solid (2.5 g, 80%). LCMS m/z = 374 [M+H]+.
Step 3. Synthesis of tert-butyl 2-(3-amino-2-morpholinophenyl)pyrrolidine-l-carboxylate. 196 WO 2024/233900 PCT/US2024/028806 Pd/C (1.50 g, 10% purity) was added to a mixture of tert-butyl 2-(2-morpholino-3- nitrophenyl)-lH-pyrrole-l-carboxylate (2.5 g, 6.70 mmol) in THE (20 mL) at 25°C and the resulting mixture stirred at 50 °C for 16 h under H2 (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by prep-HPLC-17 (25-60% MeCN). The residue was further separated by SFC (Chiralpak IC, 250 x 30 mm, 10 pm; 40% IP A (0.1% NH4OH) in CO2) to afford: Peak 2,Intermediate A75,tert-butyl (S)-2-(3-amino-2-morpholinophenyl)pyrrolidine-l- carboxylate or tert-butyl (R)-2-(3-amino-2-morpholinophenyl)pyrrolidine-l-carboxylate as a white solid (0.2 g, 9%). LCMS m/z = 348 [M+H]+.
Intermediate A76 and A77.tert-butyl (S)-2-(3-amino-2-morpholinophenyl)pyrrolidine-1- carboxylate or tert-butyl (R)-2-(3-amino-2-morpholinophenyl)pyrrolidine-l-carboxylate.
Step 1. Synthesis of tert-butyl 2-(2-fluoro-3-nitrophenyl)-lH-pyrrole-l-carboxylate.
The title compound was prepared as a yellow oil (2.5 g, 90%) from l-bromo-2-fluoro-3-nitro- benzene and tert-butyl 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrole-l-carboxylate using an analogous method to that described for Intermediate A75, Step 2). 1H NMR (400MHz, CDC13) b: 8.07-7.96 (m, 1H), 7.69-7.62 (m, 1H), 7.55-7.47 (m, 1H), 7.35-7.30 (m, 1H), 6.36-6.29 (m, 2H), 1.44 (s, 9H).
Step 2. Synthesis of tert-butyl (S)-2-(3-amino-2-morpholinophenyl)pyrrolidine-l-carboxylate or tert-butyl (R)-2-(3-amino-2-morpholinophenyl)pyrrolidine-l-carboxylate.
The title compound was prepared from tert-butyl 2-(2-fluoro-3-nitrophenyl)-lH-pyrrole-l- carboxylate (Step 1) using an analogous method to that described for A75, Step 3. Chiral- SFC (DAICEL CHIRALCEL OJ, 250 x 30 mm, 10 pm); 25% IP A (0.1% NH4OH) in CO2) . 197 WO 2024/233900 PCT/US2024/028806 Peak 1,Intermediate A76, tert-butyl (S)-2-(3-amino-2-morpholinophenyl )pyrrolidine-1- carboxylate or tert-butyl (R)-2-(3-amino-2-morpholinophenyl)pyrrolidine-l-carboxylate (White solid: 20 mg, 11%). LCMS m/z = 225 [M-56+H]+.
Peak 2,Intermediate A77, tert-butyl (R)-2-(3-amino-2-morpholinophenyl)pyrrolidine-l- carboxylate or tert-butyl (S)-2-(3-amino-2-morpholinophenyl)pyrrolidine-l-carboxylate (White solid: 20 mg, 11%). LCMS m/z = 225 [M-56+H]+.
Intermediate A78.tert-butyl (3-amino-2-(trifluoromethyl)benzyl)carbamate Step 1. Synthesis of 3-bromo-2-(trifluoromethyl)benzamide To a solution of 3-bromo-2-(trifluorom ethyl )benzoic acid (2.5 g, 9.29 mmol) in DMF (mL) was added NH4CI (2.49 g, 46.5 mmol), HATU (5.30 g, 13.9 mmol) and DIPEA (7.21 g, 55.8 mmol) and the mixture stirred at 25 °C for 2 h. Water (50 mL) was added the mixture extracted with EtOAc (3x 30 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by prep-HPLC-21 (15-45% MeCN) to give the title compound as a white solid (3.50 g, 70%). 1H NMR (400MHz, DMSO-d5) 5: 8.01 (s, 1H), 7.92 (d, 1H), 7.67 (s, 1H), 7.60 (t, 1H), 7.46 (d, 1H).
Step 2. Synthesis of (3-bromo-2-(trifluoromethyl)phenyl)methanamine To a mixture of 3-bromo-2-(trifluoromethyl)benzamide (Step 1, 1.50 g, 5.60 mmol) in THE (25 mL) was added BH3.THF(l M, 84 mL) at 0 °C and the mixture stirred at 50 °C for 17 h under N2. The reaction mixture was quenched by addition of MeOH (20 mL) at 0°C and the reaction mixture concentrated under reduced pressure. The residue was purified by prep- HPLC-22 (5-35% MeCN) to give the title compound as a white solid (950 mg, 33%). LCMS m/z = 254 [M+H]+.
Step 3. Synthesis of tert-butyl (3-bromo-2-(trifluoromethyl)benzyl)carbamate 198 WO 2024/233900 PCT/US2024/028806 To a solution of (3-bromo-2-(trifluoromethyl)phenyl)methanamine (Step 2, 830 mg, 3.mmol), (Boc)2O (1.07 g, 4.90 mmol) in H20 (2 mL) and THE (10 mL) was added Na2CO(693 mg, 6.53 mmol) and the mixture stirred at 25 °C for 1 h. The mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by prep-TLC (25% EtOAc/PE) to give the title compound as a yellow oil (460 mg, 40%). LCMS m/z = 298 [M- 56+H]+.
Step 4. Synthesis of tert-butyl (3-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)benzyl)carbamate To a solution of tert-butyl (3-bromo-2-(trifluoromethyl)benzyl)carbamate (Step 3, 410 mg, 1.16 mmol) and tert-butyl carbamate (203 mg, 1.74 mmol) in dioxane (10 mL) was added Cs2CO3 (566 mg), Xphos (55.2 mg, 0.116 mmol) and Pd2(dba)3 (106 mg, 0.116 mmol) and the mixture stirred at 100 °C for 2 h under N2. The mixture was concentrated under reduced pressure and the residue purified by prep-TLC (20% EtOAc/PE) to give the title compound as a yellow oil (370 mg, 82%). LCMS m/z = 235 [M-156+H]+.
Step 5. Synthesis of 3-(aminomethyl)-2-(trifluoromethyl)aniline A solution of tert-butyl (3-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)benzyl)carbamate (Step 4, 360 mg, 0.922 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at 25 °C for 0.h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (110 mg, 63%). LCMS m/z =191 [M+H]+.
Step 6. Synthesis of tert-butyl (3-amino-2-(trifluoromethyl)benzyl)carbamate To a solution of 3-(aminomethyl)-2-(trifluoromethyl)aniline (Step 5, 80 mg, 0.42 mmol) and (Boc)2O (73.5 mg, 0.337 mmol) in H20 (0.60 mL) and THE (3 mL) was added Na2CO3 (89.mg, 0.841 mmol) and the mixture stirred at 25 °C for 1 h. The reaction mixture was filtered, the filtrate concentrated under reduced pressure and the residue purified by prep-HPLC-(20-55% MeCN) to give the title compound as a yellow oil (40 mg, 33%). LCMS m/z = 2[M-56+H]+.
Intermediate A79.tert-butyl (R)-2-(5-aminopyridazin-3-yl)piperidine-l-carboxylate or tert- butyl (S)-2-(5-aminopyridazin-3-yl)piperidine-l-carboxylate. 199 WO 2024/233900 PCT/US2024/028806 The title compounds were prepared from 6-chloropyridazin-4-amine and tert-butyl 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1 (2H)-carboxylate using an analogous 2-step method as described for Intermediate A20.Chiral-SFC (PhenomenexCellulose-2, 250 x 30 mm, 10 pm; 40% MeOH (0.1% NH4OH) in CO2 Peak 1, Intermediate A79.tert-butyl (R)-2-(5-aminopyridazin-3-yl)piperidine-l-carboxylate or tert-butyl (S)-2-(5-aminopyridazin-3-yl)piperidine-l-carboxylate (white solid, 50 mg, 29%). LCMS m/z = 279 [M+H]+.
Intermediate ASO.(R)-6-(l-aminoethyl)pyrazin-2-amine or (S)-6-(l-aminoethyl)pyrazin-2- amine.
Step 1. Synthesis of tert-butyl (6-bromopyrazin-2-yl)carbamate.
To the solution of 6-bromopyrazin-2-amine (13 g, 74.7 mmol) in DCM (100 mL) was added DMAP(9.13 g, 74.7 mmol), TEA (11.34 g, 112 mmol) and B0C20 (16.3 g, 74.7 mmol) at 15 °C and the mixture stirred at 25 °C for 2 h. The reaction mixture was concentrated under 200 WO 2024/233900 PCT/US2024/028806 reduced pressure to give a residue that was purified by MPLC (SiO2, 0-33% EtOAc/PE) to give the title compound as a yellow solid (15.31 g, 75%). LCMS m/z = 274 [M+H]+.
Step 2. Synthesis of tert-butyl (6-(prop-l-en-2-yl)pyrazin-2-yl)carbamate.
To a solution tert-butyl (6-bromopyrazin-2-yl)carbamate (Step 1, 15.2 g, 55.5 mmol) and 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (18.64 g, ill mmol) in dioxane (100 mL) and H2O (5 mL) was added K2CO3 (15.33 g, 111 mmol) and Pd(dppf)C12 (1.22 g, 1.66 mmol) and the mixture stirred at 100 °C for 1 h under N2. The reaction mixture was concentrated under reduced pressure and the residue purified by MPLC (SiO2, 1-5% EtOAc/PE) to give the title compound as a yellow solid (12.1 g, 93%). LCMS m/z = 2[M+H]+.
Step 3. Synthesis of tert-butyl (6-acetylpyrazin-2-yl)carbamate.
Ozone was bubble through a solution of tert-butyl (6-(prop-l-en-2-yl)pyrazin-2-yl)carbamate (Step 2, 11 g, 46.8 mmol) in DCM (100 mL) at -78°C until it turned light blue (1 h, 15 psi). The reaction was quenched with Me2S (30.8 g, 496 mmol) at 25 °C and the resulting mixture stirred at 25 °C for 1 h. The mixture was diluted with H20 (100 mL ) and extracted with DCM (3x 80 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, 1-17% EtOAc/PE) to give the title compound as a brown solid (3.13 g, 28%). LCMS m/z = 238 [M+H]+.
Step 4. Synthesis of tert-butyl (Z)-(6-(l-((tert-butylsulfmyl)imino)ethyl)pyrazin-2- yl)carbamate.
To a solution of 2-methylpropane-2-sulf1namide (1.15 g, 9.48 mmol, 1.5 eq) and tert-butyl (6- acetylpyrazin-2-yl)carbamate (Step 3, 1.5 g, 6.32 mmol) in THE (20 mL) was added Ti(OEt)(2.88 g, 12.6 mmol) and the mixture stirred at 60 °C for 12 h. The reaction mixture was diluted with H20 (20 mL) and the solids removed by filtration. The filtrate was concentrated under reduced pressure and the residue diluted with H20 (20 mL) and extracted with EtOAc (3x 30 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a brown oil (1.6 g, 74%). LCMS m/z = 341 [M+H]+.
Step 5. Synthesis of tert-butyl (6-(l-((tert-butylsulfmyl)amino)ethyl)pyrazin-2-yl)carbamate.
To a solution of tert-butyl (Z)-(6-(l-((tert-butylsulf1nyl)imino)ethyl)pyrazin-2-yl)carbamate (Step 4, 1.6 g, 4.70 mmol) in MeOH (20 mL) was added NaBH4 (440 mg, 11.6 mmol) at 0 °C 201 WO 2024/233900 PCT/US2024/028806 and the mixture stirred at 25 °C for l h. The reaction mixture was quenched by addition 0.M HC1 (10 mL) at 0 °C and extracted with EtOAc (3x 30 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue purified by MPLC (SiO2, 1-50% EtOAc/PE) to give the title compound as a brown solid (1.04 g, 65% yield). LCMS m/z = 343 [M+H]+.
Step 6. Synthesis of (R)-6-(l-aminoethyl)pyrazin-2-amine or (S)-6-(l-aminoethyl)pyrazin-2- amine.
A solution of tert-butyl (6-(l-((tert-butylsulf1nyl)amino)ethyl)pyrazin-2-yl)carbamate (Step 5, 1.04 g, 3.04 mmol) in HCl/MeOH (15 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue purified by prep-HPLC-(1-5% MeCN) followed by chiral SEC (DAICEL CHIRALPAK IC, 250 x 30 mm, 10 pm); 45% IP A (0. l%NH40H) in CO2 to afford: Peak 1,Intermediate ASO. (R)-6-(l-aminoethyl)pyrazin-2-amine or (S)-6-(l- aminoethyl)pyrazin-2-amine (brown solid; 97 mg, 23%). LCMS m/z = 139 [M+H]+.
Intermediate A81.tert-butyl 2-(3-amino-2-methoxyphenyl)pyrrolidine-l-carboxylate. £ 1 Step 1 XJl 4°° Step 2OzN^Y^Br °־N F"A UrNH,OMe OMe X# MeO Step 1. Synthesis of tert-butyl 2-(2-methoxy-3-nitrophenyl)-lH-pyrrole-l-carboxylate.
A mixture of l-bromo-2-methoxy-3-nitrobenzene (463 mg, 2.00 mmol), (l-(tert- butoxycarbonyl)-IH-pyrrol-2-yl)boronic acid (633 mg, 3.00 mmol), tBuXPhos (63.7 mg, 0.15 mmol), and PdC12(PPh3)2 (70.2 mg, 0.10 mmol) in dioxane (16 mL) and saturated aqueous sodium carbonate (4 mL) was sparged with nitrogen for 10 min and then heated to °C overnight. The reaction mixture was filtered through Celite, washing with 75 mL EtOAc and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO 40g silica, 0-70% EtOAc/hex) to afford the title compound as a clear yellow oil (633 mg, 85% yield). LCMS m/z = 341 [M+Na]+.
Step 2. Synthesis of tert-butyl 2-(3-amino-2-methoxyphenyl)pyrrolidine-l-carboxylate.
A mixture of tert-butyl 2-(2-methoxy-3-nitrophenyl)-lH-pyrrole-l-carboxylate (Step 1, 6mg, 2.0 mmol) and Pt/C (5 wt %, 680 mg, 0.20 mmol, 10 mol %) in methanol (20 mL) was 202 WO 2024/233900 PCT/US2024/028806 sparged with hydrogen for 5 min and then stirred at RT under a balloon atmosphere of hydrogen for 3 days. The reaction mixture was filtered through Celite, washed with methanol and evaporated to dryness. The residue was purified by flash chromatography (ISCO 24g silica, 0-5% MeOH/DCM) followed by (ISCO 24g silica, 0-60% EtOAc/hex) to afford the title compound as a white solid (356 mg, 58%). LCMS m/z = 293 [M+H]+.
Intermediate A82.Synthesis of (3-amino-2-methoxyphenyl)methanol.
OMe A dry flask containing LiAlH4 (484 mg, 12.5 mmol) was evacuated and backfilled three times with nitrogen and anhydrous THE (20 mL) added and the mixture cooled on ice. A suspension of 3-amino-2-methoxybenzoic acid (830 mg, 5.0 mmol) in anhydrous THE (mL) was added dropwise, with stirring over 15 min and the reaction warmed to RT and heated to 60 °C for 3 h. The reaction was cooled to RT and carefully quenched with dropwise addition of water. The mixture was diluted with EtOAc (10 mL), saturated aqueous NH4C1 (1 mL) added and stirred at RT for 1.5 h. The mixture was poured into aqueous NaHCO3 and extracted with EtOAc (4x 50 mL). The combined organics were washed with water (x2), brine, dried (MgSO4), and evaporated to dryness by rotary evaporation. The residue was purified by flash chromatography (ISCO 40g silica, 0-20% MeOH/DCM) to give the title compound as a waxy amber-coloured solid (466 mg, 60%). LCMS m/z =1[M+H]+.
Intermediate A83.3-(aminomethyl)-2-ethoxyaniline.
NH2 Step 4 r H2N Step 1. Synthesis of 2-ethoxy-3-nitrobenzoic acid. 203 WO 2024/233900 PCT/US2024/028806 A solution of methyl 2-fluoro-3 -nitrobenzoate (997 mg, 5.0 mmol) in DMF (12 mL) was flushed with N2 and cooled on ice to this was added sodium ethoxide solution (2.00 mL, w/w% in ethanol, 5.25 mmol) and the reaction stirred at 0 °C for 30 min and then at RT overnight. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3x 30 mL). The combined organics were with water (x2), brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (ISCO, 24g silica, 0050% EtOAc/hex) and the residue (1.025 g) dissolved in MeOH (3 mL) and water (5 mL). To this was added NaOH (12.5 mmol, 497 mg) and the mixture heated to °C overnight. The reaction mixture was acidified to pH l with aqueous HC1 and the resulting precipitate collected by suction filtration. The solids were wash with water to give the title compound as a yellow solid (424 mg, 40% yield over 2 steps). LCMS m/z = 212 [M+H]+.
Step 2. Synthesis of 2-ethoxy-3-nitrobenzamide.
To a solution of 2-ethoxy-3-nitrobenzoic acid (Step 1, 424 mg, 2.0 mmol) in MeCN (13.mL) added sequentially DIPEA (1.40 mL, 8.0 mmol), HOBT hydrate (459 mg, 3.0 mmol) and EDC-HCl (576 mg, 3.0 mmol) and the mixture stirred at RT for 10 min before ammonium carbonate (1.17 g, 18.0 mmol) was added and then stirred atRT for 3 days. The reaction was concentrated by rotary evaporation and water (30 mL) added to the residue. The resulting slurry was stirred at RT for l h and collected by suction filtration and washed with water (50 mL) to provide the title compound as a white solid (214 mg, 51%). LCMS m/z = 211 [M+H]+.
Step 3. Synthesis of (2-ethoxy-3-nitrophenyl)methanamine.
A solution of 2-ethoxy-3-nitrobenzamide (Step 2, 211 mg, 1.0 mmol) in anhydrous THE (mL) was added dropwise to an ice-cold solution of BH3-THF (2.30 mL, I M in THE, 2.mmol) and the reaction heated to 67 °C overnight. The reaction was cooled to RT, quenched with 6 M aqueous HC1 (2 mL) and stirred for 1 hour. The volatiles were removed by rotary evaporation and the crude residue neutralized to pH >10 with saturated aqueous NaHCO3, M aqueous NaOH and extracted with EtOAc (4x 25 mL). The combined organics were washed with water, brine, dried (MgSO4) and concentrated by rotary evaporation. The residue was purified by chromatography (ISCO, 4g silica, 0-10% MeOH/DCM) to provide the title compound as a yellow solid (39 mg, 20%). LCMS m/z = 197 [M+H]+.
Step 4. Synthesis of 3-(aminomethyl)-2-ethoxyaniline. 204 WO 2024/233900 PCT/US2024/028806 A mixture of (2-ethoxy-3-nitrophenyl)methanamine (Step 3, 39.7 mg, 0.20 mmol) and Pd/C (19.1 mg, 10 wt %, 0.020 mmol) in MeOH (1.5 mL) was sparged with H2 for 10 min and stirred at RT under a balloon atmosphere of H2 for 3 h. The reaction was filtered through Celite, washed with MeOH and concentrated to provide the title compound as a yellow film (29.7 mg, 89%) which was used without purification. LCMS m/z =167 [M+H]+.
Intermediate A84.tert-butyl (3-amino-2-(difluoromethoxy)benzyl)carbamate.
Step 1. Synthesis of 2-(difluoromethoxy)-3-nitrobenzamide.
Part A: KOH (1.643 g, 30.0 mmol) and water (2.0 mL) to an ice-cold solution of methyl 2- hydroxy-3-nitrobenzoate (587 mg, 3.0 mmol) in MeCN (20 mL) and diethyl (bromodifluoromethyl)phosphonate (0.85 mL, 4.80 mmol) added dropwise over 2 min and the reaction stirred at 0 °C for 10 min and then at RT overnight. The reaction was poured into water and extracted with EtOAc (3x 50 mL) and the organic component discarded. The aqueous phase was adjusted to pH <3 with aqueous HC1 and extracted with EtOAc (3x mL). The combined organics were washed with water, brine, dried (MgSO4) and concentrated under reduced pressure to afford a yellow solid (561 mg).
Part B: To a solution of 2-(difluoromethoxy)-3-nitrobenzoic acid (Part A, 561 mg, 2.4 mmol, -35% component of mixture) in MeCN (16 mL) added sequentially DIPEA (1.60 mL, 9.mmol), HOBT hydrate (549 mg, 3.60 mmol) and EDC-HC1 (686 mg, 3.60 mmol) and stirred at RT for 10 min and ammonium carbonate (1.40 g) added and the resulting mixture was stirred at RT for 3 days. The volatiles were removed by rotary evaporation and the residue poured into water and extracted with EtOAc (3x 25 mL). The combined organics were washed with 1 M aqueous HC1 (x3), saturated aqueous NaHCO3, water, brine, dried over MgSO4 and evaporated to dryness. The residue was purified by chromatography (ISCO 24g silica, 0-10% MeOH/DCM) to afford the title compound as a yellow solid (135 mg, 19% yield over 2 steps). LCMS m/z = 233 [M+H]+.205 WO 2024/233900 PCT/US2024/028806 Step 2. Synthesis of (2-(difluoromethoxy)-3-nitrophenyl)methanamine.
The reaction was run under a nitrogen atmosphere. BH3-THF (2.40 mL, 1 M in THF, 2.mmol, 2.3 equiv) was cooled on ice. A solution of 2-(difluoromethoxy)-3-nitrobenzamide BJG-01-154 (239 mg, 1.02 mmol, 1.0 equiv) in anhydrous THF (7 mL) was added dropwise over 5 minutes. The reaction was heated to 67 °C overnight. The reaction was cooled to room temperature, quenched with 6 M aqueous HC1 (3 mL), and stirred for 1 hour. Volatiles were removed by rotary evaporation. The crude residue was neutralized to pH >10 with 1 M aqueous NaOH, then extracted with EtOAc (4x30 mL). The combined organics were washed with water and brine, dried over MgSO4, filtered, and concentrated by rotary evaporation. Flash chromatography (ISCO, 12g silica, 0 to 10% MeOH/DCM, 10 min gradient) provided the title compound as a yellow-orange solid (65.6 mg, 29% yield). LCMS m/z = 2[M+H]+.
Step 3. Synthesis of tert-butyl (3-amino-2-(difluoromethoxy)benzyl)carbamate.
To a solution of (2-(difluoromethoxy)-3-nitrophenyl)methanamine (Step 2, 65.6 mg, 0.mmol) in DCM (2 mL) was added B0C20 (73.5 mg, 0.30 mmol) followed by Et3N (46 pL, 0.33 mmol) and the reaction stirred at RT for 4 h. The reaction was diluted with DCM (mL), washed with 1 M aqueous HC1, saturated aqueous NaHCO3, brine, dried (MgSO4) and concentrated under reduced pressure. The residue and Pd/C (31.7 mg, 10 wt %, 0.030 mmol) in MeOH (3 mL) was sparged with hydrogen for 10 min and then stirred at RT overnight under a balloon atmosphere of H2. The reaction mixture was filtered through Celite and washed with methanol. The filtrate was evaporated to dryness and the residue purified by chromatography (ISCO, 4g silica, 0-100% EtOAc/Hex) to give the title compound as a clear, colorless oil (54.6 mg, 63% over 2 steps). LCMS m/z = 311 [M+Na]+.
Intermediate A85.tert-butyl 2-(3-amino-5-fluorophenyl)piperidine-l-carboxylate.
F F F Step 1. Synthesis of tert-butyl 6-(3-fluoro-5-nitrophenyl)-3,4-dihydropyridine-l(2H)- carboxylate. 206 WO 2024/233900 PCT/US2024/028806 A mixture of l-bromo-3-fluoro-5-nitrobenzene (219 mg, 1.00 mmol), tert-butyl 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-l(2H)-carboxylate (413 mg, 1.mmol), tBuXPhos (33.1 mg, 0.075 mmol), PdC12(PPh3)2 (35.6 mg, 0.050 mmol) in dioxane (4 mL) and saturated aqueous sodium carbonate (1 mL) was sparged with N2 for 10 min and heated to 80 °C overnight. The reaction was filtered through Celite, washed with EtOAc and concentrated under reduced pressure. The residue was purified by chromatography (ISCO 12g silica, 0-80% EtOAc/Hex) to afford the title compound as a clear yellow oil (83.1 mg, 26%). LCMS m/z = 345 [M+Na]+.
Step 2. Synthesis of tert-butyl 2-(3-amino-5-jluorophenyl)piperidine-l-carboxylate.
A mixture of tert-butyl 6-(3-nitrophenyl)-3,4-dihydropyridine-l(2H)-carboxylate (Step 1, 78.4 mg, 0.24 mmol) and Pd/C (27.5 mg, 10 wt %, 0.024 mmol) in MeOH (5 mL) was charged with H2 with 4 fill/vacuum cycles. The flask was pressurized to 40 psi H2, sealed and heated to 60 °C overnight. The reaction was filtered through Celite, washed with MeOH and the filtrate was concentrated to provide the title compound as a yellow oil (66.5 mg, 93%). The material was used in the next step without purification. LCMS m/z = 3[M+Na]+.
Intermediate A85.tert-butyl (S)-2-(3-amino-2-fluorophenyl)pyrrolidine-l-carboxylate or tert-butyl (R)-2-(3-amino-2-fluorophenyl )pyrrolidine-1 -carboxylate.
Pd/C (200 mg, 10% purity) was added to tert-butyl 2-(2-fluoro-3-nitrophenyl)-lH-pyrrole-l- carboxylate (Intermediate A76 and A77, Step 1, 200 mg, 0.653 mmol) in MeOH (2 mL) and the mixture stirred at 60 °C for 20 h under H2 (50 psi). The reaction mixture was filtered and the filtrate evaporated to dryness and the residue purified by prep-TLC (50% EtOAc/PE/) and by SFC (DAICEL CHIRALCEL OJ, 250 x 30 mm, 10 pm); 25% IP A (0.1% NH4OH) in CO2) to afford: Peak 1, Intermediate A85. tert-butyl (S)-2-(3-amino-2-fluorophenyl)pyrrolidine-l- carboxylate or tert-butyl (R)-2-(3-amino-2-fluorophenyl)pyrrolidine-l-carboxylate (white solid, 20 mg, 11%). LCMS m/z = 225 [M-56+l]+. 207 Boc N WO 2024/233900 PCT/US2024/028806 Intermediate Bl.methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5- carboxylate.
Step 1. Synthesis of methyl 4-chloro-6-oxo-l, 6-dihydropyrimidine-5-carboxylate.
A mixture of methyl 4,6-dichloropyrimidine-5-carboxylate (670 g, 3.10 mol, 95.7% purity) and AcOH (2.51 kg, 41.8 mol) was stirred at 120°C for 24 h under N2. The reaction mixture was concentrated under reduced pressure and the residue triturated with EtOAc (500 mL) at 25°C for 16 h. The solids were collected by filtration to afford the title compound as a brown solid (1.50 kg, crude) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) 5: 8.31 (s, 1H), 3.81 (s, 3H).
Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l, 6-dihydropyrimidine-5- carboxylate A 5 L three necked flash was charged with DMSO (2.50 L). To this was added sequentially at 20-25°C, methyl 4-chloro-6-oxo-l,6-dihydropyrimidine-5-carboxylate (300 g, 1.22 mol, 76.5% purity), bis(4-methoxybenzyl)amine (313 g, 1.22 mol), DIPEA (315 g, 2.43 mol) and the resulting mixture stirred at 75-80°C for 5 h. The reaction mixture was cooled to 20-25°C, poured into water (8 L) and extracted with DCM (2x 5 L). The combined organics were washed with brine (3x 1.5 L) and separate, dried (Na2S04) and concentrated under reduced pressure. The residue was triturated with MTBE (1 L) at 15-20°C for 1 h and the solids collected by filtration and the filter cake dried under vacuum to afford the title compound as a yellow solid (421 g, 80.4%). LCMS m/z = 410 [M+H]+.
Intermediate B2.Synthesis of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate. 208 WO 2024/233900 PCT/US2024/028806 Step 1 To a solution of methyl 4-chloro-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate Bl, Step 1, 1 g, 5.30 mmol) and bis(2,4-dimethoxybenzyl)amine (3.37 g, 10.6 mmol) in DMSO (8 mL) was added DIPEA (2.74 g, 21.2 mmol) and the mixture stirred at 100°C for 12 h. Water (10 mL) was added and the mixture extracted with EtOAc (3x 10 mL). Thecombined organics were dried (Na2S04) and concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, 0-100% EtOAc/PE) to give the title compound as a yellow oil (2.4 g, 96%). LCMS m/z = 470 [M+H]+.
Intermediate B3.Methyl 4-amino-l-((S)-2-chloro-6-methylphenyl)-6-oxo-l,6-dihydropyrimi di ne-5 -carb oxyl ate. 209 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-l-(2-bromo-6-nitrophenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate K2CO3 (6.75 g, 48.9 mmol) was added to a mixture of l-bromo-2-fluoro-3-nitro-benzene (6.45 g, 29.3 mmol) and methyl 4-(bis(2,4-dimethoxybenzyl)amino)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B2, 11.47 g, 24.4 mmol) in DMF (80 mL) and the mixture stirred at 80°C for 1 h. The solids were removed by filtration and H20 (1mL) added to the filtrate. The resulting solid was collected by filtration to afford the title compound as a yellow solid (14.5g, 89%). LCMS m/z = 669 [M+H]+.
Step 2. Synthesis of methyl l-(2-amino-6-bromophenyl)-4-(bis(2,4-dimethoxybenzyl)amino)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate Fe (12.1 g, 216 mmol) and NH4C1 (11.6 g, 216 mmol) were added to a mixture of methyl 4- (bis(2,4-dimethoxybenzyl)amino)-l-(2-bromo-6-nitrophenyl)-6-oxo-l,6-dihydropyrimidine- 5-carboxylate (14.5 g, 21.7 mmol) in THF (100 mL), H20 (20 mL) and EtOH (30 mL) and the mixture stirred at 80°C for 1 h. The solids were removed by filtration and H20 (100 mL) added to the filtrate. The resulting solid was collected to afford the title compound as a yellow solid (13 g, 94%). LCMS m/z = 607 [M+H]+.
Step 3. Synthesis of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-l-(2-bromo-6-chlorophenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate A mixture of methyl l-(2-amino-6-bromophenyl)-4-(bis(2,4-dimethoxybenzyl)amino)-6-oxo- l,6-dihydropyrimidine-5-carboxylate (5 g, 7.82 mmol, 1 eq), CuCl (1.55 g, 15.6 mmol), CuC12 (2.10 g, 15.6 mmol) in CH3CN (40 mL) was added isopentyl nitrite (2.75 g, 23.mmol, 3.16 mL) in CH3CN(2 ml) and then the mixture stirred at 20°C for 1 h under N2. The reaction mixture was evaporated under a flow of N2. The residue was diluted with H20 (mL) and extracted with EtOAc (4x 50 mL). The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo and the residue purified by column chromatography (SiO2, 0- 100% EtOAc/PE) to the title compound as a yellow oil (13 g, crude). LCMS m/z = 6[M+H]+.
Step 4. Synthesis of methyl 4-amino-l-(2-bromo-6-chlorophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate A mixture of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-l-(2-bromo-6-chlorophenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxylate (11.5 g, 17.5 mmol) in TFA (5 mL) and DCM (10 mL) 210 WO 2024/233900 PCT/US2024/028806 was stirred at 20°C for l h. The reaction mixture was evaporated to dryness under a stream of N2. The residue was diluted with H20 (50 mL) and saturated aq. Na2CO3 added until pH=8 and the mixture was extracted with EtOAc (4x 50 mL). The combined organics were dried (Na2S04) and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO2, 0-100% EtOAc/PE) to give the title compound as a yellow solid (3.g, 61%). LCMS m/z = 360 [M+H]+.
Step 5. Synthesis of methyl 4-amino-l-(2-chloro-6-methylphenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
A mixture of methyl 4-amino-l-(2-bromo-6-chloro-phenyl)-6-oxo-pyrimidine-5-carboxylate (2.02 g, 5.63 mmol), 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (2.12 g, 8.45 mmol, 2.mL, 50% purity), Pd(dppf)C12 (412.2 mg, 0.563 mmol) and K2CO3 (1.56 g, 11.3 mmol) in dioxane (20 mL) was degassed with N2 (3x) and stirred at 100°C for 1.5 h under N2. The reaction mixture was filtered and concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 0-66% EtOAc/PE) to give (rac)- methyl 4-amino- l-(2-chloro-6-methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate. The racemate was separated by chiral SEC (Diacel Chiralpak IG, 250 x 30 mm, 10 pm; 35% (0.1% NH4OH/IPA) in CO2) to afford: Peak 1, Intermediate B3:methyl 4-amino-l-((S)-2-chloro-6-methylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (yellow solid, 400 mg, 17.3%). LCMS m/z = 294 [M+H]+.
Intermediate B4.Methyl 4-amino-l-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6- dihydropyrimi di ne-5 -carb oxyl ate. 211 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-bromo-6-chloro-4- nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate DIPEA (10.1 g, 78.2 mmol) was added to a solution of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate Bl, 6.4 g, 15.63 mmol) and l-bromo-3-chloro-2-fluoro-5-nitro-benzene (3.98 g, 15.63 mmol) inDMSO (50 mL) and the mixture stirred at 100°C for 8 h. The reaction mixture was treated with H(30 mL), filtered and the filter cake dried under reduced pressure to give the title compound as a brown solid (10.2 g, crude). LCMS m/z = 645 [M+H]+. 212 WO 2024/233900 PCT/US2024/028806 Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-6-methyl-4- nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate To a solution of 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (4.06 g, 16.15 mmol, 4.52 mL, 50% purity), methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-bromo-6-chloro-4-nitrophenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (8 g, 12.42 mmol) in dioxane (100 mL) was added Pd(dppf)C12 (455 mg, 0.621 mmol) and K2CO3 (3.43 g, 24.9 mmol) and the mixture stirred at 100°C for 2 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by MPLC (SiO2, 0-50% THF/PE) to afford the title compound as a brown solid (8.26 g, crude). LCMS m/z = 579 [M+H]+.
Step 3. Synthesis of methyl l-(4-amino-2-chloro-6-methylphenyl)-4-(bis(4- methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-6-methyl-4-nitrophenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (8.2 g, 14.2 mmol), NH4C1 (7.58 g, 142 mmol), Fe (7.91 g, 142 mmol) in THF (40 mL), EtOH (40 mL) and H2O (10 mL) was stirred at 80°C for h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue which was diluted with H20 (80mL) and extracted with EtOAc (3x 60mL). The combined organics were dried (Na2S04) and evaporated to dryness under reduced pressure to give the title compound as a brown solid (7.05 g, 90%). LCMS m/z = 549 [M+H]+.
Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2-chloro-6- methylphenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxylate To a solution of methyl l-(4-amino-2-chloro-6-methylphenyl)-4-(bis(4- methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (7 g, 12.8 mmol) in MeCN (150 mL) was added TBAB (24.66 g, 76.50 mmol), CuBr (2.19 g, 15.3 mmol), ((lS,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-l-yl)methanesulfonic acid (8.89 g, 38.mmol) and NaNO2 (2.64 g, 38.3 mmol) and the mixture stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with H20 (100 mL) and extracted with EtOAc (3x 60mL). The combine extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, 0-50% EtOAc/PE) to give the title compound as a yellow solid (5 g, 64%). LCMS m/z = 6[M+H]+. 213 WO 2024/233900 PCT/US2024/028806 Step 5. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-methoxy-6- methylphenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxylate To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2-chloro-6- methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (2 g, 3.26 mmol) in MeOH (mL) and toluene (6 mL) was added Pd2(dba)3 (149.4 mg, 0.163 mmol), t-Bu Xphos (138.mg, 0.326 mmol) and KPO4 (1.04 g, 4.89 mmol) and the mixture stirred at 80°C for l h under N2. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by MPLC (SiO2, 0-50% EtOAc/PE) to give the title compound as a brown solid (870 mg, 1.54 mmol, 47%). LCMS m/z = 564 [M+H]+.
Step 6. Synthesis of (S)-methyl 4-amino-l-(2-chloro-4-methoxy-6-methylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate.
A mixture methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-methoxy-6-methylphenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate (870 mg, 1.54 mmol) in TEA (8 mL) was stirred at 80°C for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue adjusted with NaHCO3 to pH 7-8. The mixture was diluted with H20 (20 mL) and extracted with EtOAc (3x 10mL), dried (Na2S04) and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, 0-50% EtOAc/PE) followed by chiral SFC (DAICEL CHIRALPAK AD, 250 x 30 mm, 10 pm);27% (0.1% NH4OH/IPA) in CO2) to afford: Peak 1, Intermediate B4. (S)-methyl 4-amino-l-(2-chloro-4-methoxy-6-methylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (white solid, 187 mg, 37%). LCMS m/z = 3[M+H]+.
Intermediate B5. (S)-m ethyl 4-amino-l-(2-chloro-4-ethoxy-6-methylphenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate. 214 WO 2024/233900 PCT/US2024/028806 The title compounds were prepared using an analogous method to that described for Intermediate B4. chiral SFC (DAICEL CHIRALPAK IC, 250 x 30 mm, 10 pm); 45% (0.1% NH4OH/IPA) in CO2) to afford: Peak 1, Intermediate B5. (S)-m ethyl 4-amino-l-(2-chloro-4-ethoxy-6-methylphenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxylate (white oil, 730 mg, 46%). LCMS m/z = 338 [M+H]+.
Intermediate B6.Methyl 4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate. 215 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4-nitrophenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate DIPEA (1.58 g, 12.21 mmol) was added to a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate Bl, 2.5 g, 6.11 mmol) and l,3-dichloro-2-fluoro-5-nitro-benzene (5.13 g, 24.42 mmol) in DMSO (mL) and the mixture stirred at 100°C for 5 h. The reaction mixture was partitioned between EtOAc (30 mL) and H20 (20 mL) and the aqueous phase extracted with EtOAc (3x 30 mL). The combined organics were dried (Na2S04) and evaporated to dryness in vacuo. Theresidue was purified by MPLC (SiO2, 0-50% EtOAc/PE) to give the title compound as a yellow solid (4 g, crude). LCMS m/z = 599 [M+H]+.
Step 2. Synthesis of methyl l-(4-amino-2,6-dichlorophenyl)-4-(bis(4-methoxybenzyl)amino)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate.
Pd/C (0.2 g, 10% purity) was added to a solution of methyl 4-(bis(4-methoxybenzyl)amino)- l-(2,6-dichloro-4-nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 1, 4 g, 6.mmol) in MeOH (5 mL) and EtOAc (5 mL) and the mixture was stirred at 15°C for 1 hr 216 WO 2024/233900 PCT/US2024/028806 under H2 (15 psi). The reaction mixture was filtered and the filtrated evaporated to dryness in vacuo to afford the title compound as a yellow solid (2.2 g) which was used without further purification.
Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2,6-dichlorophenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate.
A mixture of methyl l-(4-amino-2,6-dichlorophenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo- l,6-dihydropyrimidine-5-carboxylate (Intermediate B6 Step 2, 3.5 g, 6.15 mmol), CuBr (1.g, 7.38 mmol), TBAB (11.89 g, 36.9 mmol), (lR,3S)-l,2,2-trimethylcyclopentane-l,3- dicarboxylic acid (3.69 g, 18.44 mmol) and NaNO2 (1.27 g, 18.44 mmol) in MeCN (40 mL) was stirred at 15°C for 12 h. The mixture was concentrated under reduced pressure and the residue partitioned between EtOAc (30 mL) and H20 (20 mL). The aqueous phase was further extracted with EtOAc (3x 30 mL). The combined organics were dried (Na2S04) and evaporated to dryness in vacuo. The residue was purified by MPLC (SiO2, 0-50% EtoAc/PE) to give the title compound as a yellow solid (1.5 g, 38.5%). LCMS m/z = 634 [M+H]+.
Step 4. Synthesis of methyl 4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
Methyl 4-(bis(4-methoxybenzyl)amino)-1 -(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6- dihydropyrimidine-5-carboxylate (Step 3, 1.5 g, 2.37 mmol) in TEA (2 mL) was stirred at 80oC for l h. The reaction mixture was concentrated under reduced pressure and the residue partitioned between EtOAc (20 mL) and sat. aq. Na2CO3 (15 mL). The aqueous phase was extracted with EtOAc (3x 20 mL) and the combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by MPLC (SiO2, 0-50% EtOAc/PE) to give the title compound as a yellow solid (800 mg, crude). LCMS m/z = 3[M+H]+.
Intermediate B7.Methyl 4-amino-l-(2,6-dichloro-4-propoxyphenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate. 217 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- propoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2,6-dichlorophenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6 Step 3, 500 mg, 0.789 mmol) in toluene (1 mL) and 1-propanol (1 mL) was added t-Bu Xphos (33.5 mg, 0,079 mmol) and Pd2(dba)3 (72.3 mg, 0.079 mmol), K3PO4 (251 mg, 1.18 mmol) and the mixture stirred at 80°C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, 0-25% EtOAc/PE) to give the title compound as a brown oil (300 mg, 62%). LCMS m/z = 6[M+H]+.
Step 2. Synthesis of methyl 4-amino-l-(2,6-dichloro-4-propoxyphenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
A solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4-propoxyphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 270 mg, 0.441 mmol) in TFA (4 mL) was stirred at 80°C for 1 h. The reaction mixture was concentrated under N2 and the residue diluted with H20 (20 mL) and sat. aq. Na2CO3 was added until pH=8 and the mixture was extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2S04)and concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 0-33% EtOAc/PE) to give the title compound as a white solid (110 mg, 67%). LCMS m/z = 372 [M+H]+.
Intermediate B8.Methyl 4-amino-l-(2,6-dichloro-4-(dimethylamino)phenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate. 218 WO 2024/233900 PCT/US2024/028806 N OMe N OCl/L ,CIN 0CK A /Cl Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- (dimethylamino)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl l-(4-amino-2,6-dichlorophenyl)-4-(bis(4-methoxybenzyl)amino)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6, Step 2; 500 mg, 0.88 mmol) inMeOH (5 mL) was added AcOH (52.73 mg, 0.88 mmol) to pH=5, and then HCHO (356 mg, 4.39 mmol) was added and the mixture stirred at 25°C for 1 h. To this was added NaBH3CN (82.8 mg, 1.32 mmol) and the mixture stirred at 25°C for l h. The reaction mixture was diluted with H20 (5 mL) and extracted with EtOAc (3x 4 mL). The combined organics were washed with brine (2x 3 mL), dried (Na2S04) and concentrated under reduced pressure to give the title compound as a white solid (500 mg). LCMS m/z = 597 [M+H]+.
Step 2. Synthesis of methyl 4-amino-l-(2,6-dichloro-4-(dimethylamino)phenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
A solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4-(dimethylamino)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 1, 450 mg, 0.mmol) in TFA (5 mL) was stirred at 80oC for 1 h. The reaction mixture was quenched by addition saturated aqueous Na2CO3 solution (3 mL) at 0°C and extracted with EtOAc (3x mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-TLC to give the title compound as a white solid (50 mg, 18%). LCMS m/z = 357 [M+H]+.
Intermediate B9.Synthesis of methyl 4-amino-l-(2,6-dichlorophenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate. 219 WO 2024/233900 PCT/US2024/028806 Br To a methyl 4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxylate (Intermediate B6, 150 mg, 0.382 mmol) in MeOH (10 mL) and THE (1 mL) was added Pd/C (0.2 g, 10% purity) and the mixture stirred at 25°C for 1 h under H2 (15psi). The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by prep-TLC (50% EtOAc/PE) to give the title compound as a yellow solid (70 mg, 58.4%). LCMS m/z = 314 [M+H]+.
Intermediate B10.Synthesis of methyl 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxylate. !0 Br OMe A mixture of methyl 4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine- 5-carboxylate (Intermediate B6, 500 mg, 1.27 mmol), C82CO3 (829 mg, 2.54 mmol) and RockPhos Pd G3 (107 mg, 0.127 mmol) in dioxane (5 mL) and MeOH (0.20 mL) was stirred at 80°C for 2 h under N2. The reaction mixture was filtered and the filtrate evaporated todryness under reduced pressure and the residue purified by prep-HPLC (Xbridge Prep OBD Cl8, 150 x 40 mm, 10 pm; 20-50% MeCN/H2O (lOmM NH4HCO3)) to give the title compound as a white solid (150 mg, 34%). LCMS m/z = 344 [M+H]+.
Intermediate Bll.Synthesis of methyl 4-amino-l-(2,6-dichloro-4-cyclopropoxyphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate. 220 WO 2024/233900 PCT/US2024/028806 The title compound was prepared as a white solid (140 mg, 30%) from methyl 4-amino-l-(4- bromo-2,6-di chi orophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B6) and cyclopropanol using an analogous method to that described for Intermediate B10. LCMS m/z = 370 [M+H]+.
Intermediate B12.Synthesis of methyl 4-amino-l-(2,6-dichloro-4-methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
Br Me To a solution of methyl 4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B6, 500 mg, 1.27 mmol) and 2,4,6-trimethyl- 1,3,5,2,4,6-trioxatriborinane (319 mg, 1.27 mmol, 355.69 uL, 50% purity) in dioxane (mL) was added Pd(dppf)C12 (93 mg, 0.127 mmol) and K2CO3 (352 mg, 2.54 mmol) and the mixture stirred at 100°C for 2 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by prep-HPLC (15-50%MeCN/H2O (0.05% NH4OH + lOmM NH4HCO3)) to give the title compound as a white solid (190 mg, 45%). LCMS m/z = 328 [M+H]+.
Intermediate B13.methyl 4-amino-l-((S)-2-chloro-4-cyano-6-methylphenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate. 221 WO 2024/233900 PCT/US2024/028806 Step 3N.Me Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4-cyanophenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate.
The title compound was prepared as a yellow solid (10g, 72%) from methyl 4-(bis(4- methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B1) and 3,5-dichloro-4-fluoro-benzonitrile using an analogous method to that described for Intermediate B6, Step 1. LCMS m/z = 579 [M+H]+.
Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-((S)-2-chloro-4-cyano-6- methylphenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4-cyanophenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (5 g, 8.63 mmol) and 2,4,6-trimethyl-l,3,5,2,4,6- trioxatriborinane (2.17 g, 8.63 mmol, 2.41 mL, 50% purity) in dioxane (20 mL) was added XPHOS-PD-G2 (679 mg, 0.863 mmol) and K3PO4 (3.66 g, 17.3 mmol) and the mixture stirred at 80°C for 3 h under N2. The solids were removed by filtration and the filtrate was concentrated under reduced pressure and the residue was purified by prep-HPLC (Phenomenex Luna Cl 8, 250 x 70 mm, 15 pm; 60-85% MeCN/(H2O + 0.2% HCO2H)) to give methyl 4-(bis(2,4-dimethoxybenzyl)amino)-l -(2-chloro-4-cyano-6-methylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate as a white solid (110 mg, 0.204 mmol, 2.4%). The racemate was separated by chiral SFC (DAICEL CHIRALPAK AD, 250 x 30 mm, 10 pm; 35% (0.1% NH4OH/IPA) in CO2 to afford: 222 NCl، .Me WO 2024/233900 PCT/US2024/028806 Peak 1, Intermediate B13: methyl 4-(bis(4-methoxybenzyl)amino)-l-((S)-2-chloro-4-cyano- 6-methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (white solid, 320 mg). LCMS m/z = 559 [M+H]+.
Step 3. Synthesis of methyl 4-amino-l-((S)-2-chloro-4-cyano-6-methylphenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxylate.
A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-((S)-2-chloro-4-cyano-6- methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 2, Peak 1, 320 mg, 0.5mmol) in TFA (2 mL) was stirred at 80°C for 15 min. The reaction mixture was filtered and the filtrate evaporated to dryness in vacuo. The residue was purified by prep-TLC (EtOAc)to give the title compound as a pale yellow solid (120 mg, 66%). LCMS m/z = 319 [M+H]+.
Intermediate B14.Synthesis of methyl 4-amino-l-(2,6-dichloro-4-cyanophenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate.
A solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4-cyanophenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxylate (Intermediate B13, Step 1; 3.00 g, 5.18 mmol) in TFA (20 mL) was stirred at 80°C for 1 hr. The reaction mixture was concentrated under reduced pressure and the residue diluted with H20 (10 mL) and extracted with EtOAc (3x 20 mL). The combined organics were washed with brine (2x 15 mL), dried (Na2S04) and evaporated to dryness in vacuo. The residue was purified by MPLC (SiO2, 0-50% EtOAc/PE) to afford the title compound as white solid (1.7 g, 97%). LCMS m/z = 339 [M+H]+.
Intermediate B15.methyl 4-amino-6-oxo-l-(2,4,6-trichlorophenyl)-l,6-dihydropyrimidine- 5-carboxylate. 223 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l-(2,4,6-trichlorophenyl)-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl l-(4-amino-2,6-dichlorophenyl)-4-(bis(4-methoxybenzyl)amino)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6, Step 2; 500 mg, 0.878 mmol), CuCl (174 mg, 1.76 mmol), CuC12 (354 mg, 2.63 mmol) in MeCN (9 mL) was added isopentyl nitrite (308 mg, 2.63 mmol) in MeCN (0.9 mL) and the mixture stirred at 25°C for l h under N2. The reaction mixture was quenched by addition H20 (30 mL) at 0°C and extracted with MeCN (3x 30mL). The combined organics were dried (Na2S04) and evaporated to dryness in vacuo to give the title compound as a brown oil (400 mg, crude). LCMS m/z = 589 [M+H]+.
Step 2. Synthesis of methyl 4-amino-6-oxo-l-(2,4,6-trichlorophenyl)-l, 6-dihydropyrimidine- 5-carboxylate.
A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l-(2,4,6-trichlorophenyl)-l,6- dihydropyrimidine-5-carboxylate (350 mg, 0.594 mmol) in TFA (8 mL) was stirred at 80°C for l h. The reaction mixture was concentrated under reduced pressure and the pH adjusted with 1 M Na2CO3 to pH 6-7. The residue was purified by column chromatography (SiO2, 0- 50% EtOAc/PE) to give the title compound as a yellow solid (150 mg, 72%). LCMS m/z = 352 [M+H]+.
Intermediate B16.methyl 4-amino-l-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate. 224 WO 2024/233900 PCT/US2024/028806 OMe Step 1. Synthesis of 1,3-dichloro-5-(difluoromethyl)-2-fluorobenzene.
To a solution of 3,5-dichloro-4-fluoro-benzaldehyde (5 g, 25.9 mmol) in DCM (50 mL) was added DAST (20.88 g, 130 mmol,) at -78°C. The mixture was stirred at 25°C for 3 h under N2. The reaction mixture was quenched by addition saturated aqueous NaHCO3 (30 mL) at 0°C and extracted with DCM (3x 20 mL). The combined organics were dried (Na2S04) and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO2, 20:1 PE/EtOAc) to give the title compound as a light yellow oil (5.3 g, 95%) which was used without further purification.
Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- (difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.
To a solution of l,3-dichloro-5-(difluoromethyl)-2-fluorobenzene (2.7 g, 12.6 mmol) and methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate Bl, 2.86 g, 6.98 mmol) in DMF (20 mL) was added K2CO3 (1.93 g, 13.mmol) and the mixture was stirred at 80oC for 2 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a light yellow solid (2.24 g, 53%). LCMS m/z = 604 [M+H]+.
Step 3. Synthesis of methyl 4-amino-l-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- (difluoromethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (2.24 g, 3.71 mmol) in TEA (10 mL) was stirred at 80°C for 1 hr. The reaction mixture was filtered and the filtrate 225 WO 2024/233900 PCT/US2024/028806 was concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a light yellow solid (1.35 g, 100%). LCMS m/z = 364 [M+H]+.
Intermediate B17.Synthesis of methyl 4-amino-l-(4-(difluoromethyl)-2,6-dimethylphenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To the mixture of methyl 4-amino-l-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B16, 500 mg, 1.37 mmol) in dioxane (9 mL) was added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (1.03 g, 4.12 mmol, 1.15 mL, 50%purity) and Xphos-Pd-G2 (108 mg, 0.137 mmol) and K3PO4 (583 mg, 2.75 mmol) was degassed and purged with N2 (x3) and the mixture stirred at 80oC for 12 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow oil (800 mg, 90%). LCMS m/z = 324 [M+H]+.
Intermediate B18.methyl 4-amino-l-(4-methoxy-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate. 226 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dimethyl-4-nitrophenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate.
To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6 Step 1, 6.00 g, 10.01 mmol) and 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (5.03 g, 20.02 mmol) in dioxane (100 mL) was added K3PO4 (4.25 g, 20.02 mmol) and Xphos-Pd-G2 (472.54 mg, 0.60 mmol) and the mixture stirred at 80°C for 12 h under N2. The mixture was filtered and concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 25-50%EtOAc/PE) to give the title compound as a yellow solid (5.00 g, 89%). LCMS m/z = 5[M+H]+.
Step 2. Synthesis of methyl l-(4-amino-2,6-dimethylphenyl)-4-(bis(4-methoxybenzyl)amino)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dimethyl-4-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 5.00 g, 8.95 mmol) in THE (50 mL) and MeOH (50 mL) was added Pd/C (6.00 g, 10% purity) and the mixture stirred at 25°C for 2 h under H2 (15 psi). The mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by prep-HPLC-23 (50-70% MeCN) to give the title compound as a yellow solid (4.50 g, crude). LCMS m/z = 529 [M+H]+.
TH WO 2024/233900 PCT/US2024/028806 Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2,6-dimethylphenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a mixture of methyl l-(4-amino-2,6-dimethylphenyl)-4-(bis(4-methoxybenzyl)amino)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Step 2, 1.92 g, 3.63 mmol, 1.00 eq), CuBr (6mg, 4.36 mmol), CSA (2.53 g, 10.9 mmol) and TBAB (7.03 g, 21.8 mmol) in MeCN (30 mL) was added NaNO2 (752 mg, 10.9 mmol) and the mixture stirred at 25°C for l h. The mixture was concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 0-100% EtOAc/PE) to give the title compound as a white solid (1.70 g, 79%). LCMS m/z = 592 [M+H]+.
Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-methoxy-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2,6-dimethylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Step 3, 1.12 g, 1.89 mmol), Pd2(dba)3 (173 mg, 0.19 mmol), t-Bu Xphos (80.3 mg, 0.19 mmol) and K3PO4 (602 mg, 2.84 mmol) in toluene (mL) and MeOH (8 mL) was stirred at 80°C for 2 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a brown oil (800 mg, 77%). LCMS m/z = 544 [M+H]+.
Step 5. Synthesis of methyl 4-amino-l-(4-methoxy-2,6-dimethylphenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
A solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-methoxy-2,6-dimethylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Step 4, 1.20 g, 2.21 mmol) in TEA (20 mL) was stirred at 80°C for 1 h. The reaction mixture was concentrated under reduced pressure and the pH adjusted with 1 M Na2CO3 to pH 6-7 and the residue purified by column chromatography (0-50% EtOAc/PE) to give the title compound as a pale yellow solid (5mg, 83%). LCMS m/z = 304 [M+H]+.
Intermediate B19.methyl 4-amino-l-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate. 228 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- (hydroxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.
To a solution of tributyl stannylmethanol (1.67 g, 5.21 mmol), methyl 4-(bis(4- methoxybenzyl)amino)-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxylate (Intermediate B6 Step 3; 1.10 g, 1.74 mmol) in dioxane (10 mL) was added Pd(PPh3)4 (100 mg, 0.087 mmol) and the mixture was stirred at 100 °C for 3 h under N2. The residue was purified by MPLC (SiO2, 0-50% EtOAc/PE) to give the title compound as a yellow solid (2.60 g, 85%). LCMS m/z = 584 [M+H]+.
Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- (methoxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- (hydroxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (2.15 g, 3.68 mmol) in THE (25 mL) was added NaOH (220 mg, 5.52 mmol) and dimethyl sulfate (4.07 g, 32.mmol) and the mixture was stirred at 25°C for 12 h. The reaction mixture was diluted with H20 (50 mL) and extracted with EtOAc (3x 25 mL), dried (Na2S04) and concentrated under reduced pressure. The residue was purified by prep-HPLC-11 (35-70% MeCN) to give the title compound as a white oil (180 mg, 0.300 mmol, 8.2%). LCMS m/z = 598 [M+H]+.
Step 3. Synthesis of methyl 4-amino-l-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate. 229 WO 2024/233900 PCT/US2024/028806 A mixture of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-l-(2,6-dichloro-4- (methoxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (180 mg, 0.300 mol) in TFA (2 mL) was stirred at 80 °C for 0.5 h. The residue was purified by prep-TLC (50% EtOAc/PE) to give the title compound as a brown solid (60 mg, 0.168 mmol, 55.7%). LCMS m/z = 358 [M+H]+.
Intermediate B20.Synthesis of tert-butyl ((5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate.
To a mixture of methyl 4-amino-l-(4-bromo-2, 6-dichloro-phenyl)-6-oxo-pyrimidine-5-carboxylate (Intermediate B6, 500 mg, 1.27 mmol) and tert-butyl ((5-aminopyridin-3- yl)methyl)(ethyl)carbamate (Intermediate A24, 479.6 mg, 1.91 mmol,) in toluene (9 mL) was added AlMe3 (2 M in toluene, 1.91 mL) at 0°C. The mixture was stirred at 100°C for 0.5 h under N2 atmosphere. The reaction mixture was quenched by addition of 1 M NaOH aq. (mL) at 0°C and extracted with EtOAc (3x 50 mL). The combined organics were dried(Na2SO4) and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO2, 0-100% EtOAc/PE) to give the title compound as a yellow solid (2 g, 64%). LCMS m/z = 613 [M+H]+.
Intermediate B21.Synthesis of 4-(4-amino-5-((5-(((tert-butoxycarbonyl)(ethyl)amino)methyl)pyridin-3-yl)carbamoyl)-6-oxopyrimidin-l(6H)-yl)-3,5-dichlorobenzoic acid. 230 CK /Cl HO WO 2024/233900 PCT/US2024/028806 To a solution of tert-butyl ((5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate (310 mg, 0.5mmol) and oxalic acid (319 mg, 3.54 mmol) in DMF (2 mL) was added Pd(OAc)2 (11.37 mg, 0.051 mmol), Xantphos (29.29 mg, 0.051mol), Ac20 (155 mg, 1.52 mmol) and DIPEA (196mg, 1.52 mmol) and the mixture stirred at 100°C for 12 h under N2. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by prep-HPLC-24 to give the title compound as a white solid (120 mg, 41%). LCMS m/z = 5[M+H]+.
Intermediate B22.methyl 4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate.
Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(hydroxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2,6-dimethylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B18 Step3, 750 mg, 1.27 mmol) andtributylstannylmethanol (1.22 g, 3.80 mmol) in dioxane (7 mL) was added Pd(PPh3)4 (1mg, 0.127 mmol). The mixture was stirred at 100°C for 12 h under N2. The reaction mixture was concentrated under reduced pressure and the residue purified by MPLC (SiO2, 0-100% 231 WO 2024/233900 PCT/US2024/028806 EtOAc/PE) to give the title compound as a yellow oil (1.30 g, 2.39 mmol, 94%). LCMS m/z = 544 [M+H]+.
Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(methoxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(hydroxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (200 mg, 0.368 mmol) in THE (5 mL) was added NaOH (22.1 mg, 0.552 mmol) and dimethyl sulfate (381 mg, 3.02 mmol) and the mixture stirred at 25 °C for 12 h. The reaction mixture was diluted with H20 (mL) and extracted with EtOAc (3x 35 mL). The combined extracts were dried (Na2S04), and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO2, 0-100% EtOAc/PE) to give the title compound as a yellow oil (300 mg, 24%). LCMS m/z = 558 [M+H]+.
Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(methoxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
A solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(methoxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (200 mg, 0.359 mmol) in TEA (5 mL) was stirred at 80 °C for l h. The reaction mixture was concentrated under reduced pressure and the pH of the residue adjusted with 1 M NH4OH to pH 6-7. The residue was purified by column chromatography (SiO2, 0-100% EtOAc/PE) to afford the title compound as a white solid (110 mg, 97%). LCMS m/z = 318 [M+H]+.
Intermediate B23.methyl 4-amino-l-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate. 232 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- (trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.
To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5- carboxylate (Intermediate Bl, 5 g, 12.21 mmol) and l,3-dichloro-2-fluoro-5- (trifluoromethyl)benzene (3.19 g, 13.43 mmol) and K2CO3 (3.38 g, 24.42 mmol) in DMF (mL) was stirred at 80°C for 3 h. The reaction mixture was filtered and H20 added to the filtrate. Then resulting solids were collected by filtration to afford the title compound as a yellow solid (7.50 g, crude) which was used without further purification. LCMS m/z = 6[M+H]+.
Step 2. Synthesis of methyl 4-amino-l-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- (trifluoromethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (7.50 g, 12.05 mmol) in TFA (20 mL) was stirred at 80°C for 1 h. The reaction mixture was concentrated under reduced pressure and the pH of the residue adjusted to pH 6-7 with IM NH4OH and extracted with EtOAc. The combined organics were dried (Na2S04) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a white solid (3.5 g, 76%) as. LCMS m/z = 382 [M+H]+.
Intermediate B24.methyl 4-amino-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate.
Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- (trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate 233 WO 2024/233900 PCT/US2024/028806 A suspension of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5- carboxylate (Intermediate Bl, 1.605 g, 4.0 mmol), KCO3 (1.129 g, 8.0 mmol, 2.0 equiv) and l,3-dichloro-2-fluoro-5-(trifluoromethyl)benzene (0.650 mL, 4.20 mmol) in DMA (8 mL) was heated to 80°C for 22 h. The reaction was cooled, diluted with EtOAc (75 mL) and washed three times with water. The aqueous phase was back-extracted with EtOAc (20 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated by rotary evaporation. Flash chromatography (ISCO 40g silica, 0-100% EtOAc/hex) provided the title compound as a light yellow foam (1.690 g, 68%). LCMS m/z = 622 [M+H]+.
Step 2. Synthesis of methyl 4-amino-l-(2,6-dimethyl-4-(trijluoromethyl)phenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
To a suspension of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- (trifluoromethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 1, 1.681 g, 2.mmol), K3PO4 (1.72 g, 8.10 mmol), and Xphos Pd G3 (240 mg, 0.270 mmol) in dioxane (mL) was added trimethylboroxine solution (50 wt% in THF, 1.80 mL, 6.75 mmol). The solution was purged with N2 for 8 min and then heated to 80 °C for 16 h. The reaction was then cooled, filtered through Celite, washed with EtOAc. Flash chromatography (ISCO 40g silica, 0-100% EtOAc/hex) provided a light yellow solid. The intermediate methyl 4-(bis(4- methoxybenzyl)amino)-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate was dissolved in TFA (8 mL) and heated to 80°C for 2 h. The reaction was poured into saturated aqueous NaHCO3 and extracted with EtOAc (3x mL). The combined organics were washed with water, brine, dried (MgSO4) and concentrated by rotary evaporation. Flash chromatography (ISCO 24g silica, 0-100% EtOAc/hex) provided the title compound as a peach-coloured solid (779 mg, 85% yield over steps). LCMS m/z = 342 [M+H]+.
Intermediate B25.methyl 4-amino-l-(4-ethoxy-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate. 234 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dimethyl-4-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.
K3PO4 (4.60 g, 21.69 mmol) and XPH0S-PD-G2 (512 mg, 0.651 mmol) were added to amixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4-nitrophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B6 Step 1, 6.5 g, 10.84 mmol) and 2,4,6- trimethyl-l,3,5,2,4,6-trioxatriborinane (5.45 g, 21.69 mmol) in dioxane (100 mL) and the mixture stirred at 80°C for 12 h under N2. The mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by MPLC (SiO2, 0-50%EtOAc/PE) to give the title compound as a yellow solid (5 g, crude). LCMS m/z = 5[M+H]+. 235 WO 2024/233900 PCT/US2024/028806 Step 2. Synthesis of methyl l-(4-amino-2,6-dimethylphenyl)-4-(bis(4-methoxybenzyl)amino)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dimethyl-4-nitrophenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (4.7 g, 8.41 mmol) in THE (30 mL) and MeOH (mL) was added Pd/C (0.5 g, 8.41 mmol, 10% purity) and the mixture stirred at 20°C for 2 h under H2 (15 psi). The mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a yellow solid (4.5 g, crude). LCMS m/z = 5[M+H]+.
Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2,6-dimethylphenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate.
NaNO2 (1.64 g, 23.84 mmol) was added to a mixture of methyl l-(4-amino-2,6- dimethylphenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5- carboxylate (Step 2, 4.2 g, 7.95 mmol), CuBr (1.37 g, 9.53 mmol), TBAB (15.37 g, 47.mmol) and CSA (5.54 g, 23.84 mmol) in MeCN (60 mL) and the mixture stirred at 20°C for h. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc (20 mL) and H20 (15 mL). The aqueous phase was extracted with EtOAc (3x 20 mL) and the combined organics dried (Na2S04) and evaporated to dryness in vacuo. The residue was purified by MPLC (SiO2, 0-50% EtOAc/PE) to give the title compound as a yellow oil ( 3.6 g, 76.5%). LCMS m/z = 592 [M+H]+.
Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-hydroxy-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2,6-dimethylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (B18 Step 3, 710 mg, 1.20 mmol) in dioxane (7.mL) and H20 (2.5 mL) was added K3PO4 (382 mg, 1.80 mmol) , t-Bu Xphos (50.9 mg, 0.1mmol) and Pd2(dba)3 (110 mg, 0.120 mmol) and the mixture stirred at 80°C for 1 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residuethat was purified by column chromatography (SiO2, 0-33% EtOAc/PE) to give the title compound as a brown oil (1.6 g, 84%). LCMS m/z = 530 [M+H]+.
Step 5. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-ethoxy-2,6-dimethylphenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate. 236 WO 2024/233900 PCT/US2024/028806 To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-hydroxy-2,6-dimethylphenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate (1 g, 1.89 mmol) and iodoethane (353.4 mg, 2.mmol,) in DMF (5 mL) was added K2CO3 (522 mg, 3.78 mmol) and the mixture stirred at 60°C for 2 h. The reaction mixture was diluted with H20 (20 mL) and extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2S04) and concentrated under reducedpressure to give the title compound as a brown oil (1 g, crude). LCMS m/z = 558 [M+H]+.
Step 6. Synthesis of methyl 4-amino-l-(4-ethoxy-2,6-dimethylphenyl)-6-oxo-1,6- dihydropyrimidine-5-carboxylate.
A solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-ethoxy-2,6-dimethylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (1 g, 1.79 mmol) in TFA (1 mL) was stirred at80oC for 1 h. The reaction mixture was evaporated under a stream of N2 and the residue and diluted with sat. aq. NaHCO3 (3 ml), extracted with EtOAc (3x 3 ml) and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a light yellow solid (340 mg, 56%). LCMS m/z = 318[M+H]+.
Intermediate B26.methyl 4-amino-l-(2,6-dimethyl-4-propoxyphenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate. 237 WO 2024/233900 PCT/US2024/028806 The title compound was prepared as a white solid from methyl 4-(bis(4- methoxybenzyl)amino)-l-(4-bromo-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxylate (Intermediate B18, Step 3) using an analogous 3-Step procedure as described for Intermediate B25 (Step 4,5 and 6). LCMS m/z = 332 [M+H]+.
Intermediate B27.methyl 4-amino-l-(4-methoxy-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate.
Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-methoxy-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2,6-dimethylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate Bl8, Step 3; 1.12 g, 1.89 mmol), Pd2(dba)3 (173 mg, 0.189 mmol), t-Bu Xphos (80.3 mg, 0.189 mmol) and K3PO4 (602 mg, 2.84 mmol) in toluene (8 mL) and MeOH (8 mL) was stirred at 80°C for 2 h under N2. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a brown oil (800 mg, 1.47 mmol, 77%). LCMS m/z = 544 [M+H]+.
Step 2. Synthesis of methyl 4-amino-l-(4-methoxy-2,6-dimethylphenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-methoxy-2,6-dimethylphenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 1, 1.20 g, 2.21 mmol) was dissolved in TEA (20 mL) and the mixture was stirred at 80oC for l h. The reaction mixture was concentrated under reduced pressure and the pH of the residue adjusted to pH 6-7 with 1M Na2CO3. The residue was purified by column chromatography (0-50% EtOAc/PE) to give the title compound as a pale yellow solid (560 mg, 83%). LCMS m/z = 304 [M+H]+.238 WO 2024/233900 PCT/US2024/028806 Intermediate B28.methyl 4-amino-l-(2,6-dichloro-4-(ethoxymethyl)phenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate.
OMe Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- (ethoxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- (hydroxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (1.20 g, 2.05 mmol) in DCM (6 mL) was added DIPEA (796 mg, 6.16 mmol) to pH 10 followed by tri ethyl oxonium tetrafluoroborate (1.56 g, 8.21 mmol) was added at 0°C. The mixture was stirred at 25°C for h, quenched by addition saturated aqueous Na2CO3 (10 mL) at 0°C, and extracted with DCM (3x 10 mL). The combined organics were dried (Na2S04) and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO2, 0-25% EtOAc/PE) to give the title compound as a yellow solid (430 mg, 34%). LCMS m/z = 588 [M+H]+.
Step 2. Synthesis of methyl 4-amino-l-(2,6-dichloro-4-(ethoxymethyl)phenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- (ethoxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (400 mg, 0.653 mmol) in TEA (5 mL) was stirred at 80°C for 1 h. The reaction mixture was concentrated under reduced pressure and the pH of the residue adjusted to pH 8-9 with Na2CO3, diluted with H(50 mL) and extracted with EtOAc (3 x 40 mL). The combined organics were washed with brine (2x 30 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a white solid (210 mg, 86%).239 WO 2024/233900 PCT/US2024/028806 Intermediate B29.methyl 4-amino-l-(4-(ethoxymethyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate Step 1. Synthesis of methyl l-(4-(ethoxymethyl)-2,6-dimethylphenyl)-4-(4- methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(hydroxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (B22, Step 1, 1.00 g, 1.mmol,) in DCM (5 mL) was added DIPEA (476 mg, 3.68 mmol) and triethyloxonium;tetrafluoroborate (1.40 g, 7.36 mmol) at 0°C and the mixture stirred at 25°C for 2 h. The reaction mixture was quenched by addition saturated aqueous NaHCO3 (20 mL) at 0°C and extracted with DCM (3x 20 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure to give a residue that was purified by prep-HPLC- (30-60% MeCN) to give the title compound as a white solid (170 mg, 20.5%). LCMS m/z = 452 [M+H]+.
Step 2. Synthesis of methyl 4-amino-l-(4-(ethoxymethyl)-2,6-dimethylphenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate Methyl 1 -(4-(ethoxymethyl)-2,6-dimethylphenyl)-4-((4-methoxybenzyl)amino)-6-oxo-1,6- dihydropyrimidine-5-carboxylate (Step 1, 170 mg, 0.377 mol) was dissolved in TEA (2 mL) and the mixture was stirred at 80oC for l h. The reaction mixture was quenched by addition saturated aqueous Na2C03 solution (20 mL) and extracted with EtOAc (3x 40 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, 50% EtOAc/PE) to give the title compound as a white solid (100 mg, 0.302 mmol, 80%). LCMS m/z = 332 [M+H]+. 240 WO 2024/233900 PCT/US2024/028806 Intermediate B30.methyl 4-amino-l-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate.
Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4-hydroxyphenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxylate To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2,6-dichlorophenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6 Step 3, 3.00 g, 4.74 mmol) in dioxane (30 mL) and H20 (10 mL) was added K3PO4 (1.51 g, 7.11 mmol), t-Bu Xphos (2mg, 0.474 mmol) and Pd2(dba)3 (434 mg, 0.474 mmol) and the mixture stirred at 80°C for l h under N2. The reaction mixture was filtered and the filtrate concentrated under reducedpressure. The residue was purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a yellow solid (4 g,). LCMS m/z = 570 [M+H]+.
Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4-ethoxyphenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4-hydroxyphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (1.96 g, 3.44 mmol) and iodoethane (804 mg, 5.mmol) in DMF (15 mL) was added K2CO3 (950 mg, 6.87 mmol) and the mixture stirred at 60°C for 2 h. The reaction mixture was quenched with H20 (5.00 mL) at 0°C and extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2S04) and concentrated 241 WO 2024/233900 PCT/US2024/028806 under reduced pressure. The residue was purified by column chromatography (SiO2, 0-100% EtOAc/PE) to give the title compound as a yellow solid (1.70 g, 83%). LCMS m/z = 5[M+H]+.
Step 3. Synthesis of methyl 4-amino-l-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxylate A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4-ethoxyphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (3.30 g, 5.51 mmol) in TEA (30 mL) was stirred at 80oC for 1 hr. The reaction mixture was added to saturated aqueous NaHCO3 solution (ml) and concentrated under reduced pressure and extracted with EtOAc (3x 10 ml). Thecombined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a white solid (1.10 g, 56% yield). LCMS m/z = 358 [M+H]+.
Intermediate B31.methyl 4-amino-l-(2,6-dichloro-4-isopropoxyphenyl)-6-oxo-l,6-dihydropyrimi di ne-5 -carb oxyl ate. 242 WO 2024/233900 PCT/US2024/028806 The title compound was prepared as a brown solid from methyl 4-(bis(4- methoxybenzyl)amino)-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxylate (Intermediate B6, Step 3) using an analogous 3-Step method as described for Intermediate B30. LCMS m/z = 372 [M+H]+.
Intermediate B32.methyl 4-amino-l-(4-(2,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate.
Step 1. Synthesis of methyl l-(4-allyl-2,6-dimethylphenyl)-4-(bis(4-methoxybenzyl)amino)-6- oxo-1,6-dihydropyrimidine-5-carboxylate To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2,6-dimethylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B18 Step 3, 500 mg, 0.844 mmol) in dioxane (6 mL) was added Pd(PPh3)4 (97.5 mg, 0.084 mol) and allyl(tributyl)stannane (1.g, 3.25 mmol) and the mixture stirred at 80°C for 12 h under N2. The reaction mixture was quenched by addition 4M KF (10 mL) at 0 °C and the mixture extracted with EtOAc (4x 10mL). The combined organics were concentrated under reduced pressure and the residue purified by MPLC (SiO2, 1-50% EtOAc/PE) to give the title compound as a yellow solid (9mg, crude). LCMS m/z = 554 [M+H]+. 243 WO 2024/233900 PCT/US2024/028806 Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(2,3-dihydroxypropyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate To a solution of methyl l-(4-allyl-2,6-dimethylphenyl)-4-(bis(4-methoxybenzyl)amino)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (903 mg, 1.63 mmol) in acetone (8 mL) and H2O (1.20 mL) was added K2Os04.2H0 (60.1 mg, 0.163 mmol) andNMO (287 mg, 2.45 mmol) and the mixture stirred at 25°C for 2 h under N2. The reaction mixture was filtered and the filtrate evaporated to dryness in vacuo. The residue was purified by prep-HPLC (C18, 250 x mm, 10 pm; 30-70% MeCN/H2O (NH4HCO3)) to give the title compound as a grey solid (810 mg, 84.5%). LCMS m/z = 588 [M+H]+.
Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dimethyl-4-(2- oxoethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(2,3-dihydroxypropyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (790 mg, 1.34 mmol) in MeOH (14 mL) was added NaIO4 (575 mg, 2.69 mmol) and the mixture stirred at 25°C for 2 h. The reaction mixture was diluted with H20 (20 mL) and extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2S04) and evaporated to dryness in vacuo. The residue was purified by MPLC (SiO2, 1-50% EtOAc/PE) to give the title compound as a white solid (810 mg, 84.5%). LCMS m/z = 556 [M+H]+.
Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(2,2-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dimethyl-4-(2- oxoethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 3, 580 mg, 1.04 mmol) in DCM (10 mL) was added DAST (1.68 g, 10.44 mmol) at -78°C under N2 and the mixture stirred at -78°C for 0.5 h under N2 and then at 25°C for 1 h under N2. The reaction mixture was quenched by addition saturated aqueous NaHCO3 solution (20 mL) at 0°C and extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2S04) and evaporated to dryness and the residue purified by MPLC (SiO2, 1-50% EtOAc/PE) to give the title compound as a white solid (450 mg, 74.6%). LCMS m/z = 578 [M+H]+.
Step 5. Synthesis of methyl 4-amino-l-(4-(2,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6- dihydropyrimidine-5-carboxylate 244 WO 2024/233900 PCT/US2024/028806 A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(2,2-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (440 mg, 0.762 mmol) in TFA (3 mL) was stirred at 80°C for 0.5 h. The reaction mixture was concentrated under reduced pressure and the pH of the residue was adjusted with NaHCO3 to pH 8-9. The mixture wasdiluted with H20 (30 mL) and extracted with EtOAc (3x 15 mL). The combined extracts were dried (Na2S04) and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, 1-50% EtOAc/PE) to give the title compound as a white solid (190 mg, 74%). LCMS m/z = 338 [M+H]+.
Intermediate B33.methyl 4-amino-l-(4-(2-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimi di ne-5 -carb oxyl ate.
OMe OMe Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(2-hydroxyethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dimethyl-4-(2-oxoethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B32 Step 3, 650mg, 1.17 mmol) in MeOH (5 mL) was added NaBH4 (46.5 mg, 1.23 mmol) and he mixture 245 WO 2024/233900 PCT/US2024/028806 was stirred at 25°C for 10 min. The reaction mixture was quenched by addition aqueous HCI (IM, 2 mL ) at 0°C and extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2S04), concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-100% EtOAc/PE) to give the title compound as a light yellow oil (440 mg, 67%). LCMS m/z = 558 [M+H]+.
Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(2-fluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(2-hydroxyethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 1, 440 mg, 0.789 mmol) in DCM (4 mL) was added DAST (636 mg, 3.95 mmol)at -78°C for 0.5 h and the mixture stirred at 25°C for l h. The reaction mixture was quenched by addition saturated aqueous NaHCO3 (5 mL) at 0°C and extracted with EtOAc (3x 10 mL). The combined organic layers were dried (Na2SO4), concentrated under reduced pressure and the residue purified by prep- TLC (EtOAc) to give the title compound as a pale yellow oil (310 mg, 70%). LCMS m/z = 560 [M+H]+.
Step 3. Synthesis of methyl 4-amino-l-(4-(2-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6- dihydropyrimidine-5-carboxylate.
A solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(2-fluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 2, 310 mg, 0.554 mmol) in TEA (1 mL) was stirred at 80°C for 1 h. The reaction was quenched by addition saturated aqueous NaHCO3 (5 mL) at 0°C and then extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by prep-TLC (EtOAc) to give the title compound as a pale yellow oil (150 mg, 84%). LCMS m/z = 320 [M+H]+.
Intermediate B34.Synthesis of methyl 4-amino-l-(4-bromo-2,6-dimethylphenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxylate 246 WO 2024/233900 PCT/US2024/028806 A solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2,6-dimethylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B18 Step 3, 3.40 g, 5.74 mmol) in TFA (40 mL) was stirred at 80°C for 0.5 h. The mixture was concentrated under reduced pressure and the residue partitioned between DCM (40 mL) and Na2CO3 (15 mL). The water phase was extracted with DCM (3x 40 mL) and the combined organics dried (Na2S04) and evaporated to dryness in vacuo. The residue was purified by MPLC (SiO2, 0-5-% EtOAc/PE) to give the title compound as a yellow solid (2 g, crude). 1H NMR (400 MHz, CDC13): 8.(s, 1H), 7.59 (s, 1H), 7.25 (s, 2H), 3.80 (s, 3H), 2.05 (s, 6H).
Intermediate B35.Synthesis of methyl 4-amino-l-mesityl-6-oxo-l,6-dihydropyrimidine-5- carboxylate. nh 2 o nh 2 o Me^ A -MeN o To the mixture of methyl 4-amino-l-(4-bromo-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B34, 300 mg, 0.852 mmol) and 2,4,6- trimethyl-l,3,5,2,4,6-trioxatriborinane (1.07 g, 4.26 mmol) in dioxane (5 mL) was added Xphos-Pd-G2 (67.02 mg, 0.085 umol) and K3PO4 (271 mg, 1.28 mmol) and the mixture stirred at 80 °C for 12 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by column chromatography (SiO2; 1-50% EtOAc/PE) to give the title compound as a white solid (350 mg, 71.5%).LCMS m/z = 288 [M+H]+.247 NMe^ -Me N O-k ^Me WO 2024/233900 PCT/US2024/028806 Intermediate B36.Synthesis of tert-butyl ((5-(4-amino-l-(4-(difluoromethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamido)pyri din-3- yl)methyl)(methyl)carbamate.
To a mixture of methyl 4-amino-l-(4-(difluoromethyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B17, 50 mg, 0.155 mmol) and tert-butyl ((5- aminopyridin-3-yl)methyl)(methyl)carbamate (55.1 mg, 0.232 mmol) in toluene (4 mL) was added AlMe3 (2 M, 0.232 mL) at 0°C and the mixture stirred at 0°C for another 5 min. The mixture was stirred at 100°C for l h under N2. The reaction mixture was quenched with H20(1 mL) and TFA (1 mL) at 0°C and concentrated under reduced pressure to give the titlecompound as a white solid (80 mg, 98%). LCMS m/z = 529 [M+H]+.
Intermediate B37.methyl 4-amino-l-(2,6-dichloro-4-(trifluoromethoxy)phenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate. 248 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of 2-chloro-6-nitro-4-(trifluoromethoxy)aniline To a solution of 2-nitro-4-(trifluoromethoxy)aniline (8.4 g, 37.82 mmol) in AcOH (15 mL) was added sulfuryl chloride (7.66 g, 56.73 mmol, 5.67 mL) at 0°C. The mixture was stirredat 25°C for 12 h and then evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO2, 25-100% EtOAc/PE) to give the title compound as a yellow solid (7.4 g, 76%). 1HNMR (400 MHz, DMSO-d6): 8.05-8.01 (m, 1 H), 7.97 (d, 1 H), 7.(hr s, 2 H).
Step 2. Synthesis of l,2-dichloro-3-nitro-5-(trifluoromethoxy)benzene To a mixture of 2-chloro-6-nitro-4-(trifluoromethoxy)aniline (5 g, 19.49 mmol) in MeCN (mL) was added CuC12 (3.14 g, 23.4 mmol) at 25°C followed by tert-butyl nitrite (3.01 g, 29.23 mmol) and the mixture stirred at 60°C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue purified by prep-TLC (1:10 EtOAc/PE) to give the 249 WO 2024/233900 PCT/US2024/028806 title compound as a white solid (4.1 g, 76%). 1HNMR (400 MHz, DMSO-d6): 8.36-8.32 (m, H), 8.30-8.27 (m, 1 H).
Step 3.Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-6-nitro-4- (tri fluoromethoxy )phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5- carboxylate (Intermediate Bl, 5 g, 12.21 mmol) and l,2-dichloro-3-nitro-5- (trifluoromethoxy )benzene (Step 2, 3.71 g, 13.43 mmol) in DMF (15 mL) was added K2CO(3.38 g, 24.42 mmol) and the mixture stirred at 80°C for 12 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue was purified by prep-HPLC-26 (50-80% MeCN) to give the title compound as a white solid (1.9 g, 24%). LCMS m/z = 649 [M+H]+.
Step 4. Synthesis of methyl l-(2-amino-6-chloro-4-(trifluoromethoxy)phenyl)-4-(bis(4- methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-6-nitro-4- (trifluoromethoxy)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 3, 1.6 g, 2.mmol) in H20 (10 mL) and EtOH (30 mL) was added Fe (1.38 g, 24.7 mmol) and NHCl (1.32 g, 24.7 mmol) and the mixture stirred at 80°C for 6 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a yellow solid (850 mg, 55%). LCMS m/z = 619 [M+H]+.
Step 5. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- (trifluoromethoxy)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate Isopentyl nitrite (454 mg, 3.88 mmol) in MeCN (3 mL) was added dropwise to a mixture of methyl l-(2-amino-6-chloro-4-(trifluoromethoxy)phenyl)-4-(bis(4-methoxybenzyl)amino)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (800 mg, 1.29 mmol), CuCl (256 mg, 2.58 mmol) and CuC12 (521 mg, 3.88 mmol) in MeCN (10 mL) and the mixture stirred at 25°C for l h under N2. The residue was diluted with H20 (20mL) and extracted with EtOAc (3x 20mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure to give the title compound as a white solid (800 mg, 97% yield). LCMS m/z = 639 [M+H]+.
Step 6. Synthesis of methyl 4-amino-l-(2,6-dichloro-4-(trifluoromethoxy)phenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate250 WO 2024/233900 PCT/US2024/028806 A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- (trifluoromethoxy )phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (600 mg, 0.94 mmol) in TFA (3 mL) was stirred at 80 °C for l h. The reaction mixture was concentrated under reduced pressure and the pH of the residue adjusted to pH 6-7 with 1M Na2CO3 (10 ml) andthe residue purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a yellow solid (330 mg, 88%). LCMS m/z = 398 [M+H]+.
Intermediate B38.Synthesis of methyl 4-amino-l-(2,6-dimethyl-4- (tri fluoromethoxy )phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate OCF3 ocf 3 A mixture of methyl 4-amino-l-(2,6-dichloro-4-(trifluoromethoxy)phenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B37, 180 mg, 0.452 mmol), 2,4,6-trimethyl- 1,3,5,2,4,6-trioxatriborinane (568 mg, 2.26 mmol), XPHOS-PD-G2 (35.6 mg, 0.045 mmol), K3PO4 (192 mg, 0.904 mmol) in dioxane (6 mL) was degassed and purged with N2 (3x) and the mixture stirred at 80 °C for 6 h under N2. The reaction mixture was filtered and thefiltrate was concentrated under reduced pressure and the residue purified by prep-TLC (50% EtOAc/PE) to give the title compound as a yellow solid (130 mg, 80%). LCMS m/z = 3[M+H]+.
Intermediate B39.Synthesis of methyl 4-amino-l-(2,6-dichloro-4-fluorophenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate 251 WO 2024/233900 PCT/US2024/028806 Step 4 The title compound was prepared from methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B1) and l,2-dichloro-5-fluoro-3-nitrobenzene using an analogous method to that described in Steps 3-6 for Intermediate B37. LCMS m/z =332 [M+H]+.
Intermediate B40 and B41.methyl (S)-4-amino-l-(4-(l,2-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate and methyl (R)-4-amino-l-(4- (l,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate. 252 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dimethyl-4-vinylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate.
A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B18 Step 3, 3 g, 5.06 mmol), 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (1.17 g, 7.60 mmol), K2CO3(1.40 g, 10.13 mmol) , Pd(dppf)C12 (370.5 mg, 0.51 mmol) in dioxane (30 mL) and H20 (2 mL) was degassed and purged with N2 (x3) and the mixture stirred at 100°C for l h under N2. The solids were removed by filtration and the filtrate evaporated to dryness in vacuo. The residue waspurified by column chromatography (SiO2, 0-50 EtOAc/PE) to give the title compound as a yellow solid (2.6 g, 95%). LCMS m/z = 540 [M+H]+.
Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(l,2-dihydroxyethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dimethyl-4-vinylphenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxylate (2.57 g, 4.76 mmol), 4-methylmorpholine 4-oxide (8 253 WO 2024/233900 PCT/US2024/028806 mg, 7.14 mmol) and K2Os04.2H2O (175 mg, 0.476 mmol) in acetone (30 mL) and H20 (mL) was degassed and purged with N2 (x3) and the mixture stirred at 25 °C for 2 h under N2. The reaction mixture was partitioned between DCM (30 mL) and H20 (30 mL) and the aqueous phase extracted with DCM (3x 30 mL). The combined organics were dried (Na2S04) and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO2, 0-100% EtOAc/PE) to give the title compound as a yellow solid (1.g, 42%). LCMS m/z = 574 [M+H]+.
Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(l,2-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
DAST (843 mg, 5.23 mmol) was added to a solution of methyl 4-(bis(4- methoxybenzyl)amino)-l-(4-(l,2-dihydroxyethyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (300 mg, 0.523 mmol) in DCM (20 mL) and the mixture stirred at -78°C for 0.5 h and then stirred at 25°C for 1 h under N2. The reaction mixture was quenched by addition of saturated aqueous NaHCO3 (20 mL) at 0°C and extracted with DCM (3x 20 mL). The combined organics were dried (Na2S04) and evaporated to dryness in vacuo to afford the title compound as a yellow solid (800 mg, 88%). LCMS m/z = 578 [M+H]+.
Step 4. Synthesis of methyl (S)-4-amino-l-(4-(l,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxylate and methyl (R)-4-amino-l-(4-(l ,2-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
A solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(l,2-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (700 mg, 1.21 mmol) in TEA (20 mL) was stirred at 80°C for 1 h under N2. The reaction mixture was evaporated to dryness in vacuo and the residue dissolved in THE (20 ml) and the pH was adjusted with NH4OH to pH 9-11 at 0°C. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, 0-50% EtOAc/PE) to afford methyl 4-amino-l-(4-(l,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxylate which was separated by chiral SEC (DAICEL CHIRALCEL OJ (250 x 30 mm, pm); 13% (0.1% NH4OH/IPA) in CO2) to afford: Intermediate B40,Peak 1; methyl (S)-4-amino-l-(4-(l,2-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate or methyl (R)-4-amino-l-(4- (l,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (yellow solid, 100 mg). LCMS m/z = 338 [M+H]+.254 WO 2024/233900 PCT/US2024/028806 Intermediate B41,Peak 2; methyl (S)-4-amino-l-(4-(l,2-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate or methyl (R)-4-amino-l-(4- (l,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (yellow solid, 110 mg). LCMS m/z = 338 [M+H]+.
Intermediate B42 and B43.methyl (S)-4-amino-l-(2,6-dichloro-4-(l,2- difluoroethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate and methyl (R)-4-amino- l-(2,6-dichloro-4-(l,2-difluoroethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
The title compounds were prepared from methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B6Step 3) using an analogous 4 step procedure as described for Intermediates B40 and B41. Chiral SFC (DAICEL CHIRALCEL OJ (250 x 30 mm, 10 pm); 30% (0.1% NH4OH/IPA) in CO2) to afford: Intermediate B42,Peak 1; methyl (S)-4-amino-l-(2,6-dichloro-4-(l,2-difluoroethyl)phenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate or methyl (R)-4-amino-l-(2,6-dichloro-4-(l,2- 255 WO 2024/233900 PCT/US2024/028806 difluoroethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (white solid, 250 mg,25.6%). LCMS m/z = 378 [M+H]+.
Intermediate B43,Peak 2; methyl (S)-4-amino-l-(2,6-dichloro-4-(l,2-difluoroethyl)phenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate or methyl (R)-4-amino-l-(2,6-dichloro-4-(l,2-difluoroethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (white solid, 300 mg,30.7%). LCMS m/z = 378 [M+H]+.
Intermediate B44.methyl 4-amino-l-(2-chloro-4-fluoro-6-methylphenyl)-6-oxo-l,6-dihydropyrimi di ne-5 -carb oxyl ate.
OMe OMe F Part 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-fluoro-6- nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate To a solution of l-chloro-2,5-difluoro-3-nitrobenzene (539 mg, 2.75 mmol) in anhydrous MeCN (8 mL) were added methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate Bl, 1.03 g, 2.50 mmol) and K2CO3 (701 mg, 5.00 mmol) and the mixture heated to 80°C for 2 h. The reaction was cooled, poured intoH20 (100 mL) and extracted with EtOAc (4x 30 mL). The combined organics were washed twice with water, brine, dried (MgSO4) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO 40g silica, 0-10% MeOH/DCM) to afford the title compound as a yellow foam (1.29 g, 89%). LCMS m/z = 583 [M+H]+. 256 WO 2024/233900 PCT/US2024/028806 Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-bromo-6-chloro-4- fluorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate A suspension of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-fluoro-6-nitrophenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 1, 1.25 g, 2.15 mmol) and iron powder (811 mg, 12.90 mmol) in MeOH (22 mL)/glacial acetic acid (2 mL) was heated to 50°C for h. The reaction was cooled and residual iron was removed with a magnet. The mixture was poured into H20 (200 mL) and stirred at it for 15 min to generate a precipitate. The precipitate was collected by filtration, washed with H20 (200 mL) and dried to provide a beige powder which was dissolved in MeCN (25 mL). To the was added 48% aqueous HBr (0.61 mL, 5.38 mmol) and the mixture cooled on ice before tert-Butyl nitrite (0.31 mL, 5.mmol) was added and the mixture was stirred at 0°C for 45 min and then CuBr (383 mg, 2.mmol) added at 0 °C and the reaction mixture left in the ice bath to gradually warm to it. Another portion of tBuONO (0.30 mL, 2.58 mmol) was added and stirring continued for 1.h. The mixture was filtered washing with EtOAc and MeOH. The combined organics were evaporated to dryness and the residue dissolved in EtOAc (75 mL) and dilute aqueous HCI (150 mL). The aqueous component was extracted with EtOAc (2x50 mL). The combined organics were washed with saturated aqueous NaHCO3, water, brine, dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by flash chromatography (ISCO 40g silica, 0-100% EtOAc/hex) to give the title compound as a light yellow foam (748 mg, 56% yield over 2 steps). LCMS m/z = 616 [M+H]+.
Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-fluoro-6- methylphenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxylate To a suspension of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-bromo-6-chloro-4- fluorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 2, 505 mg, 0.81 mmol), K2CO3 (224 mg, 1.62 mmol), and Pd(dppf)C12 DCM adduct (40.2 mg, 0.041 mmol) in dioxane (3 mL) was added trimethylboroxine solution (50 wt% in THE, 0.30 mL, 1.mmol). The mixture was purged with N2 for 10 min and heated to 100°C for 90 min. The reaction was cooled, filtered through Celite and washed with EtOAc. The combined organics were evaporated to dryness and the residue purified by flash chromatography (ISCO 40g silica, 0-70% EtOAc/hex) afforded an off-white foam. The foam was dissolved in TFA (3.mL) and heated to 80°C for 1 h. The reaction was then cooled, poured into saturated aqueous NaHCO3 and extracted with EtOAc (3x 25 mL). The combined organics were washed with 257 WO 2024/233900 PCT/US2024/028806 water, brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO 12g silica, 10-80% EtOAc/hex) to afford the title compound as an off-white solid (155 mg, 61% yield over 2 steps). LCMS m/z = 3[M+H]+.
Intermediate B45.methyl 4-amino-l-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate.
Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4-hydroxyphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (1.39 g, 2.44 mmol) and sodium 2-chloro-2,2- difluoroacetate (743 mg, 4.87 mmol) in DMF (15 mL) was added K2CO3 (370 mg, 2.mmol) and the mixture stirred at 60°C for 6 h under N2. The reaction mixture was diluted with H20 (30 mL) and extracted with EtOAc (3x 20mL). The combined organics were washed with brine (2x 20 mL), dried (Na2S04) and evaporated to dryness under reduced pressure. The residue was purified by MPLC (SiO2, 1-50% EtOAc/PE) to give the title compound as a brown solid (657 mg, 43.5%). LCMS m/z = 620 [M+H]+.
Step 2. Synthesis of methyl 4-amino-l-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4- (difluoromethoxy)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (657 mg, 1.06 mmol) in TEA (5 mL) was stirred at 80 °C for 0.5 h. The reaction mixture was concentrated under 258 WO 2024/233900 PCT/US2024/028806 reduced pressure and the pH of the residue was adjusted with NaHCO3 to pH 7-8. The mixture was diluted with H20 (15 mL) and extracted with EtOAc (3x 8 mL). The combined extracts were dried (Na2S04) and evaporated to dryness in vacuo. The residue was purified by MPLC (SiO2, 1-33% EtOAc/PE) to give the title compound as a brown solid (381 mg, 94.7%).
Intermediate B46.(S)-methyl 4-amino-l-(2-chloro-4-(difluoromethyl)-6-methylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate.
Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2-chloro-6-nitrophenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxylate. 259 WO 2024/233900 PCT/US2024/028806 To a solution of 5-bromo-l-chloro-2-fluoro-3-nitrobenzene (5 g, 19.65 mmol) and methyl 4- (bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B1, 8.05 g, 19.65 mmol) in DMSO (15 mL) was added DIPEA (5.08 g, 39.3 mmol) and the mixture stirred at 100°C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (3x 20mL), dried (Na2S04) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a brown oil (12.5 g, 98%). LCMS m/z = 645 [M+H]+.
Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-(hydroxymethyl)-6- nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2-chloro-6-nitrophenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 1, 12.5 g, 19.4 mmol) and tributylstannylmethanol (12.47 g, 38.8 mmol) in dioxane (30 mL) was added Pd(PPh3)4 (1.g, 0.97 mmol) and the mixture was stirred at 100°C for 2 h under N2. The reaction mixture was quenched by addition saturated aqueous KF (20 mL) at 0°C and then extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a brown solid (5.2 g, 45%). LCMS m/z = 5[M+H]+.
Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-formyl-6- nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-(hydroxymethyl)-6- nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 2, 5.2 g, 8.74 mmol) in DCM (2 mL) was added Dess-Martin periodinane (5.56 g, 13.11 mmol) at 0°C and the mixture was stirred at 25°C for l h. The reaction mixture was quenched by addition saturated aqueous NaHCO3 (20 mL) at 0°C and extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow solid (3.6 g, 69%). LCMS m/z = 593 [M+H]+.
Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-(difluoromethyl)-6- nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate. 260 WO 2024/233900 PCT/US2024/028806 To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-formyl-6- nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (3.6 g, 6.07 mmol) in DCM (3 mL) was added DAST (4.89 g, 30.36 mmol) at -78°C and the mixture stirred at 25°C for 3 h under N2. The reaction mixture was quenched by addition saturated aqueous NaHCO3 (15 mL) at 0°C and extracted with DCM (3x 15 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow solid (2.64 g, 71%). LCMS m/z = 615 [M+H]+.
Step 5. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(difluoromethyl)-2-methyl-6- nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-(difluoromethyl)-6- nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 4, 2.6 g, 4.23 mmol) and 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (2.12 g, 8.46 mmol) in dioxane (15 mL) was added XPHOS-PD-G2 (333 mg, 0.423 mmol) and K3PO4 (1.79 g, 8.46 mmol) and the mixture stirred at 80°C for 2 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H20 (15mL) and extracted with EtOAc (3x 15mL), dried (Na2SO4) and concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a white solid (2.2 g, 87%). LCMS m/z = 595 [M+H]+.
Step 6. Synthesis of methyl l-(2-amino-4-(difluoromethyl)-6-methylphenyl)-4-(bis(4- methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(difluoromethyl)-2-methyl-6- nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 5, 2.1 g, 3.53 mmol) in MeOH (15 mL) was added Pd/C (2 g, 3.53 mmol, 10% purity) and the mixture stirred at 25°C for 1 h under H2 (15Psi). The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a yellow solid (1.36 g, 68%). LCMS m/z = 564 [M+H]+.
Step 7. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-(difluoromethyl)-6- methylphenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxylate.
To a solution of methyl l-(2-amino-4-(difluoromethyl)-6-methylphenyl)-4-(bis(4- methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 6, 1.36 g, 2. 261 WO 2024/233900 PCT/US2024/028806 mmol) in MeCN (10 mL) was added CuCl (477 mg, 4.82 mmol), CuC12 (972mg, 7.23 mmol) and isopentyl nitrite (847 mg, 7.23 mmol) and the mixture stirred at 25°C for 1 h under N2. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a light yellow solid (1 g, 71%). LCMS m/z = 584 [M+H]+.
Step 8. Synthesis of (S)-methyl 4-amino-l-(2-chloro-4-(dijluoromethyl)-6-methylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate.
A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-(difluoromethyl)-6- methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 7, 1 g, 1.71 mmol) in TEA (5 mL) was stirred at 80°C for 1 h. The reaction mixture was quenched by addition saturated aqueous NaHCO3 (10 mL) at 0°C and extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure to give racemic methyl 4-amino-1 -(2-chloro-4-(difluoromethyl)-6-methylphenyl)-6-oxo-1,6- dihydropyrimidine-5-carboxylate as a yellow solid (170 mg, 29%). The racemate was separated by SFC (DAICEL CHIRALPAK AS; 250 x 30 mm, 10 pm); 23% MeOH (0.1% NH4OH)) to afford: Peak 1, Intermediate B46.(S)-methyl 4-amino-l-(2-chloro-4-(difluoromethyl)-6- methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (white solid, 407 mg, 23%). LCMS m/z = 344 [M+H]+.
Intermediate B47.Synthesis of methyl 4-amino- l-((S)-2-chloro-6-methyl-4- (tri fluoromethyl )phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate. 262 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-6-nitro-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.
K2CO3 (5.67 g, 41.1 mmol) was added to the mixture of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate Bl, 8.41 g, 20.53 mmol) and l-chloro-2-fluoro-3-nitro-5-(trifluoromethyl)benzene (5 g, 20.53 mmol, 3.11 mL) in DMF (50 mL) was added and the mixture was stirred at 80°C for l h. The mixture was diluted with H20 (200 mL), filtered and extracted with EtOAc (3x 200 mL) to give the title compound as a yellow solid (12.8 g, 98%). LCMS m/z = 633 [M+H]+.
Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-methyl-6-nitro-4- (trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-6-nitro-4- (trifluoromethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 1, 7 g, 11.mmol) in dioxane (30 mL) was added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (8.33 g, 33.2 mmol), XPHOS-PD-G2 (870 mg, 1.11 mmol) and KPO4 (4.69 g, 22.1 mmol) and themixture degassed and purged with N2 (3x) and stirred at 80°C for 12 h under N2. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the 263 WO 2024/233900 PCT/US2024/028806 residue purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a yellow oil (5 g73%). LCMS m/z = 613 [M+H]+.
Step 3. Synthesis of methyl l-(2-amino-6-methyl-4-(trifluoromethyl)phenyl)-4-(bis(4- methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
Fe (7.29 g, 130 mmol) and NH4Cl (6.99 g, 130 mmol) were added to a solution of methyl 4- (bis(4-methoxybenzyl)amino)-l-(2-methyl-6-nitro-4-(trifluoromethyl)phenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Step 2, 8 g, 13.1 mmol) in THF (30 mL), EtOH (30 mL) and H20 (10 mL) and the mixture stirred at 80oC for 2 h. The reaction mixture was filtered and the filtrate evaporated to dryness and the residue purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow solid (4.5 g, 59%). LCMS m/z = 583 [M+H]+.
Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-6-methyl-4- (trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl l-(2-amino-6-methyl-4-(trifluoromethyl)phenyl)-4-(bis(4- methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 3, 4.3 g, 7.mmol) in MeCN (40 mL) was added CuCl (1.46 g, 14.8 mmol), CuC12 (2.98 g, 22.1 mmol) and isopentyl nitrite (2.59 g, 22.1 mmol) and the mixture stirred at 25°C for 1 h. The reaction mixture was diluted with H20 (20mL) and extracted with EtOAc (4x 20 mL). The combined extracts were concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow oil (3.5 g, 78%). LCMS m/z = 602 [M+H]+.
Step 5. Synthesis of methyl 4-amino-l-((S)-2-chloro-6-methyl-4-(trifluoromethyl)phenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate.
A solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-6-methyl-4- (trifluoromethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 4, 1.5 g, 2.mmol) in TFA (2 mL) was stirred at 80oC for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) followed by chiral SFC (DAICEL CHIRALCEL OD, 250 x 30 mm, pm; 15% IP A (0.1% NH40H) in CO2) to afford: 264 WO 2024/233900 PCT/US2024/028806 Peak 2, Intermediate B47.methyl 4-amino-l-((S)-2-chloro-6-methyl-4- (trifluoromethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (white solid, 400 mg, 40%). LCMS m/z = 362 [M+H]+.
Intermediate B48.Synthesis of methyl 4-amino-l-((S)-2-chloro-6-(difluorom ethyl )phenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate.
OMe Step 1. Synthesis of l-(difluoromethyl)-2-fluoro-3-nitrobenzene.
To the mixture of 2-fluoro-3-nitrobenzaldehyde (5 g, 29.6 mmol) in DCM (50 mL) was added DAST (14.30 g, 88.7 mmol) at -78°C under N2 and the mixture stirred at -78°C for 0.10 h for by stirring at 20°C for 0.5 h under N2. The reaction mixture was partitioned betweenDCM (50 mL) and sat. aq. NaHCO3 (50 mL). The aqueous phase was extracted with DCM (3x 50 mL) and the combined organics were dried (Na2S04) and concentrated under reduced. The residue was purified by MPLC (SiO2, 0-16% EtOAc/PE) to give the title compound as a yellow oil (5 g, 88%). 1H NMR (400 MHz, CDCI3) 6: 8.24 (t, 1H), 7.97 (br t, 1H), 7.49 (t, 1H), 7.15-6.88 (m, 1H).
Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-(difluoromethyl)-6- nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate. 265 WO 2024/233900 PCT/US2024/028806 A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5- carboxylate (Intermediate Bl, 3.32 g, 8.11 mmol) and l-(difluoromethyl)-2-fluoro-3- nitrobenzene (Step 1, 3.1 g, 16.2 mmol) in DMSO (40 mL) was added DIPEA (2.10 g, 16.mmol) and the mixture was stirred at 100°C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-33% EtOAc/PE) to give the title compound as a white solid (4.7 g, 99%). LCMS m/z = 581 [M+H]+.
Step 3. Synthesis of methyl l-(2-amino-6-(difluoromethyl)phenyl)-4-(bis(4- methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-(difluoromethyl)-6- nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 2, 4.7 g, 8.10 mmol) in MeOH (2 mL) and THE (2 mL) was added Pd/C (50 mg, 8.10 mmol, 10% purity) and the mixture stirred at 25°C for 1 h under H2 (15 Psi). The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a light yellow solid (4.8 g, crude). LCMS m/z = 551 [M+H]+.
Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-6- (difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl l-(2-amino-6-(difluoromethyl)phenyl)-4-(bis(4- methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 3, 4.8 g, 8.mmol) in MeCN (30 mL) was added CuCl (1.73 g, 17.44 mmol), CuC12 (3.52 g, 26.2 mmol), and a solution of isopentyl nitrite (3.06 g, 26.2 mmol) in MeCN (5 mL) and the mixture was stirred at 20°C for 1 h under N2. The reaction mixture was concentrated under reduced pressure and the residue diluted with H20 (20 mL) and extracted with EtOAc (3x 20mL).The combined extracts were dried (Na2S04) and concentrated under reduced pressure and the residue purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow solid (3.13 g, 63%). LCMS m/z = 570 [M+H]+.
Step 5. Synthesis of methyl 4-amino-l-((S)-2-chloro-6-(difluoromethyl)phenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-6-(difluoromethyl)phenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 4, 3.13 g, 5.49 mmol) in TFA (30 mL) was stirred at 80°C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated 266 WO 2024/233900 PCT/US2024/028806 under reduced pressure and the residue was purified by column chromatography on silica gel (0-100% EtOAc/PE) to give racemic methyl 4-amino-l-(2-chloro-6-(difluorom ethyl )phenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate as a yellow solid (1.76 g, 97%). The racemic material was separated by chiral SEC (DAICEL CHIRALPAK AD, 250 x 30 mm, 10pm);30% IP A (0.1%NH4OH)) to afford: Intermediate B48,Peak 1; methyl 4-amino-l-((S)-2-chloro-6-(difluoromethyl)phenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (white solid, 445 mg, 44%). LCMS m/z = 3[M+H]+.
Intermediate B49.methyl 4-amino-l-(2,6-dichloro-4-(2-methoxyethyl)phenyl)-6-oxo-l,6-dihydropyrimi di ne-5 -carb oxyl ate.
Step 1. Synthesis of l-chloro-2-fluoro-3-nitro-5-vinylbenzene.
To the mixture of 5-bromo-l-chloro-2-fluoro-3-nitrobenzene (8 g, 31.4 mmol) and 4,4,5,5- tetramethyl-2-vinyl-l,3,2-dioxaborolane (7.26 g, 47.2 mmol) in dioxane (80 mL) and H 267 WO 2024/233900 PCT/US2024/028806 (10 mL) was added K2CO3 (8.69 g, 62.8 mmol) and Pd(dppf)C12 (2.30 g, 3.14 mmol) ans the mixture stirred at 100°C for 2 h under N2. The solid were removed by filtration and the filtrate concentrated under reduced pressure and the residue purified by MPLC (SiO2, 0-16% EtOAc/PE) to give the title compound as a yellow oil (4.2 g, 66%). 1H NMR (400 MHz, CDCh) 5: 7.87 (dd, 1H), 7.64 (dd, 1H), 6.57 (dd, 1H), 5.75 (d, 1H), 5.41 (d, 1H).
Step 2. Synthesis of 2-(3-chloro-4-fluoro-5-nitrophenyl)ethan-l-ol.
To the mixture of l-chloro-2-fluoro-3-nitro-5-vinylbenzene (Step 2, 2.1 g, 10.42 mmol) in THE (20 mL) was added 9-BBN (0.5 M, 62.5 mL) at 0°C and the mixture stirred at 20°C for h under N2. The pH of the reaction mixture was adjusted to pH 10 by the addition of NaOH (IM, 36.46 mL, 3.5 eq) at 0°C. To this was added HO2 (10.87 g, 0.096 mmol, 9.mL, 30% purity) under N2 and the resulting mixture stirred at 20°C for 2 h under N2. The mixture was added to sat. aq. Na2S03 (50 mL) at 0°C and extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure and the residue purified by MPLC (SiO2, 0-50% EtOAc/PE) to give the title compound as a yellow oil (700 mg, 30%). 1H NMR (400 MHz, CDCh) 5: 7.77 (dd, 1H,), 7.54 (dd, 1H), 3.(t, 2H), 2.83 (t, 2H).
Step 3. Synthesis of l-chloro-2-fluoro-5-(2-methoxyethyl)-3-nitrobenzene.
To a mixture of 2-(3-chloro-4-fluoro-5-nitrophenyl)ethan-l-ol (1.3 g, 5.92 mmol) in CHC(15 mL) was added trimethyloxonium tetrafluoroborate (3.5 g, 23.7 mmol) and the stirred at 40°C for l h. The reaction mixture was partitioned between EtOAc (20 mL) and sat. aq. NaHCO3 (15 mL) and the aqueous phase was extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure to give a residue which was purified by MPLC (SiO2, 0-33% EtOAc/PE) to give the title compound as a yellow oil (700 mg, 50%). 1H NMR (400 MHz, CDC13) 6: 7.86 (dd, 1H), 7.63 (td, 1H), 3.65 (t, 2H), 3.38 (s, 3H), 2.95-2.87 (m, 2H).
Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-(2-methoxyethyl)- 6-nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To the mixture of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5- carboxylate (Intermediate Bl, 1 g, 2.44 mmol) and l-chloro-2-fluoro-5-(2-methoxyethyl)-3- nitrobenzene (Step 3, 570 mg, 2.44 mmol) in DMF (6 mL) was added KCO3 (675 mg, 4.mmol) and the mixture stirred at 80oC for l h. The mixture was filtered and the filtrate 268 WO 2024/233900 PCT/US2024/028806 evaporated to dryness in vacuo and the residue partitioned between EtOAc (20 mL) and H(15 mL) and the aqueous was extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure and the residue purified by MPLC (SiO2, 0-66% EtOAc/PE) to give the title compound as a yellow oil (1.1 g, 1.mmol, 72.29% yield) as a yellow oil. LCMS m/z = 623 [M+H]+.
Step 5. Synthesis of methyl l-(2-amino-6-chloro-4-(2-methoxyethyl)phenyl)-4-(bis(4- methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
Fe (968 mg, 17.3 mmol) and NHCl (927 mg, 17.3 mmol) were added to a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-(2-methoxyethyl)-6-nitrophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Step 4, 1.08 g, 1.73 mmol) in THE (8 mL), EtOH (8 mL) and H20 (3 mL) and stirred at 70°C for 2 h. The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was treated with DCM (10 mL), filtered and concentrated under reduced pressure to give the title compound as a yellow oil (1.0 g, crude). LCMS m/z = 593 [M+H]+.
Step 6. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4-(2- methoxyethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl l-(2-amino-6-chloro-4-(2-methoxyethyl)phenyl)-4-(bis(4- methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 5, 950 mg, 1.mmol) in MeCN (15 mL) was added CuC12 (646 mg, 4.81 mmol), CuCl (317 mg, 3.mmol). To this was added dropwise a solution of isopentyl nitrite (563 mg, 4.81 mmol) in MeCN (2 mL) and the mixture stirred at 20°C for l h. The reaction mixture was partitioned between EtOAc (20 mL) and H20 (15 mL) and the aqueous phase extracted with EtOAc (3x mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue purified by MPLC (SiO2, 0-100% EtOAc/PE) to give the title compound as a yellow oil (700 mg, 71%). LCMS m/z = 612 [M+H]+.
Step 7. Synthesis of methyl 4-amino-l-(2,6-dichloro-4-(2-methoxyethyl)phenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
A solutio of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dichloro-4-(2- methoxyethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (680 mg, 1.11 mmol) in TFA (5 mL) was stirred at 80°C for 0.5 hr. The mixture was concentrated under reduced pressure and the residue partitioned between EtOAc (20 mL) and sat. aq. NaHCO3 (15 mL). 269 WO 2024/233900 PCT/US2024/028806 The aqueous phase was extracted with EtOAc (3x 20 mL) and the combined organics dried (Na2SO4), concentrated under reduced pressure and the residue purified by MPLC (SiO2, 0- 100% EtOAc/PE) to give the title compound as a brown solid (350 mg, 84%). LCMS m/z = 372 [M+H]+.
Intermediate B50.methyl 4-amino-l-(4-fluoro-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate.
Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-fluoro-6- nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of l-chloro-2,5-difluoro-3-nitrobenzene (1.156 g, 6.0 mmol) in anhydrous MeCN (20 mL) were added methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate Bl, 2.71 g, 6.6 mmol) and K2CO3 (1.70 g, 12.0 mmol) and the reaction heated to 80°C overnight. The reaction was poured into 200 mL water and extracted with EtOAc (4x 75 mL). The combined organics were washed twice with water, brine, dried (MgSO4) and concentrated by rotary evaporation. Flash chromatography (ISCO 40g silica, 0-80% EtOAc/hex) provided the title compound as a yellow foam (3.286 g, 94%). LCMS m/z = 583 [M+H]+.
Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-bromo-6-chloro-4- fluorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
A suspension of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-4-fluoro-6-nitrophenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 1, 3.286 g, 5.65 mmol) and iron powder 270 WO 2024/233900 PCT/US2024/028806 (2.02 g, 33.9 mmol) in MeOH (33 mL)/glacial acetic acid (6 mL) was heated to 50°C overnight. The reaction was then cooled and residual iron was removed with a magnet. The mixture was poured into 250 mL water and stirred at room temp for 15 minutes to generate a precipitate. The precipitate was collected by filtration, washing with 150 mL water and dried to provide a yellow powder which was used without purification. LCMS m/z = 5[M+Na]+.
A solution of the crude methyl l-(2-amino-6-chloro-4-fluorophenyl)-4-(bis(4- methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (5.65 mmol) in MeCN (55 mL) and 48% aqueous HBr (1.60 mL, 14.1 mmol) was cooled on ice. Sodum nitrite (4mg, 6.78 mmol) was added and the mixture was stirred at 0°C for 75 minutes before CuBr (979 mg, 6.78 mmol) was added at 0°C. The reaction mixture was stirred for 3 h leaving in the ice bath to gradually warm to RT. The mixture was filtered to remove copper salts, washing w/EtOAc and MeOH. The combined organics were concentrated by rotary evaporation. The crude residue was dissolved in EtOAc (150 mL) and dilute aqueous HCI (200 mL). The aqueous phase was extracted with EtOAc (2x 50 mL). The combined organics were washed with saturated aqueous NaHCO3, water, brine, dried (MgSO4) and evaporated to dryness. The residue was purified by flash chromatography (ISCO 40g silica, 0-100% EtOAc/hex,) to afford the title compound as a light yellow foam (1.641 g, 47% yield over 2 steps). The material was carried on to the next step without further purification. LCMS m/z = 616 [M+H]+.
Step 3. Synthesis of methyl 4-amino-l-(4-fluoro-2,6-dimethylphenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
To a suspension of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-bromo-6-chloro-4- fluorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 2, 1.64 g, 2.65 mmol), K3PO4 (1.703 g, 7.95 mmol), and Xphos Pd G3 (223 mg, 0.265 mmol) in dioxane (10 mL) was added trimethylboroxine solution (50 wt% in THE, 1.90 mL, 6.63 mmol) and the mixture was purged with N2 for 10 min and heated to 80°C for 16 h. The reaction was filtered through Celite and washed with EtOAc. The combined organics were evaporated to dryness and the residue purified by flash chromatography (ISCO 40g silica, 0-100% EtOAc/hex) to give a viscous amber oil. The oil was dissolved in TFA (6 mL) and heated to 80°C for l h, cooled, poured into saturated aqueous NaHCO3 and extracted with EtOAc (3x 30 mL). The combined organics were washed with water, brine, dried (MgSO4) and concentrated by rotary 271 WO 2024/233900 PCT/US2024/028806 evaporation. The residue was purified by flash chromatography (ISCO 24g silica, 0-10% MeOH/DCM) to afford the title compound as a light yellow powder (767 mg, 79% yield over steps). LCMS m/z = 292 [M+H]+.
Intermediate B51.methyl 4-amino-l-(4-(l-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate.
Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(l-ethoxyvinyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2,6-dimethylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B18 Step 3, 3.5 g, 5.91 mmol),tributyl(!-ethoxyvinyl)stannane (3.20 g, 8.86 mmol), Pd(PPh3)4 (683 mg, 0.591 mmol) in dioxane (15 mL) was degassed and purged with N2 (3x) and the mixture stirred at 80°C for h under N2. The reaction mixture was quenched by addition saturated aqueous KF solution (30 mL) at 0°C and extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure to give the title compound as a brown oil (3 g, crude). LCMS m/z = 584 [M+H]+.
T11 WO 2024/233900 PCT/US2024/028806 Step 2. Synthesis of methyl l-(4-acetyl-2,6-dimethylphenyl)-4-(bis(4-methoxybenzyl)amino)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(l-ethoxyvinyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 1, 3 g, 5.14 mmo) in THE (10 mL) was added aqueous citric acid solution (2 M, 50 mL) and the mixture stirred at 25°C for 2 h. The reaction mixture was diluted with H20 (50 mL) and extracted with EtOAc (3x mL). The combined organics were washed with brine (2x 30 mL), dried (Na2S04) and concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 0-66% EtOAc/PE) to give the title compound as a yellow solid (10.2 g, crude). LCMS m/z = 556 [M+H]+.
Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(l-hydroxyethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a mixture of methyl l-(4-acetyl-2,6-dimethylphenyl)-4-(bis(4-methoxybenzyl)amino)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Step 2, 10 g, 9.00 mmol) in MeOH (100 mL) was added NaBH4 (2.04 g, 54 mmol, 6 eq) at 0°C and the mixture stirred at 0°C for 20 min. The reaction mixture was quenched by addition IM HCI (10 ml) at 0°C basified with Na2CO3 aq. and extracted with EtOAc (4x 50 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure. The residue was purified by prep-HPLC-27 (50-80% MeCN) to give the title compound as a white solid (1 g, 20%). LCMS m/z = 558 [M+H]+.
Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(l-methoxyethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(l-hydroxyethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 3, 300 mg, 0.538 mmol) in THE (6 mL) was added NaOH (32.3 mg, 0.81 mmol) and dimethyl sulfate (679mg, 5.mmol) and the mixture stirred at 25°C for 12 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3x 20 mL), dried (Na2S04) and concentrated under reduced pressure. The residue was purified by prep-HPLC-1 1 (35-65% MeCN) to give the title compound as a white solid (150 mg, 49%). LCMS m/z = 572 [M+H]+.
Step 5. Synthesis of methyl 4-amino-l-(4-(I -methoxy ethyl)-2,6-dimethylphenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
T73 WO 2024/233900 PCT/US2024/028806 A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(l-methoxyethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 4, 140 mg, 0.245 mmol) in TFA (2.5 mL) was stirred at 50°C for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue dissolved in THE and the pH adjusted to pH 9-11 with aqueous NaHCO3 and concentrated under reduced pressure. The residue was purified by prep-HPLC-11 (10-40% MeCN) to give the title compound as a white solid (60 mg, 74%). LCMS m/z = 332 [M+H]+.
Intermediate B52.methyl 4-amino-l-(3,5-dichloropyridin-4-yl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate.
Step 1. Synthesis of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-l-(3,5-dichloropyridin-4-yl)- 6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5- carboxylate (Intermediate B2, 2 g, 4.26 mmol) and 3,5-dichloro-4-fluoropyridine (1.06 g, 6.39 mmol) in DMF (10 mL) was added K2CO3 (1.18 g, 8.52 mmol) and the mixture stirred at 80°C for l h. The reaction mixture was concentrated under reduced pressure and the residue diluted with H20 (50 mL) and extracted with EtOAc (3x 40mL). The combined organics were washed with brine (2x 30 mL), dried (Na2S04) and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, 1-100% EtOAc/PE) to give the title compound as a white solid (2.3 g, 87%). LCMS m/z = 615 [M+H]+.
Step 2. Synthesis of methyl 4-amino-l-(3,5-dichloropyridin-4-yl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-l-(3,5-dichloropyridin-4-yl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 2.3 g, 3.74 mmol) in TFA (3 mL) and 274 N 0CH /X /Cl WO 2024/233900 PCT/US2024/028806 DCM (20 mL) was stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure and the residue diluted with H20 (50 mL) and extracted with EtOAc (3x 40mL). The combined organics were washed with brine (2x 30 mL), dried (Na2S04) and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, 1-50%EtOAc/PE) to give the title compound as a white solid (942 mg, 80% yield). LCMS m/z = 315 [M+H]+.
Intermediate B53.methyl 4-amino-l-(2,6-dimethyl-4-((methylsulfonyl)methyl)phenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate.
Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(hydroxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-bromo-2,6-dimethylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B18 Step 3, 2.00 g, 3.38 mmol) in dioxane (100 mL) was added cataCXium® A Pd G2 (226 mg, 0.338 mmol) andtributylstannylmethanol (4.34 g, 13.5 mmol) at 0°C and the reaction mixture stirred at 110°C for 12 h under N2. The reaction mixture was filtered and the filtrate was concentrated under 275 WO 2024/233900 PCT/US2024/028806 reduced pressure and the residue was purified by column chromatography (SiO2, 0-100% EtOAc/PE) to give the title compound as a black solid (1.80 g, 98%). LCMS m/z = 5[M+H]+.
Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dimethyl-4- ((f1ethylsulfonyl)oxy)methyl)phenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxylate.
To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-l-(4-(hydroxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 1, 500 mg, 0.92 mmol) in DCM (10 mL) was added TEA (186 mg, 1.84 mmol) and MsCl (220 mg, 1.92 mmol) at 0°C and the reaction mixture stirred at 25°C for 30 mins. The reaction mixture was quenched with sat. aq. NaHCO3 (2 mL) and H20 (8 mL) and extracted with DCM (3x 10 mL). The combined organics were washed with brine (10 mL) and dried (Na2S04) and concentrated to give the title compound as a yellow oil (570 mg, crude) which was used without further purification.
Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dimethyl-4- ((methylsulfonyl)methyl)phenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dimethyl-4- (((methylsulfonyl)oxy)methyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 2, 200 mg, 0.322 mmol) in DMF (1 mL) was added sodium methanesulfinate (131 mg, 1.mmol) and the mixture stirred at 100°C for 1.5 h. The reaction mixture was extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure to give the title compound as a white solid (190 mg, crude). LCMS m/z = 606 [M+H]+.
Step 4. Synthesis of methyl 4-amino-l-(2,6-dimethyl-4-((methylsulfonyl)methyl)phenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate.
A solution of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2,6-dimethyl-4- ((methylsulfonyl)methyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (180 mg, 0.2mmol) in TEA (2 mL) was stirred at RT. The reaction mixture was concentrated under reduced pressure and the residue was extracted with DCM (3x 10 mL). The combined organics were dried (Na2SO4) and evaporated to dryness. The residue was purified by prep- TLC (10% EtOAc/MeOH) to give the title compound as a yellow oil (90 mg, 83%). LCMS m/z = 366 [M+H]+. 276 WO 2024/233900 PCT/US2024/028806 Intermediate B54.methyl (R)-4-amino-l-(4-(l-fluoroethyl)-2,6-dimethylphenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxylate or methyl (S)-4-amino-l-(4-(l-fluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
Step 1. Synthesis of methyl 4-amino-l-(4-(l-ethoxyvinyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate.
A mixture of methyl 4-amino-l-(4-bromo-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B34, 3 g, 8.52 mmol) tributyl(!- ethoxyvinyl)stannane (4.61 g, 12.8 mmol) , Pd(PPh3)4 (984 mg, 0.85 mmol) in dioxane (mL) was degassed and purged with N2 (x3) and the mixture stirred at 80°C for 12 h under N2. The reaction mixture was quenched by addition saturated aqueous KF solution (30 mL) at 0°C and then extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a yellow solid (2 g, 68%). LCMS m/z = 344 [M+H]+.
Step 2. Synthesis of methyl l-(4-acetyl-2,6-dimethylphenyl)-4-amino-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
A mixture of methyl 4-amino-l-(4-(l-ethoxyvinyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Step 1, 2 g, 5.82 mmol), citric acid (2 M, 75 mL) in THF (15 mL) was degassed and the mixture stirred at 25 °C for 40 min. The reaction mixture was concentrated under reduced pressure and the residue diluted with H20 (10 mL) and extracted Til WO 2024/233900 PCT/US2024/028806 with EtOAc (3x 10 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure to give the title compound as a white solid (3.60 g, 98%). LCMS m/z = 316 [M+H]+.
Step 3. Synthesis of methyl 4-amino-l-(4-(l-hydroxyethyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate.
To a mixture of methyl l-(4-acetyl-2,6-dimethylphenyl)-4-amino-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B54 Step 2, 1.50 g, 4.76 mmol) in MeOH (mL) was added NaBH4 (360 mg, 9.51 mmol) at 0°C, and then the mixture was stirred at 0°C for 2 min. The reaction was quenched with aq. Na2CO3 (10 mL) until pH=10 and the mixture was extracted with EtOAc (4x 10 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-HPLC (C18; 250 x mm, 10 pm); 10-35% MeCN/H2O (NH4HCO3)) to give the title compound as a white solid (1.00 g, 33%). LCMS m/z = 318 [M+H]+.
Step 4. Synthesis of methyl (R)-4-amino-l-(4-(I -fluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6- dihydropyrimidine-5-carboxylate or methyl (S)-4-amino-l-(4-(l-fluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate To a solution of methyl 4-amino-l-(4-(l-hydroxyethyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Step 3, 410 mg, 1.29 mmol) in DCM (8 mL) was added DAST (479 mg, 2.97 mmol) at -78°C under N2 and the mixture stirred at -78°C for 3 h and 25°C for 9 h. The reaction mixture was quenched by addition saturated NaHCO3 (30 mL) at 0°C and extracted with EtOAc (3x 30 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue separated by SEC (DAICEL CHIRALCEL OJ, 250 x 30 mm,10 pm); 20% IP A (0.1% NH4OH)) to afford: Peak 2, Intermediate B54:methyl (R)-4-amino-l-(4-(l-fluoroethyl)-2,6-dimethylphenyl)-6- 0x0-1,6-dihydropyrimidine-5-carboxylate or methyl (S)-4-amino-l-(4-(l-fluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (white solid, 190 mg, 46%); LCMS m/z = 320 [M+H]+.
Intermediate B55.Synthesis of methyl 4-amino-l-(4-(l,l-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate. 278 WO 2024/233900 PCT/US2024/028806 A solution of methyl l-(4-acetyl-2,6-dimethylphenyl)-4-amino-6-oxo-l,6-dihydropyrimidine- 5-carboxylate (Intermediate B54, Step 2; 120 mg, 0.38 mmol) in DAST (4 mL) was stirred at 45°C for 12 h under N2. The reaction mixture was quenched by addition of sat aq NH4C1 (15mL) at 0°C and then extracted with EtOAc (3x 20 mL). The combined organics were washed with brine (10 mL), dried (Na2S04) and concentrated under reduced pressure. The residue was purified by TLC (100% EtOAc 1) to give the title compound as a yellow solid (80 mg, 62%). LCMS m/z = 338 [M+H]+.
Intermediate B56.methyl 4-amino-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-thioxo-l,6-dihydropyrimidine-5-carboxylate.
Step 1. Synthesis of methyl 4-(bis(tert-butoxycarbonyl)amino)-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate To a suspension of methyl 4-amino-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B24, 607 mg, 1.76 mmol) in THE (9 mL) were added DMAP (21.4 mg, 0.176 mmol), triethylamine (0.50 mL, 3.52 mmol), and BocO (1.085 g, 5.28 mmol) sequentially at RT. The reaction mixture was stirred at RT for 5 h. The reaction was diluted with EtOAc (50 mL) and washed with water, saturated aqueous NaHCO3, brine, dried (MgSO4) and concentrated by rotary evaporation. Flash 279 WO 2024/233900 PCT/US2024/028806 chromatography (ISCO 24g silica, 0-80% EtOAc/Hex) provided the title compound as a yellow solid (755 mg, 79%). LCMS m/z = 542 [M+H]+.
Step 2. Synthesis of methyl 4-amino-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-thioxo-l, 6- dihydropyrimidine-5-carboxylate.
A suspension of methyl 4-(bis(tert-butoxycarbonyl)amino)-l-(2,6-dimethyl-4- (trifluoromethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 1, 412 mg, 0.mmol) and Lawesson's reagent (308 mg, 0.76 mmol) in anhydrous toluene (3 mL) was heated to 110°C for 24 h. The reaction was cooled, diluted with EtOAc (40 mL) and washed with dilute aqueous HCI, water and brine. The organics were dried (MgSO4) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO 24g silica, 0- 65% EtOAc/hex) to afford a mixture of Boc-protected intermediates as a yellow foam (3mg). The yellow foam (366 mg) was dissolved in DCM (4 mL) and TEA (1 mL) and stirred at RT for 2 h. The reaction was poured into saturated aqueous NaHCO3 and extracted with DCM (3x 15 mL). The combined organics were washed with water and brine, dried over (MgSO4) and concentrated by rotary evaporation. Flash chromatography (ISCO 24g silica, 0-100% EtOAc/hex) provided the title compound as a yellow solid (63.5 mg, 23% yield over steps). LCMS m/z = 358 [M+H]+.
Intermediate B57.methyl 4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-thioxo- l,6-dihydropyrimidine-5-carboxylate.
Step 1. Synthesis of methyl 4-(bis(tert-butoxycarbonyl)amino)-l-(4-(methoxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate.
To a solution of methyl 4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B22, 53.6 mg, 0.170 mmol) in THF (2 mL) were added sequentially at RT, DMAP (3.1 mg, 0.017 mmol), triethylamine (48 pL, 0.3 280 WO 2024/233900 PCT/US2024/028806 mmol) and B0C20 (113 mg, 0.510 mmol) and the reaction was stirred at RT overnight. The reaction mixture was evaporated to dryness and the residue purified by flash chromatography (ISCO, 4g silica, 0-100% EtOAc/Hex) to provide the title compound as a white solid (77.mg, 88%). LCMS m/z = 518 [M+H]+.
Step 2. Synthesis of methyl 4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-thioxo-l, 6- dihydropyrimidine-5-carboxylate.
A suspension of methyl 4-(bis(tert-butoxycarbonyl)amino)-l-(4-(methoxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Step 1, 77.8 mg, 0.150 mmol) and Lawesson's reagent (61.7 mg, 0.150 mmol) in anhydrous toluene (0.75 mL) was heated to 110°C for 19 h. The reaction was cooled, diluted with EtOAc (30 mL), washed with dilute aqueous HCI, water and brine (2x). The combined organics were dried (MgSO4) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO 4g silica, 0-75% EtOAc/hex) provided a yellow oil. The yellow oil was dissolved in DCM (2 mL) and TEA (0.5 mL) and stirred at RT for 2 h. The reaction was poured into saturated aqueous NaHCO3 and extracted with DCM (3x 10 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated by rotary evaporation. Flash chromatography (ISCO 4g silica, 0-100% EtOAc/hex) to afford the title compound as a yellow solid (13.3 mg, 26% yield over 2 steps). LCMS m/z = 334 [M+H]+.
Intermediate B58.Synthesis of methyl 4-amino-l-(4-ethyl-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate.
The title compound was prepared from methyl 4-amino-l-(4-bromo-2,6-dimethylphenyl)-6- 0x0-1,6-dihydropyrimidine-5-carboxylate (Intermediate B34) using an analogous method to that described for Intermediate B35. LCMS m/z = 288 [M+H]+.
Intermediate B59.methyl 4-amino-l-(2-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxylate. 281 WO 2024/233900 PCT/US2024/028806 OMe Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-methoxyphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate.
To methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate BP1491664 A1(Intermediate Bl, 400 mg, 0.977 mmol) and (2-methoxyphenyl)boronic acid (445 mg, 2.93 mmol) in DMF (4.00 mL) was added pyridine (232 mg, 2.93 mmol) and Cu(OAc)2 (266 mg, 1.47 mmol) and the mixture stirred at 100 °C for 12 h under 02 (15 psi). The mixture was filtered, the filtrate concentrated under reduced pressure and the residue purified by MPLC (SiO2, 0-50% EtOAc/PE/EtOAc) to give the title compound as a yellow solid (230 mg, crude). LCMS m/z = 516 [M+H]+.
Step 2. Synthesis of methyl 4-amino-l-(2-methoxyphenyl)-6-oxo-l, 6-dihydropyrimidine-5- carboxylate.
Methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine- 5-carboxylate (Step 1, 230 mg, 0.446 mmol) in TFA (3 mL) was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue partitioned between EtOAc (3 mL) and saturated aqueous Na2CO3 solution (5 mL) at 0 °C. The aqueous was extracted with EtOAc (3x 5 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure. The residue was purified by prep-TLC (100% EtOAc) to give the title compound (110 mg, 89%) as an off-white solid. LCMS m/z = 276 [M+H]+.
Intermediate B60.methyl 4-amino-l-(2-chloro-6-hydroxyphenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxyl ate. 282 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-6-nitrophenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate The title compound was prepared as a yellow oil (2.3 g, 83%) from methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate Bl) and 1- chloro-2-fluoro-3-nitro-benzene using an analogous method to that described for Intermediate B4, Step 1. LCMS m/z = 565 [M+H]+.
Step 2. Synthesis of methyl l-(2-amino-6-chlorophenyl)-4-(bis(4-methoxybenzyl)amino)-6- oxo-1,6-dihydropyrimidine-5-carboxylate.
The title compound was prepared as a yellow oil (2.03 g, 93%) from methyl 4-(bis(4- methoxybenzyl)amino)-l-(2-chloro-6-nitrophenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxylate (Step 1) using an analogous method to that described for Intermediate B3, Step 2. LCMS m/z = 535 [M+H]+.
Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-bromo-6-chlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.
The title compound was prepared as a yellow solid (700 mg, 31%) from methyl l-(2-amino-6-chlorophenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-l,6-dihydropyrimidine-5-carboxylate 283 WO 2024/233900 PCT/US2024/028806 (Step 2) using an analogous method to that described for Intermediate B4, Step 4. LCMS m/z = 600 [M+H]+.
Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-l-(2-chloro-6-hydroxyphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate.
The title compound was prepared as a yellow oil (170 mg, 53%) from methyl 4-(bis(4- methoxybenzyl)amino)-l-(2-bromo-6-chlorophenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxylate (Step 3) using an analogous method as described for Intermediate B25, Step 4. LCMS m/z = 536 [M+H]+.
Step 5. Synthesis of methyl 4-amino-l-(2-chloro-6-hydroxyphenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxylate.
The title compound was prepared as an oil (40m mg, 43%) from methyl 4-(bis(4- methoxybenzyl)amino)-l-(2-chloro-6-hydroxyphenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxylate (Step 4) using an analogous method as described for Intermediate B7, Step 2. LCMS m/z = 296 [M+H]+.
Example 1.Synthesis of (S)-4-amino-N-(3-(l-amino-2-methoxyethyl)phenyl)-l-((S)-2- chloro-4-methoxy-6-methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide.
OMe AlMez (2 M in toluene, 69.5 pL) was added to a mixture of methyl 4-amino-l-((S)- 2-chloro- 4-methoxy-6-methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B4, mg, 0.046 mmol) and (S)-3-(l-amino-2-m ethoxy ethyl)aniline (Intermediate Al, 10.78 mg, 0.065 mmol) in toluene (3 mL) at 0°C and the mixture stirred at 0°C for 5 min. The mixture was stirred at 100°C for l h under N2. The reaction mixture was treated with H20 (0.2 mL) and TFA (0.2 mL) at 0°C concentrated under reduced pressure. The residue was purified by prep-HPLC-2 (10-45% MeCN) to give the title compound as a white solid (9.4 mg, 44%). LCMS m/z = 458 [M+H]+; 1HNMR (400 MHz, CDCI3): 11.80 (s, 1H), 10.07 (d, 1H), 7.284 WO 2024/233900 PCT/US2024/028806 (s, 1H), 7.66 (s, 1H), 7.57 (d, 1H), 7.32-7.29 (m, 1H), 7.13 (d, 1H), 6.99 (d, 1H), 6.85 (d, 1H), 5.95 (d, 1H), 4.20 (dd, 1H), 3.87 (s, 3H), 3.55 (dd, 1H), 3.45 (d, 1H), 3.40 (s, 3H), 2.23 (s, 3H).
Example 2.Synthesis of (R)-4-amino-l-((S)-2-chloro-4-methoxy-6-methylphenyl)-N-(3-(l- (methylamino)ethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide.
AlMez (2 M in toluene, 46.3 pL) was added to a solution of methyl 4-amino-l-((S)-2-chloro- 4-methoxy-6-methyl-phenyl)-6-oxo-pyrimidine-5-carboxylate (Intermediate B4, 10 mg, 0.031 mmol) and (R)-3-(l-(methylamino)ethyl)aniline (Intermediate A2, 6.96 mg, 0.04mmol) in toluene (1 mL) and THE (0.5 mL) at 0°C under N2 and the mixture was stirred at 40°C for 1 h under N2. The reaction mixture was quenched with 10% NaOH solution (5 mL) at 0°C and extracted with EtOAc (3x 3 mL). The combined organics were dried (Na2S04) and evaporated to dryness in vacuo. The residue was purified by prep-HPLC-1 (5-45% MeCN) to give the title compound as a yellow oil (8.1 mg, 53%) as yellow oil. LCMS m/z = 442 [M+H]+; 1HNMR (400 MHz, DMSO-d6): 11.96 (s, 1H), 9.67 (d, 1H), 8.55 (d, 1H), 8.(s, 1H), 8.29 (s, 1H), 7.63-7.63 (m, 1H), 7.65 (d, 1H), 7.48 (s, 1H), 7.30 (t, 1H), 7.09-7.04 (m, 2H), 3.86 (s, 3H), 3.74-3.65 (m, 1H), 2.18 (s, 3H), 2.15 (s, 3H), 2.10 (s, 1H), 1.29 (d, 3H).
Example 3-32.
The title compounds were prepared using an analogous method to that described for Example Example Example Name, Reactants, HPLC, DataNo 285 WO 2024/233900 PCT/US2024/028806 3 (R)-4-amino-l-((S)-2-chloro-6-methylphenyl)-N-(3-(l- (methylamino)ethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B3, Intermediate A2HPLC-1 (10-44% MeCN); Pale yellow solid (4.4 mg, 10%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, DMSO-d6): 11.91 (s, 1H), 9.68 (d, 1H), 8.58 (d, 1H), 8.33-8.31 (m, 2H), 7.65 (d, 1H), 7.58-7.56 (m, 1H), 7.52-7.50 (m, 1H), 7.47-7.45 (m, 2H), 7.29 (t, 1H), 7.06 (d, 1H), 3.70 (d, 1H), 2.19 (d, 6H, J), 1.(d, 3H).(R)-4-amino-l-((S)-2-chloro-4-methoxy-6-methylphenyl)-N-(5-(l-((methyl- d3)amino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-l-((S)-2-chloro-4-methoxy-6-methylphenyl)-N-(5-(l-((methyl- d3)amino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B4, Intermediate A54HPLC-1 (1-40% MeCN); White solid (29.9 mg, 49%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.98 (s, 1H), 9.98 (br d, 1H), 8.68 (d, 1H), 8.31-8.37 (m, 2H), 7.76 (s, 1H), 6.99 (d, 1H), 6.85 (d, 1H), 6.06 (br d, 1H), 3.94 (q, 1H), 3.87 (s, 3H), 2.23 (s, 3H), 1.58 (d, 3H).4-amino-l-(2,6-dichlorophenyl)-N-(5-((ethylamino)methyl)pyridin-3-yl)-6-oxo- l,6-dihydropyrimidine-5-carboxamideIntermediate B9, Intermediate A12HPLC-1 (3-35% MeCN); White solid (2.5 mg, 9%); LCMS m/z = 433 [M+H]+; 1HNMR (400 MHz, CDCI3): 11.78 (s, 1H), 10.00 (s, 1H), 8.61 (d, 1H), 8.44 (s, 1H), 8.38 (s, 1H), 7.74-7.72 (m, 1H), 7.56-7.54 (m, 2H), 7.47-7.43 (m, 1H), 6.(s, 1H), 4.00 (s, 2H), 2.87 (q, 2H), 1.26 (t, 3H).(R)-4-amino-l-(2,6-dichlorophenyl)-N-(3-fluoro-5-(l- (methylamino)ethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide tri fluoroacetateIntermediate B9, Intermediate A67HPLC-10 (20-50% MeCN); White solid (19.4 mg, 23%); LCMS m/z = 4[M+H]+; 1HNMR (500 MHz, DMSO-d6): 12.02 (s, 1H), 9.53 (d, 1H), 8.86 (s, 1H), 8.74 (d, 1H), 8.66 (s, 1H), 8.41 (s, 1H), 7.82 (dt, 1H), 7.71-7.68 (m, 2H), 7.57 (t, 1H), 7.25 (s, 1H), 6.97 (d, 1H), 4.20 (q, 1H), 2.36 (t, 3H), 1.43 (d, 3H). 286 WO 2024/233900 PCT/US2024/028806 7 (S)-4-amino-N-(3-(l-amino-2-methoxy ethyl )phenyl)-l-((S)-2-chl oro-6- (difluoromethyl )phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B48, Intermediate AlHPLC-1 (1-45% MeCN); White solid (3.4 mg, 14%); LCMS m/z = 464 [M+H]+; 1HNMR (400 MHz, CDCI3): 11.57 (s, 1H), 10.12 (d, 1H), 7.84-7.69 (m, 3H), 7.69-7.57 (m, 2H), 7.53 (d, 1H), 7.34-7.29 (m, 1H), 7.14 (d, 1H), 6.86-6.45 (m, 1H), 6.10 (d, 1H), 4.22 (dd, 1H), 3.60-3.54 (m, 1H), 3.53-3.45 (m, 1H), 3.39 (s, 3H).(R)-4-amino-N-(3-(l-aminoethyl)phenyl)-l-((S)-2-chloro-4-cyano-6- methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate Bl3, Intermediate A: (R)-3-(l-aminoethyl)anilineHPLC-2 (8-40%); Pale yellow solid (3.8 mg, 9%); LCMS m/z = 406 [M+H]+; 1HNMR (400 MHz, DMSO-d6): 11.78 (s, 1H), 9.71 (d, 1H), 8.68 (d, 1H), 8.38- 8.34 (m, 1H), 8.25 (d, 1H), 8.03 (d, 1H), 7.69-7.65 (m, 1H), 7.50 (s, 1H), 7.29 (t, 1H), 7.11 (d, 1H), 4.11 (q, 1H), 2.24 (s, 3H), 1.33 (d, 3H).(R)-4-amino-l-(2,6-dichloro-4-cyanophenyl)-N-(5-(l- (methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1 -(2,6-di chloro-4-cyanophenyl)-N-(5 -(1 -(methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B14, Intermediate A14HPLC-2 (20-60% MeCN); Off-white solid (19.4 mg, 58%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 1.75 (s, 3H) 2.55 (s, 3H) 4.18-4.25 (m, 1H) 6.23-6.28 (m, 1H) 7.73 (s, 1H) 7.88 (s, 2H) 8.37 (s, 1H) 8.57 (s, 1H) 8.(d, 1H) 10.07 (d, 1H) 11.70 (s, 1H).4-amino-l-(2,6-dichloro-4-(difluoromethoxy)phenyl)-N-(5- ((ethylamino)methyl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B45, Intermediate A12HPLC-2 (3-33% MeCN); Colourless oil (6.8 mg, 20%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, DMSO-d6): 11.76 (s, 1H), 9.65 (s, 1H), 8.79 (d, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 7.73 (s, 2H), 7.50 (t, 1H), 3.75 (s, 2H), 2.58-2.56 (m, 2H), 1.04 (t, 3H).4-amino-l-((S)-2-chloro-4-(difluoromethyl)-6-methylphenyl)-N-(3-((ethylamino)methyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide 287 WO 2024/233900 PCT/US2024/028806 Intermediate B46, Intermediate A41HPLC-1 (20-50% MeCN); White solid (20.9 mg, 47%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, CDCI3): 11.66 (s, 1H), 10.05 (hr d, 1H), 7.83 (s, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 7.46 (s, 1H), 7.39 (hr d, 1H), 7.30-7.27 (m, 1H), 7.12 (hr d, 1H), 6.80-6.51 (m, 1H), 6.07 (hr d, 1H), 3.91 (s, 2H), 2.84 (q, 2H), 2.31 (s, 3H), 1.19 (t, 3H).(R)-4-amino-N-(5-(l-(methylamino)ethyl)pyridin-3-yl)-6-oxo-l-(2,4,6- trichlorophenyl)-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(l- (methylamino)ethyl)pyridin-3-yl)-6-oxo-l-(2,4,6-tri chlorophenyl)-!,6- dihydropyrimidine-5-carboxamideIntermediate B15, Intermediate A14HPLC-2 (5-35% MeCN); White solid (12 mg, 28%); LCMS m/z = 468 [M+H]+; 1H NMR (400 MHz, CDCI3): 11.63 (s, 1H), 9.99-9.98 (m, 1H), 8.60 (br d, 1H), 8.20 (s, 1H), 8.12 (br s, 1H), 7.63 (s, 1H), 7.50 (s, 2H), 6.13 (br s, 1H), 3.73 (br d, 1H), 2.27 (s, 3H), 1.39 (br d, 3H).(S)-4-amino-N-(5-(l-(methylamino)ethyl)pyridin-3-yl)-6-oxo-l-(2,4,6- trichlorophenyl)-l,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-N-(5-(l- (methylamino)ethyl)pyridin-3-yl)-6-oxo-l-(2,4,6-tri chlorophenyl)-!,6- dihydropyrimidine-5-carboxamideIntermediate Bl5, Intermediate Al5HPLC-1 (10-30); White solid (9.3 mg, 15%); LCMS m/z = 468 [M+H]+; 1H NMR (400 MHz, CDCI3): 1.43-1.47 (m, 1H) 1.51 (d, 3H) 2.21 (d, 1H) 2.28 (s, 1H) 2.35-2.43 (m, 3H) 2.44-2.48 (m, 1H) 2.78-3.23 (m, 6H) 3.82-3.91 (m, 1H) 6.16-6.39 (m, 1H) 7.13-7.17 (m, 1H) 7.25-7.28 (m, 1H) 7.34-7.41 (m, 1H) 7.47- 7.53 (m, 1H) 7.58-7.63 (m, 1H) 7.71-7.78 (m, 1H) 8.24-8.36 (m, 2H) 8.67-8.(m, 1H) 9.98-10.14 (m, 1H) 11.74 (s, 1H) 11.85 (d, 1H) 11.96-12.01 (m, 1H).4-amino-l-(2,6-dichloro-4-(difluoromethyl)phenyl)-N-(5- ((ethylamino)methyl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B16, Intermediate A12HPLC-2 (3-33% MeCN); Orange solid (8.1 mg, 24%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, DMSO-d6): 11.73 (s, 1H), 9.67 (s, 1H), 8.83 (d, 1H), 8.68 (s, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.04 (s, 3H), 7.16 (t, 1H), 3.75 (s, 2H), 2.58-2.56 (m, 2H), 1.04 (t, 3H). 288 WO 2024/233900 PCT/US2024/028806 4-amino-N-(5-(2-aminopropan-2-yl)pyridin-3-yl)-l-(2,6-dichloro-4- (methoxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A52HPLC-1 (1-40% MeCN); Yellow solid (25.2 mg, 90%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, CDCI3): 11.78 (s, 1H), 9.95 (s, 1H), 8.62 (s, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 7.73 (s, 1H), 7.52 (s, 2H), 6.57 (d, 1H), 4.51 (s, 2H), 3.48 (s, 3H), 1.66 (s, 6H).(R)-4-amino-l-((S)-2-chloro-6-methyl-4-(trifluoromethyl)phenyl)-N-(5-(l- ((methyl-d3)amino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or (S)-4-amino-l-((S)-2-chloro-6-methyl-4-(trifluoromethyl)phenyl)-N-(5-(l-((methyl-d3)amino)ethyl)pyridin-3-yl)-6-oxo- l,6-dihydropyrimidine-5-carboxamideIntermediate B47, Intermediate A54HPLC-1 (1-40% MeCN); White solid (34.6 mg, 64%); LCMS m/z = 4[M+H]+; 1HNMR(400MHz, CDCI3): 11.84 (s, 1H), 10.06 (d, 1H), 8.66 (s, 1H), 8.44 (s, 1H), 8.37 (s, 1H), 7.76 (d, 2H), 7.63 (s, 1H), 6.31 (d, 1H), 4.03 (q, 1H), 2.37 (s, 3H), 1.64 (d, 3H).4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((ethylamino)methyl)pyridin- 3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B10, Intermediate A12HPLC-2 (3-35% MeCN); White solid 2.1 mg, 5%); LCMS m/z = 463 [M+H]+; 1H NMR (400 MHz, CDCI3): 11.74 (s, 1H), 9.92 (d, 1H), 8.58 (d), 8.31 (s, 1H), 8.26 (s, 1H), 7.66-7.65 (m, 1H), 6.99-6.98 (m, 2H), 5.94 (s, 1H), 3.87 (s, 2H), 3.80 (s, 3H), 2.72 (q, 2H), 1.18 (t, 3H).(S)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-(l- (methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-(l-(methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A14HPLC-11 (20-50% MeCN); White solid (8.8 mg, 31%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.79 (s, 1H), 10.06 (d, 1H), 8.69 (d, 1H), 8.25 (d, 1H), 8.11 (t, 1H), 7.74 (s, 1H), 7.07 (s, 2H), 6.22 (d, 1H), 3.88 (s, 3H), 3.69 (q, 1H), 2.31 (s, 3H), 1.38 (d, 3H). 289 WO 2024/233900 PCT/US2024/028806 19 (R)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-(l- (methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-(l-(methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A15HPLC-2 (5-40% MeCN); White solid (21.2 mg, 56%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.90 (s, 1H), 10.00 (d, 1H), 8.67 (d, 1H), 8.49 (s, 1H), 8.38 (d, 1H), 8.33 (d, 1H), 7.75 (s, 1H), 7.09 (s, 2H), 6.15 (d, 1H), 4.00 (q, 1H), 3.90 (s, 3H), 2.41 (s, 3H), 1.61 (d, 3H).4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5- ((isopropylamino)methyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B10, Intermediate A25HPLC-2 (5-35% MeCN); White solid (38.8 mg, 50%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.83 (s, 1H), 10.00 (br d, 1H), 8.63 (d, 1H), 8.34 (s, 2H), 7.74 (s, 1H), 7.08 (s, 2H), 6.11 (br d, 1H), 3.93 (s, 2H), 3.(s, 3H), 3.02 (td, 1H), 1.22 (d, 6H).4-amino-N-(5-(l-aminocyclopentyl )pyri din-3-yl)-l-(2,6-di chi oro-4- methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B10, Intermediate A39HPLC-3 (15-40% MeCN); Yellow solid (7.2 mg, 18%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.78 (s, 1H), 10.08 (d, 1H), 8.79-8.(m, 1H), 8.48 (s, 1H), 8.19 (s, 1H), 7.76 (s, 1H), 7.10 (s, 2H), 6.08 (d, 1H), 3.(s, 3H), 2.09-1.91 (m, 8H).4-amino-l-(2,6-dichloro-4-(trifluoromethyl)phenyl)-N-(5- ((ethylamino)methyl )pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B23, Intermediate A12HPLC-1 (5-45% MeCN); White solid (75 mg, 80%); LCMS m/z = 503 [M+H]+; 1HNMR (400 MHz, CDCI3): 11.67 (s, 1H), 10.09 (s, 1H), 8.61 (s, 1H), 8.45- 8.34 (m, 3H), 7.85 (s, 2H), 7.74 (s, 1H), 6.21 (d, 1H), 3.97 (s, 2H), 2.84 (q, 2H), 1.22 (t, 3H). 290 WO 2024/233900 PCT/US2024/028806 23 4-amino-l-(2,6-dichloro-4-(trifluoromethyl)phenyl)-N-(5-(((2- hydroxyethyl)amino)methyl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B23, Intermediate A71HPLC-1 (1-40% MeCN); White solid (35.3 mg, 39%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.69 (s, 1H) 10.02 (br d, 1H) 8.57 (br s, 1H) 8.44 (br s, 1H) 8.35 (br s, 1H) 7.83 (s, 2H) 7.72 (s, 1H) 6.38 (br d, 1H) 4.(br s, 2H) 3.79 (br s, 2H) 2.99 (br s, 2H).(R)-4-amino-l-(2,6-dichloro-4-ethoxyphenyl)-N-(5-(l- (methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-l-(2,6-dichloro-4-ethoxyphenyl)-N-(5-(l-(methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B30, Intermediate A15HPLC-1 (5-40% MeCN); White solid (22.7 mg, 38%)LCMS m/z = 477 [M+H]+; 1HNMR (400 MHz, CDCI3): 11.84 (s, 1H), 10.02 (d, 1H,), 8.67 (d, 1H), 8.27 (dd, 2H), 7.73 (s, 1H), 7.05 (s, 2H), 6.18 (d, 1H), 4.(q, 2H), 3.85 (q, 1H), 2.36 (s, 3H), 1.51-1.43 (m, 6H).4-amino-l-(2,6-dichloro-4-ethoxyphenyl)-N-(5-(((2-m ethoxy ethyl)amino)m ethyl )pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B30, Intermediate A73HPLC-3 (5-45% MeCN); White solid (13.1 mg, 31%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 1.48 (t, 3H), 2.82 (t, 2H), 3.37 (s, 3H), 3.53 (t, 2H), 3.85 (s, 2H), 4.10 (q, 2H), 6.02 (s, 1H), 7.06 (s, 2H), 7.74 (s, 1H), 8.16 (s, 1H), 8.30 (d, 1H), 8.69 (d, 1H), 10.05 (d, 1H), 11.79 (s, 1H).4-amino-l-(2,6-dichloro-4-ethoxyphenyl)-N-(5-(((2- hydroxyethyl)amino)methyl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B30, Intermediate A71HPLC-1 (10-40% MeCN); White solid (28.3 mg, 46%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.87 (s, 1H), 9.93 (d, 1H), 8.59 (d, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 7.74 (s, 1H), 7.05 (s, 2H), 6.21 (d, 1H) 4.00 - 4.17 (m, 4H) 3.78 (s, 2H) 2.99 (s, 2H) 1.47 (t, 3H). 291 WO 2024/233900 PCT/US2024/028806 27 (R)-4-amino-N-(7-amino-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)- l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or (S)-4-amino-N-(7-amino-7-methyl-6,7-dihydro-5H- cyclopenta[c]pyridin-4-yl)-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxamideIntermediate B22, Intermediate A43HPLC-1 (1-35% MeCN); White solid (10.8 mg, 38%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.78 (s, 1H), 9.93 (br d, 1H), 9.26 (s, 1H), 8.39 (s, 1H), 7.72 (s, 1H), 7.21 (s, 2H), 6.02 (br d, 1H), 4.47 (s, 2H), 3.(s, 3H), 3.10-2.97 (m, 1H), 2.93-2.78 (m, 1H), 2.19 (d, 8H), 1.55 (s, 3H).5-(4-amino-l-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5- carb oxami do)pyri dazine-3 -carb oxami deIntermediate B30, Intermediate A59HPLC-1 (20-50% MeCN); Yellow solid (2.9 mg, 4.8%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 12.26 (s, 1H), 9.90 (d, 1H), 9.43 (d, 1H), 8.73 (d, 1H), 7.99 (s, 1H), 7.77 (s, 1H), 7.06 (s, 2H), 6.21-6.13 (m, 1H), 5.71 (d, lH),4.10(q, 2H), 1.47 (t, 3H).5-(4-amino-l-(4-ethoxy-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5- carb oxami do)pyri dazine-3 -carb oxami deIntermediate B25, Intermediate A59HPLC-3 (15-45% MeCN); White solid (5.4 mg, 9%); LCMS m/z = 424 [M+H]+; 1HNMR (400 MHz, DMSO-d6): 1.32-1.36 (m, 3H), 2.04 (s, 6H), 4.06 (q, 2H), 6.81 (s, 2H), 7.87 (s, 1H), 8.24 (s, 1H), 8.49 (s, 1H), 8.66-8.76 (m, 2H), 9.31 (d, 1H), 9.39 (d, 1H), 12.51 (s, 1H).5-(4-amino-1 -(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6- dihydropyrimidine-5-carboxamido)pyridazine-3-carboxamideIntermediate B22, Intermediate A59HPLC-3 (20-45% MeCN); White solid (10.4 mg, 23%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, DMSO-d6): 2.09 (s, 6H), 3.33 (s, 3H), 4.42 (s, 2H), 7.20 (s, 2H), 7.87 (s, 1H), 8.27 (s, 1H), 8.49 (s, 1H), 8.72 (d, 1H), 8.74 (d, 1H), 9.31 (d, 1H), 9.41 (d, 1H), 12.47 (s, 1H).(R)-4-amino-N-(5-(2-amino-l-methoxypropan-2-yl)pyridin-3-yl)-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)- 292 WO 2024/233900 PCT/US2024/028806 4-amino-N-(5 -(2-amino-1 -methoxypropan-2-yl)pyri din-3 -yl)-1 -(2,6-dichloro-4- methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B10, Intermediate A26HPLC-1 (1-40% MeCN); White solid (51.9 mg, 64%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, CDCI3): 11.83 (s, 1H), 9.93 (d, 1H), 8.70 (d, 1H), 8.47-8.43 (m, 1H), 8.30 (s, 1H), 7.74-7.71 (m, 1H), 7.06 (s, 2H), 6.24 (d, 1H), 3.87 (s, 3H), 3.61 (s, 1H), 3.55-3.52 (m, 1H), 3.35 (s, 3H), 1.59 (s, 3H).4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((lR,3aS,6aR)- octahydrocyclopenta[c]pyrrol-1 -yl)pyri din-3 -yl)-6-oxo-1,6-dihydropyrimidine- 5-carboxamide or 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5- ((1 S,3 aR,6aS)-octahydrocyclopenta[c]pyrrol-1 -yl)pyri din-3 -yl)-6-oxo-1,6- dihydropyrimidine-5-carboxamideIntermediate B10, Intermediate A47HPLC-1 (1-50% MeCN); White solid (33.3 mg, 71%); LCMS m/z = 5[M+H]+; 1HNMR(400MHz, DMSO-d6): 11.87 (s, 1H), 9.63 (d, 1H), 8.75-8.(m, 2H), 8.41 (s, 1H), 8.30 (d, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.38 (s, 2H), 3.(s, 3H), 3.62 (d, 2H), 3.37-3.31 (m, 1H), 2.77-2.64 (m, 2H), 2.39 (q, 1H), 1.69- 1.48 (m, 6H).
Example 33.Synthesis of 4-amino-l-((S)-2-chloro-6-methyl-4-(trifluoromethyl)phenyl)-N- (3 -((R)-1 -(methylamino)ethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.
CF3 AlMe3 (2 M in toluene, 104 pL) was added to a solution of methyl 4-amino-l-((S)-2-chloro- 6-methyl-4-(trifluoromethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B47, 25 mg, 0.069 mmol) and (R)-3-(l-(methylamino)ethyl)aniline (Intermediate A2, 20.77 mg, 0.138 mmol) in toluene (2 mL) at 0°C and the mixture stirred at 40°C for 0.5 h under N2. The reaction mixture was quenched by addition saturated 0.2 M 293 WO 2024/233900 PCT/US2024/028806 NaOH (5 mL) at 0°C and extracted with EtOAc (3x 5 mL). The combined organics were dried (Na2S04) and evaporated to dryness in vacuo. The residue was purified by prep-HPLC- (10-50% MeCN) to give the title compound as a white solid (3.2 mg, 9.7%). LCMS m/z = 480 [M+H]+; 1HNMR (400 MHz, CDCI3): 11.59 (s, 1H), 10.06 (d, 1H), 8.55 (s, 1H), 7.65- 7.62(m, 3H), 7.52 (s, 1H), 7.45 (d, 1H), 7.26 (t, 1H), 7.12 (d, 1H), 5.98 (d, 1H), 3.83 (q, 1H), 2.27 (d, 6H), 1.50 (d, 3H).
Example 34.Synthesis of (S)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-N-(5- (piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide.
Step 1. Synthesis of tert-butyl (S)-2-(5-(4-amino-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)piperidine-l-carboxylate.
To a mixture of methyl 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B10, 30 mg, 0.087 mmol) and tert-butyl (S)- 2-(5-aminopyridin-3-yl)piperidine-l-carboxylate (Intermediate A5, 48.4 mg, 0.174 mmol) in toluene (2 mL) was added AlMe3 (2 M in toluene, 130 pL) and the mixture stirred at 0°C for 5min and then at 100°C for 0.5 h under N2. The reaction mixture was quenched by addition IN NaOH aq. (4 mL) at 0°C and extracted with EtOAc (4x 5 mL). The combined organics were washed with brine (5 mL), dried (Na2SO4) and evaporated to dryness in vacuo to give the title compound as a black oil (40 mg, crude) which was used without further purification. LCMS m/z = 589 [M+H]+.
Step 2. Synthesis of (S)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-N-(5-(piperidin-2- yl)pyridin-3-yl)-l, 6-dihydropyrimidine-5-carboxamide. 294 WO 2024/233900 PCT/US2024/028806 tert-butyl (S)-2-(5-(4-amino-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)piperidine-l-carboxylate (Step 1, 40 mg, 0.068 mmol) was dissolved into DCM (1 mL) and TFA (I mL) and the mixture stirred at 20°C for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue purified by prep-HPLC-1 (1-50% MeCN) to give the title compound as a white solid (16.5 mg, 45%). LCMS m/z = 489 [M+H]+; 1H NMR (400 MHz, CDCI3): 11.78 (s, 1H), 10.03 (br d, 1H), 8.67 (d, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 7.73 (s, 1H), 7.07 (s, 2H), 6.00 (br d, 1H), 3.88 (s, 3H), 3.76-3.69 (m, 1H), 3.19 (br d, 1H), 2.87-2.70 (m, 2H), 1.95-1.82 (m, 2H), 1.73-1.62 (m, 3H), 1.57-1.46 (m, 1H).
Example 35.Synthesis of (R)-4-amino-N-(5-(l-aminopropyl)pyridin-3-yl)-l-(4- (methoxymethyl)-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-aminopropyl)pyri din-3-yl)-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6- oxo-l,6-dihydropyrimidine-5-carboxamide.
Step 1. Synthesis of tert-butyl (R)-(l-(5-(4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)propyl)carbamate or tert-butyl (S)- (l-(5-(4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamido)pyridin-3-yl)propyl)carbamate To a solution of methyl 4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B22, 30 mg, 0.095 mmol) and tert-butyl (S)- (l-(5-aminopyridin-3-yl)propyl)carbamate or tert-butyl (R)-(l-(5-aminopyridin-3- 295 WO 2024/233900 PCT/US2024/028806 yl)propyl)carbamate (Intermediate A8, 47.52 mg, 0.189 mmol) in toluene (4 mL) was added AlMeg (2 M, 141 pL) at 0°C and the mixture stirred at 40°C for 1 h under N2. The reaction mixture was quenched by addition of H20 (0.20 mL) and TFA (0.20 mL) at 0°C and ten the reaction mixture concentrated under reduced pressure to give the title compound as a yellow oil (40.00 mg, crude). LCMS m/z = 537 [M+H]+.
Step 2. Synthesis of (R)-4-amino-N-(5-(l-aminopropyl)pyridin-3-yl)-l-(4-(methoxymethyl)- 2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(l- aminopropyl)pyridin-3-yl)-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamide A solution of tert-butyl (R)-(l-(5-(4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6- 0x0-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)propyl)carbamate or tert-butyl (S)- (l-(5-(4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamido)pyridin-3-yl)propyl)carbamate (Step 1, 40 mg, 0.075 mmol) in TFA (0.50 mL) and DCM (1.50 mL) was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under N2 and the residue purified by prep-HPLC-1 (20-50% MeCN) to give the title compound as a white solid (10 mg, 27%). LCMS m/z = 537 [M+H]+; 1H NMR (400 MHz, CDCI3): 0.85 (t, 3 H) 1.74-1.89 (m, 2 H) 2.18 (d, 6 H) 3.45 (s, 3 H) 3.93 (t, 1 H) 4.46 (s, 2 H) 6.04-6.15 (m, 1 H) 7.21 (s, 2 H) 7.73 (s, 1 H) 8.23 (d, 2 H) 8.59 (s, 1 H) 9.84 (d, 1 H) 12.(s, 1 H).
Example 36-173 The title compound were prepared from the appropriate amine and ester using an analogous 2-Step method as described for Example 35.
Intermediate B Intermediate A Example Example No Structure, Reactants, HPLC, Data(S)-4-amino-l-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-N-(3-(pyrrolidin-2-yl)phenyl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B4, Intermediate A61 296 WO 2024/233900 PCT/US2024/028806 HPLC-2 (5-35% MeCN); Pale yellow solid (25.8 mg, 57%); LCMS m/z = 454 [M+H]+; 1HNMR (400 MHz, CDCI3): 11.80 (s, 1H), 10.00 (d, 1H), 7.78-7.69 (m, 2H), 7.46 (d, 1H), 7.27-7.23 (m, 1H), 7.15 (d, 1H), 6.96 (d, 1H), 6.83 (d, 1H), 6.02 (d, 1H), 4.37 (t, 1H), 3.85 (s, 3H), 3.36-3.04 (m, 2H), 2.35-2.25 (m, 1H), 2.21 (s, 3H), 2.15-1.91 (m, 3H).(S)-4-amino-l-(2-chloro-4-fluoro-6-methylphenyl)-6-oxo-N-(3-(pyrrolidin- 2-yl)phenyl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B44, Intermediate A61HPLC-1 (10-50% MeCN); Orange solid (8.6 mg, 42%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.69 (s, 1H), 10.14 (br.s, 1H), 7.(s, 1H), 7.67-7.53 (m, 2H), 7.24 (dd, 1H), 7.17 (d, 1H), 7.09 (dd, 1H), 5.(br.s, 1H), 4.40-4.00 (m, 1H), 3.30-3.17 (m, 1H), 3.15-2.97 (m, 1H), 2.29 (s, 3H), 2.25-2.20 (m, 1H), 2.00-1.88 (m, 2H), 1.82-1.73 (m, 1H), 1.38-1.(m, 1H).4-amino-N-(3 -(1 -aminocyclobutyl )phenyl)-1 -((S)-2-chloro-4-m ethoxy-6- methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B4, Intermediate A70HPLC-1 (20-60% MeCN); White solid (28.2 mg, 44%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.76 (s, 1H), 9.91 (d, 1H), 7.71 (s, 1H), 7.63 (br s, 1H), 7.43 (d, 1H), 7.27 (s, 1H), 7.12 (d, 1H), 6.96 (s, 1H), 6.82 (br s, 1H), 6.09 (s, 1H), 3.84 (s, 3H), 2.53 (s, 2H), 2.41 (br dd, 2H), 2.21 (s, 3H), 2.12 (d, 1H), 1.83-1.68 (m, 1H).(S)-4-amino-l-(2-chloro-4-fluoro-6-methylphenyl)-6-oxo-N-(3-(pyrrolidin- 2-yl)phenyl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B44, Intermediate A61HPLC-1 (10-45% MeCN); Pale yellow solid (21 mg, 52%); LCMS m/z = 442 [M+H]+; 1HNMR (400 MHz, CDCI3): 11.59 (s, 1H), 10.03 (br d, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.47 (d, 1H), 7.13 (dd, 1H), 7.04 (br d, 1H), 6.(dd, 1H), 5.95 (s, 1H), 4.11 (brt, 1H), 3.16-3.09 (m, 1H), 3.02-2.93 (m, 1H), 2.18 (s, 3H), 2.16-2.09 (m, 1H), 1.94-1.64 (m, 3H).(S)-4-amino-l-(2,6-dichlorophenyl)-6-oxo-N-(5-(pyrrolidin-2-yl)pyridin-3- yl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B9, Intermediate A13 297 WO 2024/233900 PCT/US2024/028806 HPLC-1 (10-44% MeCN); White solid (85.1 mg, 94%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.77 (s, 1H), 9.95 (hr s, 1H), 8.(s, 1H), 8.51-8.50 (m, 1H), 8.42 (s, 1H), 8.37-8.29 (m, 1H), 8.33 (s, 1H), 7.79-7.70 (m, 1H), 7.61-7.52 (m, 2H), 7.50-7.43 (m, 1H), 7.51-7.43 (m, 1H), 6.61-6.19 (m, 1H), 4.49 (t, 1H), 3.42-3.19 (m, 2H), 2.37 (d, 1H), 2.25- 2.00 (m, 3H).(S)-4-amino-1 -((S)-2-chloro-4-cyano-6-methylphenyl)-6-oxo-N-(3 - (piperidin-2-yl)phenyl)-l ,6-dihydropyrimidine-5-carboxamide or (R)-4- amino-l-((S)-2-chloro-4-cyano-6-methylphenyl)-6-oxo-N-(3-(piperi din-2- yl)phenyl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B13, Intermediate A20HPLC-2 (3-33% MeCN); White solid (4.6 mg, 25%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.55 (s, 1H), 10.13 (d, 1H), 7.75 (d, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.48 (d, 1H), 7.24 (s, 1H), 7.22- 7.18 (m, 1H), 6.15 (d, 1H), 3.73 (dd, 1H), 3.12 (d, 1H), 2.74 (dt, 1H,), 2.(s, 3H), 1.93-1.82 (m, 3H), 1.74-1.63 (m, 2H), 1.50 (dd, 1H).(S)-4-amino-N-(3-(l-amino-2-methoxy ethyl )phenyl)-l-((S)-2-chl oro-4- cyano-6-methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B13, Intermediate AlHPLC-1 (5-40% MeCN); White solid (3.9 mg, 18%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.54 (s, 1H), 10.09 (br d, 1H), 7.(s, 1H), 7.70-7.67 (m, 2H), 7.62 (s, 1H), 7.45 (d, 1H), 7.30-7.27 (m, 1H), 7.13 (d, 1H), 6.26 (d, 1H), 4.22 (d, 1H), 3.56-3.49 (m, 2H), 3.37 (s, 3H), 2.32 (s, 3H), 1.21 (d, 1H).(S)-4-amino-N-(5-(l-aminoethyl )pyri din-3-yl)-l-(2,6-di chi oro-4-cyanophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (R)-4-amino- N-(5-(l-aminoethyl)pyridin-3-yl)-l-(2,6-dichloro-4-cyanophenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxamideIntermediate B14, Intermediate A16HPLC-2 (5-35% MeCN); White solid (11.3 mg, 69%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, DMSO-d6): 11.65 (s, 1H), 9.71 (br d, 1H), 8.86 (br d, 1H), 8.72 (d, 1H), 8.54-8.40 (m, 3H), 8.28 (d, 1H), 8.00 (t, 1H), 4.06 (q, 1H), 1.29 (d, 3H). 298 WO 2024/233900 PCT/US2024/028806 44 (S)-4-amino-N-(5-(l-amino-2-methoxyethyl)pyridin-3-yl)-l-(2,6-di chloro- 4-cyanophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (R)-4- amino-N-(5-(l-amino-2-methoxyethyl)pyridin-3-yl)-l-(2,6-dichloro-4- cyanophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B14, Intermediate A22HPLC-1 (10-45% MeCN); White solid (6.4 mg, 46%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, MeOH-d3): 8.85-8.82 (m, 1H), 8.33 (d, 1H), 8.28 (d, 1H), 8.16 (s, 1H), 8.15 (d, 2H), 4.52 (br dd, 1H), 3.76-3.71 (m, 2H), 3.45 (s, 3H).(S)-4-amino-l-(2,6-dichloro-4-methylphenyl)-6-oxo-N-(5-(pyrrolidin-2- yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B12, Intermediate A13HPLC-2 (5-35% MeCN); White solid (19.4 mg, 86%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.78 (s, 1H ), 10.01 (d, 1H), 8.(d, 1H), 8.34 (d, 1H), 8.23-8.27 (m, 1H ), 7.72 (s, 1H ), 7.35 (s, 2H ), 6.(d, 1H), 4.31 (t, 1H), 3.20-3.31 (m, 1H), 3.09-3.18 (m, 1H), 2.43 (s, 3H), 2.24-2.33 (m, 1H), 2.00-2.08 (m, 1H), 1.86-1.98 (m, 2H).(S)-4-amino-l-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-N-(5- (piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide Intermediate B45, Intermediate A5HPLC-1 (30-80% MeCN); White solid (18.1 mg, 56%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.90 (s, 1H), 9.82 (d, 1H), 8.69 (s, 1H), 8.62 (s, 1H), 8.45 (s, 1H), 7.71 (s, 1H), 7.34 (s, 2H), 6.81-6.43 (m, 1H), 6.20 (d, 1H), 4.13 (d, 1H), 3.36 (d, 1H), 3.02-2.93 (m, 1H), 2.13 (q, 1H), 2.06-1.90 (m, 3H), 1.87-1.78 (m, 1H), 1.68-1.57 (m, 1H).(R)-4-amino-N-(5-(l-amino-2-methoxyethyl)pyridin-3-yl)-l-(2,6-di chloro- 4-(difluoromethoxy)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(l-amino-2-m ethoxy ethyl )pyri din-3-yl)-l-(2,6- dichloro-4-(difluoromethoxy)phenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B45, Intermediate A22HPLC-2 (5-35% MeCN); White solid (10.7 mg, 58%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, DMSO-d6): 11.76 (s, 1H), 9.66 (br d, 1H), 299 WO 2024/233900 PCT/US2024/028806 8.80-8.73 (m, 2H), 8.44 (s, 1H), 8.27 (br s, 1H), 8.00 (br s, 1H), 7.72 (s, 2H), 7.67-7.30 (m, 1H), 4.10 (br s, 1H), 3.41 (br s, 2H), 3.25 (s, 3H).(S)-4-amino-6-oxo-N-(5-(piperidin-2-yl)pyridin-3-yl)-l-(2,4,6- trichlorophenyl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B15, Intermediate A5HPLC-1 (5-40% MeCN); White solid (43.9 mg, 95%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, CDCI3): 11.70 (s, 1H), 10.01 (d, 1H), 8.58 (s, 1H), 8.38 (d, 3H), 7.71 (s, 1H), 7.58 (s, 2H), 6.34 (s, 1H), 3.91-3.82 (m, 1H), 3.22 (d, 1H), 2.88-2.77 (m, 1H), 2.01-1.85 (m, 3H), 1.81-1.69 (m, 2H), 1.63-1.49 (m, 1H).(R)-4-amino-N-(5-(l-amino-2-methoxyethyl)pyridin-3-yl)-6-oxo-l-(2,4,6- trichlorophenyl)-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N- (5-(l -amino-2-methoxy ethyl )pyri din-3 -yl)-6-oxo-1 -(2,4,6-tri chlorophenyl)- l,6-dihydropyrimidine-5-carboxamideIntermediate B15, Intermediate A22HPLC-4 (1-40% MeCN); Yellow solid (9.2 mg, 26%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.67 (s, 1H), 10.07 (s, 1H), 8.69 (d, 1H), 8.30-8.36 (m, 1H), 8.20 (s, 1H), 7.71 (s, 1H), 7.57 (s, 2H), 6.14 (d, 1H), 4.24 (dd, 1H), 3.48-3.57 (m, 1H), 3.40-3.45 (m, 1H), 3.38-3.40 (m, 3H).(R)-4-amino-N-(5-(l-aminoethyl)pyridin-3-yl)-6-oxo-l-(2,4,6- trichlorophenyl)-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N- (5-(l -aminoethyl)pyri din-3 -yl)-6-oxo-1 -(2,4,6-tri chlorophenyl)-1,6- dihydropyrimidine-5-carboxamideIntermediate Bl5, Intermediate Al6HPLC-1 (1-40% MeCN); Yellow oil (16.4 mg, 50%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.61 (s, 1 H), 9.97 (d, 1H), 8.57 (d, 1H), 8.24 (d, 1H), 8.10-8.17 (m, 1H), 7.63 (s, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 6.08 (d, 1H), 4.14 (q, 1H), 1.38 (d, 3H).(R)-4-amino-N-(5-(l-aminoethyl)pyri din-3-yl)-l-(2,6-di chi oro-4- cyclopropoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-aminoethyl)pyridin-3-yl)-l-(2,6-di chi oro-4-cyclopropoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide 300 WO 2024/233900 PCT/US2024/028806 Intermediate Bl 1, Intermediate Al6HPLC-1 (10-40% MeCN); Yellow solid (18.1 mg, 40%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 0.82-0.86 (m, 2 H), 0.88 (d, 2H), 1.52 (d, 3H), 3.79 (tt, 1H), 4.27 (dd, 1H), 6.12-6.37 (m, 1H), 7.21 (s, 2H), 7.72 (s, 1H), 8.29 (s, 2H), 8.56 (s, 1H), 9.89 (d, 1H), 11.81 (s, 1H).4-amino-N-(5-(aminom ethyl )pyri din-3-yl)-l-(2,6-di chi oro-4- cyclopropoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B11, Intermediate ASOHPLC-3 (15-45% MeCN); White solid (7 mg, 17%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.84-11.72 (m, 1H), 9.96-9.78 (m, 1H), 8.56-8.44 (m, 1H), 8.32-8.20 (m, 2H), 7.72 (s, 1H), 7.16 (s, 2H), 6.52- 6.16 (m, 1H), 4.16-3.84 (m, 2H), 3.76 (d,lH), 0.92-0.86 (m, 2H), 0.84 (s, 2H).(R)-4-amino-N-(5-(azepan-2-yl)pyridin-3-yl)-l-(4-methoxy-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(azepan-2-yl)pyridin-3-yl)-l-(4-methoxy-2,6-dimethylphenyl)- 6-oxo-1,6-dihydropyrimi dine-5 -carboxamideIntermediate B18, Intermediate A29HPLC-4 (1-35% MeCN); White solid (12.8 mg, 42%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 12.06 (s, 1H), 9.91 (s, 1H), 8.62 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 7.75 (s, 1H), 6.75 (s, 2H), 6.01 (s, 1H), 3.95- 4.01 (m, 1H), 3.83 (s, 3H), 3.15 (d, 1H), 2.90-2.98 (m, 1H), 2.15 (s, 6H), 2.01 (s, 2H), 1.89 (s, 2H), 1.78 (s, 2H), 1.61-1.71 (m, 2H).(S)-4-amino-l-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-N-(3- (pyrrolidin-2-yl)phenyl)-l,6-dihydropyrimidine-5-carboxamide Intermediate B16, Intermediate A61HPLC-1 (10-50% MeCN); White solid (3.4 mg, 16%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.56 (s, 1H), 10.15 (d, 1H), 7.81- 7.69 (m, 4H), 7.52 (d, 1H), 7.32 (s, 1H), 7.19 (br d, 1H), 6.93-6.50 (m, 1H), 6.10 (d, 1H), 4.40 (d, 1H), 3.43-3.09 (m, 2H), 2.39-2.22 (m, 1H), 2.20-1.(m, 3H).(S)-4-amino-l-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-N-(5-(pyrrolidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide 301 WO 2024/233900 PCT/US2024/028806 Intermediate Bl6, Intermediate Al3HPLC-1 (10-50% MeCN); White solid (3.4 mg, 20%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, DMSO-d6): 11.75 (s, 1H), 9.67 (d, 1H), 8.(d, 1H), 8.76 (d, 1H), 8.49 (s, 1H), 8.31 (d, 1H), 8.23 (s, 1H), 8.07 (s, 1H), 8.03 (s, 2H), 7.36-6.96 (m, 1H), 4.28 (t, 1H), 3.21-3.00 (m, 2H), 2.27-2.(m, 1H), 1.93-1.81 (m, 2H), 1.77-1.66 (m, 1H).(S)-4-amino-l-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-N-(5- (piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B16, Intermediate A5HPLC-1 (1-50% MeCN); White solid (21.2 mg, 84%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.66 (s, 1H), 10.07 (d, 1H), 8.61 (d, 1H), 8.40-8.32 (m, 3H), 7.71 (d, 3H), 6.84-6.54 (m, 1H), 6.20 (d, 1H), 3.(dd, 1H), 3.17 (d, 1H), 2.79 (td, 1H), 2.07-1.61 (m, 6H), 1.60-1.46 (m, 1H).(R)-4-amino-N-(5-(l-aminoethyl)pyri din-3-yl)-l-(2,6-di chi oro-4- (difluoromethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(l-aminoethyl )pyri din-3-yl)-l-(2,6-di chi oro-4- (difluoromethyl )phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate Bl6, Intermediate Al7HPLC-1 (3-33% MeCN); White solid (12.4 mg, 68%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, DMSO-d6): 11.74 (s, 1 H) 9.68 (br d, 1H) 8.83 (br d, 1H) 8.75 (d, 1H) 8.49 (s, 1 H) 8.27-8.34 (m, 1 H) 6.96-7.37 (m, H)4.11 (q, 1H) 1.31 (d, 3H).(R)-4-amino-N-(5-(l-amino-2-methoxyethyl)pyridin-3-yl)-l-(2,6-di chloro- 4-(difluoromethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(l-amino-2-methoxyethyl)pyridin-3-yl)-l-(2,6-di chloro- 4-(difluoromethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B16, Intermediate A22HPLC-2 (1-35% MeCN); Yellow solid (9.2 mg, 50%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, MeOH-d4): 8.83 (s, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.86 (s, 2H), 7.06-6.77 (m, 1H), 4.39 (t, 1H), 3.71-3.(m, 2H), 3.42 (s, 3H).(R)-N-(5-(l,4-oxazepan-3-yl)pyridin-3-yl)-4-amino-l-(2,6-dichloro-4-(difluoromethyl )phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 302 WO 2024/233900 PCT/US2024/028806 (S)-N-(5-(l,4-oxazepan-3-yl)pyridin-3-yl)-4-amino-l-(2,6-dichloro-4- (difluoromethyl )phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B16, Intermediate A27HPLC-3 (1-40% MeCN); White solid (25.1 mg, 91%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.60 (s, 1H), 9.96 (s, 1H), 8.60 (s, 1H), 8.29-8.14 (m, 2H), 7.68-7.60 (m, 3H), 6.61 (t, 1H), 6.21 (s, 1H), 4.(d, 1H), 3.88 (d, 2H), 3.76-3.76 (m, 1H), 3.78 (d, 1H), 3.63 (d, 1H), 3.16 (d, 1H), 3.05-2.92 (m, 1H), 2.13-1.87 (m, 2H).4-amino-l-(2,6-dichloro-4-(methoxymethyl)phenyl)-N-(5- ((ethylamino)methyl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B19, Intermediate A24HPLC-1 (15-45% MeCN); Yellow solid (14.7 mg, 44%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 10.05-9.94 (m, 1H), 8.58 (d, 1H), 8.20 (d, 1H), 8.06 (d, 1H), 7.64 (s, 1H), 7.44 (s, 2H), 5.97 (d, 1H), 4.43 (s, 2H), 3.73 (s, 2H), 3.40 (s, 3H), 2.60 (d, 2H), 1.05 (t, 3H).(S)-4-amino-l-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-N-(5- (piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A5HPLC-1 (10-40% MeCN); Yellow solid (4.2 mg, 30%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.87 (s, 1H), 9.88 (d, 1H), 8.63 (s, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 7.71 (s, 1H), 7.51 (s, 2H), 6.09 (d, 1H), 4.(s, 2H), 4.09-4.02 (m, 1H), 3.48 (s, 3H), 3.30-3.21 (m, 1H), 2.96-2.86 (m, 1H), 2.15-2.08 (m, 1H), 2.07-1.97 (m, 4H), 1.69-1.55 (m, 1H).(R)-4-amino-N-(5-(l-amino-2-methoxyethyl)pyridin-3-yl)-l-(2,6-di chloro- 4-(methoxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(l-amino-2-methoxyethyl)pyridin-3-yl)-l-(2,6-di chloro- 4-(methoxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A22HPLC-1 (10-40% MeCN); White solid (18.3 mg, 50%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.80 (s, 1H), 9.83 (d, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 7.73 (s, 1H), 7.50 (s, 2H), 6.40 (d, 1H), 4.50 303 WO 2024/233900 PCT/US2024/028806 (s, 2H), 4.41 (s, 1H), 3.73 (t, 1H), 3.65-3.60 (m, 1H), 3.46 (s, 3H), 3.39 (s, 3H).4-amino-l-(2,6-dichloro-4-(methoxymethyl)phenyl)-N-(5-(((2- hydroxyethyl)amino)methyl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B19, Intermediate A71HPLC-1 (1-30% MeCN); Yellow solid (16.3 mg, 72%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.79 (s, 1H), 9.94 (s, 1H), 8.57 (s, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 7.70 (s, 1H), 7.49 (s, 2H), 6.47 (s, 1H), 4.(s, 2H), 4.02 (s, 2H), 3.76 (s, 2H), 3.46 (s, 3H), 2.94 (s, 2H).4-amino-l-(2,6-dichloro-4-(methoxymethyl)phenyl)-N-(5- ((isopropylamino)methyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B19, Intermediate A25HPLC-1 (1-40% MeCN); White solid (28.3 mg, 67%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.66 (s, 1H), 9.95 (d, 1H), 8.55 (d, 1H), 8.21 (d, 2H), 7.64 (s, 1H), 7.44 (s, 2H), 6.03 (d, 1H), 4.43 (s, 2H), 3.(s, 2H), 3.40 (s, 3H), 2.88 (td, 1H), 1.08 (d, 6H).4-amino-N-(5-(l-aminocyclobutyl )pyri din-3-yl)-l-(2,6-di chi oro-4- (methoxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A51HPLC-1 (15-45% MeCN); Yellow gum (11.2 mg, 30%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, DMSO-d6): 11.93 (s, 1H), 9.64 (s, 1H), 8.(s, 1H), 8.85 (d, 1H), 8.47 (d, 2H), 8.12 (d, 1H), 7.71 (s, 2H), 4.55 (s, 2H), 3.39 (s, 3H), 2.66-2.59 (m, 2H), 2.48-2.42 (m, 2H), 2.18-2.09 (m, 1H), 1.87- 1.77 (m, 1H).(R)-4-amino-N-(5-(l-aminoethyl)pyri din-3-yl)-l-(2,6-di chi oro-4- (methoxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(l-aminoethyl )pyri din-3-yl)-l-(2,6-di chi oro-4- (methoxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate Bl9, Intermediate Al7HPLC-1 (1-40% MeCN); Yellow solid (11.4 mg, 30%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.67 (s, 1H), 9.94 (d, 1H), 8.57 (s, 304 WO 2024/233900 PCT/US2024/028806 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.64 (s, 1H), 7.44 (s, 2H), 6.02 (d, 1H), 4.(s, 2H), 4.15 (d, 1H), 3.40 (s, 3H), 1.43-1.38 (m, 3H).(S)-4-amino-N-(5-(l-aminoethyl )pyri din-3-yl)-l-(2,6-di chi oro-4- (methoxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-N-(5-(l-aminoethyl)pyri din-3-yl)-l-(2,6-di chi oro-4- (methoxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate Bl9, Intermediate Al6HPLC-1 (1-40% MeCN); Yellow solid (11.4 mg, 31%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.77 (s, 1H), 9.87 (d, 1H), 8.64- 8.43 (m, 1H), 8.40-8.16 (m, 2H), 7.72 (s, 1H), 7.51 (s, 2H), 7.28 (s, 3H), 6.39-6.24 (m, 1H), 4.51 (s, 2H), 4.43-4.27 (m, 1H), 3.48 (s, 3H), 1.56 (s, 3H).(S)-4-amino-l-(2,6-di chi oro-4-(methoxymethyl)phenyl)-N-(5-(2-methoxy- -(methyl amino)ethyl)pyri din-3 -yl)-6-oxo-1, 6-dihydropyrimidine-5 - carboxamide or (R)-4-amino-l-(2,6-dichloro-4-(methoxymethyl)phenyl)-N- (5-(2-methoxy-l-(methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6- dihydropyrimidine-5-carboxamideIntermediate B19, Intermediate A23HPLC-1 (15-55% MeCN); White solid (16.5 mg, 36%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.82 (s, 1H), 10.02 (d, 1H), 8.69 (s, 1H), 8.41 (s, H), 8.33 - 8.38 (m, 1H), 7.72 (s, 1H), 7.52 (s, 2H), 6.11 (d, 1H), 4.51 (s, 2H), 3.98-4.16 (m, 1H), 3.70-3.79 (m, 2H), 3.62-3.70 (m, 1H), 3.48 (s, 3H), 3.39 (s, 3H), 2.49 (s, 3H).(R)-4-amino-N-(5-(l-amino-2-ethoxyethyl)pyridin-3-yl)-l-(2,6-di chi oro-4- (methoxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(l-amino-2-ethoxyethyl)pyridin-3-yl)-l-(2,6-di chi oro-4- (methoxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A10HPLC-1 (20-60% MeCN); White solid (15.3 mg, 40%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.80 (s, 1H), 9.94 (d, 1H), 8.62 (d, 1H), 8.36 (d, 2H), 7.73 (s, 1H), 7.53 (s, 2H), 6.25 (d, 1H), 4.52 (s, 2H), 4.(dd, 1H), 3.68-3.60 (m, 2H), 3.57 (ddd, 2H), 3.49 (s, 3H), 1.21 (t, 3H). 305 WO 2024/233900 PCT/US2024/028806 70 (R)-4-amino-N-(5-(l-amino-3,3-difluoropropyl)pyridin-3-yl)-l-(2,6- dichloro-4-(methoxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or (S)-4-amino-N-(5-(l-amino-3,3-difluoropropyl)pyridin-3- yl)-1 -(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6- dihydropyrimidine-5-carboxamideIntermediate B19, Intermediate A44HPLC-1 (5-35% MeCN); White solid (24.7 mg, 53%); LCMS m/z = 5[M+H]+; 1H NMR (400 MHz, CDCI3): 11.83 (s, 1H), 10.04 (d, 1H), 8.68 (d, 1H), 8.31 (d, 1H), 8.24 (s, 1H), 7.74 (s, 1H), 7.54 (s, 2H), 6.18 (d, 1H), 5.(tt, 1H), 4.52 (s, 2H), 4.26 (dd, 1H), 3.49 (s, 3H), 2.27-2.18 (m, 2H).(R)-4-amino-l -((S)-2-chloro-4-ethoxy-6-methylphenyl)-N-(3-(l - (methylamino)ethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B5, Intermediate A2HPLC-1 (1-40% MeCN); White solid (50.2 mg, 70%); LCMS m/z = 4[M+H]+; 1HNMR(400MHz, CDCI3): 11.83 (s, 1H), 10.04 (d, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.53 (d, 1H), 7.31 (t, 1H), 7.11 (d, 1H), 6.95 (d, 1H), 6.(d, 1H), 6.04 (d, 1H), 4.06 (q, 2H), 3.82 (q, 1H), 2.34 (s, 3H), 2.20 (s, 3H), 1.50 (d, 3H), 1.44 (t, 3H).(S)-4-amino-N-(3-(l-amino-2-methoxy ethyl )phenyl)-l-((S)-2-chl oro-4- ethoxy-6-methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B5, Intermediate AlHPLC-1 (5-40% MeCN); Pale yellow solid (7.9 mg, 11%); LCMS m/z = 472 [M+H]+; 1H NMR (400 MHz, CDCI3): 11.79 (s, 1H), 10.01 (d, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.52 (d, 1H), 7.30 (s, 1H), 7.10 (d, 1H), 6.95 (d, 1H), 6.81 (d, 1H), 5.97 (d, 1H), 4.19 (dd, 1H), 4.06 (q, 2H), 3.56-3.51 (m, 1H), 3.48-3.43 (m, 1H), 3.38 (s, 3H), 2.20 (s, 3H), 1.45 (t, 3H).(S)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-N-(5-(pyrrolidin-2- yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B10, Intermediate A13HPLC-1 (10-50% MeCN); White solid (3.6 mg, 13%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, DMSO-d6): 11.90 (s, 1H), 9.63 (d, 1H), 8.(d, 1H), 8.76 (d, 1H), 8.43 (s, 1H), 8.32 (s, 1H), 8.10 (s, 1H), 7.40 (s, 1H), 306 WO 2024/233900 PCT/US2024/028806 7.42-7.37 (m, 1H), 4.32 (t, 1H), 3.91 (s, 3H), 3.22-2.99 (m, 2H), 2.32-2.(m, 1H), 1.99-1.90 (m, 1H), 1.89-1.66 (m, 2H).(R)-4-amino-N-(5-(l-aminoethyl)pyri din-3-yl)-l-(2,6-di chi oro-4- methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-aminoethyl)pyridin-3-yl)-l-(2,6-dichloro-4-methoxyphenyl)- 6-oxo-1,6-dihydropyrimi dine-5 -carboxamideIntermediate B10, Intermediate A17HPLC-1 (5-35% MeCN); Yellow oil (14.1 mg, 57%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, DMSO-d6): 11.83 (s, 1H), 9.59 (s, 1H), 8.(d, 2H), 8.38 (s, 1H), 8.26 (s, 1H), 8.00 (s, 1H), 7.35 (s, 2H), 4.09 (d, 1H), 3.86 (s, 3H), 1.29 (d, 3H).(R)-N-(5-(l,4-oxazepan-3-yl)pyridin-3-yl)-4-amino-l-(2,6-dichloro-4- methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-N-(5- (l,4-oxazepan-3-yl)pyri din-3-yl)-4-amino-l-(2,6-di chi oro-4- methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A27HPLC-1 (5-40% MeCN); White solid (11.8 mg, 28%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.71 (s, 1H), 9.95 (br d, 1H), 8.(d, 1H), 8.23 (s, 1H), 8.08 (s, 1H), 7.66 (s, 1H), 6.99 (s, 2H), 5.97 (br d, 1H), 3.95-3.84 (m, 3H), 3.80 (s, 3H), 3.80-3.73 (m, 1H), 3.45 (dd, 1H), 3.(dt, 1H), 2.94 (ddd, 1H), 1.92-1.89 (m, 2H).(S)-4-amino-l-(2,6-di chi oro-4-methoxyphenyl)-N-(6-fluoro-5-(piperi din-2- yl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (R)-4- amino-1-(2,6-di chi oro-4-methoxyphenyl)-N-(6-fluoro-5-(piperi din-2- yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A21HPLC-2 (5-40% MeCN); White solid (30 mg, 65%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.75 (s, 1H), 9.97 (br d, 1H), 8.(dd, 1H), 8.30-8.27 (m, 1H), 7.72 (s, 1H), 7.06 (s, 2H), 6.14 (br d, 1H), 4.02-3.95 (m, 1H), 3.88 (s, 3H), 3.27 (br d, 1H), 2.83 (td, 1H), 1.91 (br d, 2H, J = 10.4 Hz), 1.70-1.50 (m, 4H).(S)-4-amino-N-(5-(l-amino-2-methoxyethyl)pyridin-3-yl)-l-(2,6-di chloro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide 307 WO 2024/233900 PCT/US2024/028806 Intermediate B10, Intermediate A22HPLC-1 (1-40% MeCN); Yellow solid (57.7 mg, 79%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, DMSO-d6): 11.83 (s, 1H), 9.63 (d, 1H), 8.(d, 1H), 8.72 (d, 1H), 8.40 (s, 1H), 8.26 (d, 1H), 8.00 (d, 1H), 7.37 (s, 2H), 4.08 (t, 1H), 3.89 (s, 3H), 3.38 (d, 2H), 3.24 (s, 3H).4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,5R)-5- methylpyrrolidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,5S)- 5-methylpyrrolidin-2-yl)pyri din-3 -yl)-6-oxo-1,6-dihydropyrimidine-5 - carboxamide or 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,5S)- 5-methylpyrrolidin-2-yl)pyri din-3 -yl)-6-oxo-1,6-dihydropyrimidine-5 - carboxamide or 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,5R)- 5-methylpyrrolidin-2-yl)pyri din-3 -yl)-6-oxo-1,6-dihydropyrimidine-5 - carboxamideIntermediate B10, Intermediate A3 5HPLC-1 (15-55% MeCN); White solid (50.5 mg, 93%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.80 (s, 1H), 9.99 (d, 1H), 8.64 (d, 1H), 8.39-8.25 (m, 2H), 7.74 (s, 1H), 7.08 (s, 2H), 6.15 (d, 1H), 4.40 (t, 1H), 3.89 (s, 3H), 3.61-3.46 (m, 1H), 2.37-2.25 (m, 1H), 2.20-2.09 (m, 1H), 2.09- 1.96 (m, 1H), 1.82-1.61 (m, 1H), 1.29 (d, 3H).4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,5S)-5- methylpyrrolidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,5R)- 5-methylpyrrolidin-2-yl)pyri din-3 -yl)-6-oxo-1,6-dihydropyrimidine-5 - carboxamide or 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,5R)- 5-methylpyrrolidin-2-yl)pyri din-3 -yl)-6-oxo-1,6-dihydropyrimidine-5 - carboxamide or 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,5S)- 5-methylpyrrolidin-2-yl)pyri din-3 -yl)-6-oxo-1,6-dihydropyrimidine-5 - carboxamideIntermediate B10, Intermediate A3 8HPLC-3 (30-65% MeCN); Yellow solid (8.8 mg, 17%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 12.11 (s, 1H), 9.81 (d, 1H), 8.80- 9.05 (m, 1H), 8.40-8.63 (m, 2H), 7.73 (s, 1H), 6.98-7.10 (m, 2H), 6.15 (d, 308 WO 2024/233900 PCT/US2024/028806 1H), 4.80-4.99 (m, 1H), 3.85-4.00 (m, 4H), 2.39-2.52 (m, 2H), 2.27-2.(m, 1H), 1.76-1.96 (m, 1H), 1.44 (d, 3H).(R)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-(2-methoxy-l- (methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or (S)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-(2- methoxy-l-(methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine- 5-carboxamideIntermediate B10, Intermediate A23HPLC1-1 (05-36% MeCN); White solid (45.5 mg, 71%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, CDCI3): 11.79 (s, 1H), 10.06 (br d, 1H), 8.(d, 1H), 8.29 (d, 1H), 8.14 (t, 1H), 7.74 (s, 1H), 7.07 (s, 2H), 6.11 (d, 1H), 3.88 (s, 3H), 3.80 (dd, 1H), 3.49-3.42 (m, 2H), 3.37 (s, 3H), 2.31 (s, 3H).4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,6S)-6- methylpiperidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,6R)- 6-methylpiperidin-2-yl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,6R)- 6-methylpiperidin-2-yl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,6S)- 6-methylpiperidin-2-yl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B10, Intermediate A33HPLC-1 (1-40% MeCN); White solid (33 mg, 98%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.79 (s, 1H), 9.99 (d, 1H), 8.57 (d, 1H), 8.41-8.39 (m, 1H), 8.36 (d, 1H), 7.72 (s, 1H), 7.06 (s, 2H), 6.12 (d, 1H), 4.18 (dd, 1H), 3.88 (s, 3H), 3.42-3.38 (m, 1H), 1.97-1.88 (m, 3H), 1.80-1.67 (m, 2H), 1.51-1.47 (m, 1H), 1.27 (d, 3H).(R)-4-amino-N-(5-(l-amino-3,3-difluoropropyl)pyridin-3-yl)-l-(2,6- dichloro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-( 1 -amino-3,3 -difluoropropyl )pyri din-3 -yl)-1 -(2,6- dichloro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A44 309 WO 2024/233900 PCT/US2024/028806 HPLC-1 (1-40% MeCN); White solid (22.1 mg, 39%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.86 (s, 1H), 9.98 (d, 1H), 8.65 (s, 1H), 8.32-8.21 (m, 2H), 7.74 (d, 1H), 7.07 (d, 2H), 6.14 (d, 1H), 6.08-5.(m, 1H), 4.26 (t, 1H), 3.88 (d, 3H), 2.36-2.24 (m, 2H).4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,6R)-6- methylpiperidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,6S)- 6-methylpiperidin-2-yl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,6S)- 6-methylpiperidin-2-yl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,6R)- 6-methylpiperidin-2-yl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B10, Intermediate A32HPLC-1 (5-35% MeCN); White solid (18.6 mg, 39%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 1.05 (d, 3H), 1.21-1.29 (m, 1H), 1.47-1.63 (m, 2H), 1.67 (d, 1H), 1.79 (d, 1H), 1.87-1.93 (m, 1H), 2.83-2.(m, 1H) 3.73-3.79 (m, 1H), 3.88 (s, 3H), 6.06 (s, 1H), 7.07 (s, 2H), 7.73 (s, 1H), 8.17 (s, 1H), 8.34 (s, 1H), 8.72 (d, 1H), 10.04 (d, 1H), 11.76 (s, 1H).4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,6R)-6- methylpiperidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,6S)- 6-methylpiperidin-2-yl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,6S)- 6-methylpiperidin-2-yl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,6R)- 6-methylpiperidin-2-yl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B10, Intermediate A31HPLC-1 (1-40% MeCN); White solid (20.6 mg, 50%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.79 (s, 1H), 10.01 (d, 1H), 8.58 (d, 1H), 8.39 (d, 2H), 7.72 (s, 1H), 7.06 (s, 2H), 6.10 (d, 1H), 4.17 ( dd, 1H), 310 WO 2024/233900 PCT/US2024/028806 3.88 (s, 3H), 3.45-3.33 (m, 1H), 2.03-1.87 (m, 3H), 1.81-1.66 (m, 2H), 1.55-1.44 (m, 1H), 1.27 (d, 3H).(R)-4-amino-N-(5-(l-amino-3,3-difluoropropyl)pyridin-3-yl)-l-(2,6- dichloro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-( 1 -amino-3,3 -difluoropropyl )pyri din-3 -yl)-1 -(2,6- dichloro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A44HPLC-1 (10-40% MeCN); White solid (8.7 mg, 23%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, CDCI3): 11.86 (s, 1H), 10.01 (d, 1H), 8.67 (d, 1H), 8.30 (d, 1H), 8.23 (s, 1H), 7.74 (s, 1H), 7.07 (s, 2H), 6.06-6.03(m, 1H), 5.94-5.75 (m, 1H), 4.24 (dd, 1H), 3.88 (s, 3H), 2.29-2.16 (m, 2H).4-amino-l-(2,6-dichloro-4-propoxyphenyl)-N-(5- ((ethylamino)methyl )pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B7, Intermediate A24HPLC-3 (5-35% MeCN); White solid (23.7 mg, 48%); LCMS m/z = 4[M+H]+; 1HNMR(400MHz, CDCI3): 11.73 (s, 1H), 9.93 (br.d, 1H), 8.(d, 1H), 8.21 (s, 1H), 8.15 (br.s, 1H), 7.65 (s, 1H), 6.98 (s, 2H), 6.07 (br.d, 1H), 3.89 (t, 2H), 3.77 (s, 2H), 2.64 (q, 2H), 1.77 (sxt, 2H), 1.08 (br.t, 3H), 0.98 (t, 3H).4-amino-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-N-(5-((2R,5S)-5- methylpyrrolidin-2-yl )pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-N-(5- ((2S,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-l,6- dihydropyrimidine-5-carboxamide or 4-amino-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-N-(5-((2R,5R)-5-methylpyrrolidin-2-yl )pyri din-3- yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1 -(2,6- dimethyl-4-(trifluoromethyl)phenyl)-N-(5-((2S,5S)-5-methylpyrrolidin-2- yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B24, Intermediate A37HPLC-1 (1-40% MeCN); Yellow solid (21.9 mg, 65%); LCMS m/z = 4[M+H]+; 1HNMR(400MHz, CDCI3): 11.82 (s, 1H), 10.03 (d, 1H), 8.69 (d, 1H), 8.30 (s, 1H), 8.12 (s, 1H), 7.71 (s, 1H), 7.51 (s, 2H), 6.10 (d, 1H), 4.44 311 WO 2024/233900 PCT/US2024/028806 (t, 1H), 3.55-3.50 (m, 1H), 2.37-2.33 (m, 1H), 2.26 (s, 6H), 2.20-2.09 (m, 1H), 1.85-1.78 (m, 1H), 1.52-1.45 (m, 1H), 1.24 (d, 3H).(R)-4-amino-N-(5-(l-aminopropyl)pyridin-3-yl)-l-(2,6-dimethyl-4- (trifluoromethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(l-aminopropyl)pyridin-3-yl)-l-(2,6-dimethyl-4- (trifluoromethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B24, Intermediate A8HPLC-1 (5-35% MeCN); White solid (22.5 mg, 34%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.90 (s, 1H), 10.00 (d, 1H), 8.66 (d, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 7.74 (s, 1H), 7.54 (s, 2H), 6.26 (d, 1H), 3.(t, 1H), 2.29 (d, 6H), 1.85-1.75 (m, 2H), 0.90 (t, 3H).(R)-4-amino-N-(5-(azepan-2-yl)pyridin-3-yl)-l-(2,6-dimethyl-4- (trifluoromethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(azepan-2-yl)pyridin-3-yl)-l-(2,6-dimethyl-4- (trifluoromethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B24, Intermediate A29HPLC-1 (10-50% MeCN); Brown oil (32.2 mg, 63%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.89 (s, 1H), 10.01 (d, 1H), 8.63 (d, 1H), 8.41-8.27 (m, 2H), 7.74 (s, 1H), 7.55 (s, 2H), 6.14 (d, 1H), 4.12-3.(m, 1H), 3.21-3.09 (m, 1H), 3.05-2.89 (m, 1H), 2.29 (s, 6H), 2.11-2.01 (m, 2H), 1.98-1.88 (m, 2H), 1.86-1.75 (m, 2H), 1.75-1.59 (m, 2H).4-amino-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-N-(5-((2R,6S)-6- methylpiperidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-N-(5- ((2 S, 6R)-6-methylpiperi din-2-yl)pyri din-3 -yl)-6-oxo-1,6- dihydropyrimidine-5-carboxamide or 4-amino-l-(2,6-dimethyl-4-(tri fluoromethyl)phenyl)-N-(5-((2R,6R)-6-methylpiperidin-2-yl)pyri din-3- yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1 -(2,6- dimethyl-4-(trifluoromethyl)phenyl)-N-(5-((2S,6S)-6-methylpiperidin-2- yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B24, Intermediate A31HPLC-1 (10-40% MeCN); Pink solid (38.3 mg, 91%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 1.28 (d, 3H), 1.42-1.57 (m, 1H), 312 WO 2024/233900 PCT/US2024/028806 1.66-1.84 (m, 2H), 1.84-2.00 (m, 3H), 2.27 (s, 6H), 3.41 (d, 1H), 4.18 (t, 1H), 6.03 (d, 1H), 7.52 (s, 2H), 7.72 (s, 1H), 8.26-8.47 (m, 2H), 8.63 (s, 1H), 9.99 (d, 1H), 11.85 (s, 1H).(R)-4-amino-l-(4-ethoxy-2,6-dimethylphenyl)-6-oxo-N-(5-(piperi din-2- yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B25, Intermediate A4HPLC-4 (1-40% MeCN); White solid (72 mg, 66%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 12.07 (s, 1H), 9.85 (d, 1H), 8.57 (d, 1H), 8.35 (d, 2H), 7.74 (s, 1H), 6.72 (s, 2H), 6.32 (d, 1H), 4.04 (q, 2H), 3.(dd, 1H), 3.18 (d, 1H), 2.82-2.74 (m, 1H), 2.12 (s, 6H), 1.92 (d, 1H), 1.89- 1.81 (m, 2H), 1.74-1.66 (m, 2H), 1.57-1.48 (m, 1H), 1.42 (t, 3H).4-amino-l-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2R,5S)-5- methylpyrrolidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2S,5R)-5- methylpyrrolidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2R,5R)- 5-methylpyrrolidin-2-yl)pyri din-3 -yl)-6-oxo-1,6-dihydropyrimidine-5 - carboxamide or 4-amino-l-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2S,5S)-5- methylpyrrolidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B25, Intermediate A37HPLC-1 (1-40% MeCN); White solid (23 mg, 35%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 12.07 (s, 1H), 9.87 (d, 1H), 8.62 (s, 1H), 8.30 (d, 2H), 7.75 (s, 1H), 6.73 (s, 2H), 6.01 (d, 1H), 4.59 (t, 1H), 4.(q, 3H), 3.69 (d, 1H), 2.42-2.33 (m, 1H), 2.30-2.19 (m, 1H), 2.13 (d, 6H), 2.08-1.98 (m, 1H), 1.72-1.59 (m, 1H), 1.43 (t, 3H), 1.30 (d, 3H).4-amino-l-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2R,5S)-5- methylpyrrolidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2S,5R)-5- methylpyrrolidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2R,5R)- 5-methylpyrrolidin-2-yl)pyri din-3 -yl)-6-oxo-1,6-dihydropyrimidine-5 - carboxamide or 4-amino-l-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2S,5S)-5- 313 WO 2024/233900 PCT/US2024/028806 methylpyrrolidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B25, Intermediate A38HPLC-1 (1-40% MeCN); White solid (29.6 mg, 90%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 1.30 (d, 3 H), 1.47 (t, 3 H), 1.53-1.(m, 1 H), 1.88-2.02 (m, 1 H), 2.17 (s, 6 H), 2.21 (d, 1 H), 2.32-2.45 (m, H), 3.59-3.69 (m, 1 H), 4.09 (q, 2 H), 4.53 (t, 1 H), 6.02 (d, 1 H), 6.77 (s, H), 7.78 (s, 1 H), 8.23 (s, 1 H), 8.31-8.38 (m, 1 H), 8.70 (s, 1 H), 9.94 (d, H), 12.07 (s, 1 H).(R)-4-amino-N-(5-(l-aminobutyl)pyridin-3-yl)-l-(4-ethoxy-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B25, Intermediate A7HPLC-1 (20-60% MeCN); White solid (19.8 mg, 30%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 12.07 (s, 1H), 9.76 (s, 1H), 8.53 (s, 1H), 8.31-8.21 (m, 2H), 7.74 (s, 1H), 6.73 (s, 2H), 6.20 (d, 1H), 4.05 (q, 3H), 2.13 (d, 6H), 1.89-1.72 (m, 2H), 1.43 (t, 3H), 1.31-1.14 (m, 2H), 0.(t, 3H).(R)-4-amino-N-(5-(azepan-2-yl)pyridin-3-yl)-l-(4-ethoxy-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(azepan-2-yl)pyridin-3-yl)-l-(4-ethoxy-2,6-dimethylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxamideIntermediate B25, Intermediate A29HPLC-1 (20-60% MeCN); White solid (19 mg, 38%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.97 (s, 1 H), 9.83 (d, 1H), 8.52 (s, H), 8.12-8.30 (m, 2 H), 7.67 (s, 1 H), 6.66 (s, 2 H), 5.83 (d, 1H), 3.96-4.(m, 2 H), 3.91-3.95 (m, 1 H), 2.98-3.14 (m, 1 H), 2.82-2.93 (m, 1 H), 2.(s, 6 H), 1.90-2.02 (m, 2 H), 1.78-1.90 (m, 2 H), 1.53-1.75 (m, 4 H), 1.36 (t, 3H).4-amino-l-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2R,6S)-6- methylpiperidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2S,6R)-6- methylpiperidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2R,6R)- 314 WO 2024/233900 PCT/US2024/028806 6-methylpiperidin-2-yl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2S,6S)-6- methylpiperidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B25, Intermediate A31HPLC-1 (10-40% MeCN); White solid (51 mg, 85%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.96 (s, 1H), 9.83 (d, 1H), 8.52 (d, 1H), 8.29 (d, 2H), 7.67 (s, 1H), 6.65 (s, 2H), 5.90 (d, 1H), 4.08 (dd, 1H), 3.98 (q, 2H), 3.38-3.22 (m, 1H), 2.05 (s, 6H), 1.92-1.77 (m, 3H), 1.72-1.(m, 2H), 1.41 (d, 1H), 1.36 (t, 3H), 1.18 (d, 3H).(R)-4-amino-l-(4-(difluoromethyl)-2,6-dimethylphenyl)-6-oxo-N-(5- (piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide Intermediate B17, Intermediate A4HPLC-1 (15-45% MeCN); White solid (33.6 mg, 81%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.90 (s, 1H), 9.89 (d, 1H), 8.63- 8.41 (m, 2H), 8.28 (d, 1H), 7.73 (s, 1H), 7.40 (s, 2H), 6.84-6.49 (m, 1H), 6.09 (d, 1H), 3.92 (dd, 1H), 3.21 (d, 1H), 2.86 (dt, 1H), 2.25 (d, 6H), 2.04- 1.89 (m, 3H), 1.88-1.69 (m, 2H), 1.65-1.48 (m, 1H).(R)-4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-N-(5- (piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide Intermediate B22, Intermediate A4HPLC-1 (15-55% MeCN); White solid (21.8 mg, 81%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 12.02 (s, 1 H) 9.88 (s, 1 H) 8.48 (s, H) 7.72 (s, 1 H) 7.21 (s, 2 H) 6.03 (s, 1 H) 4.46 (s, 2 H) 3.83-3.96 (m, 1 H) 3.45 (s, 3 H) 3.16 (d, 1 H) 2.73-2.87 (m, 1 H) 2.18 (d, 6 H) 1.88-2.02 (m, H) 1.68-1.85 (m, 2 H) 1.49-1.60 (m, 1 H).4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5- ((methylamino)methyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B22, Intermediate A6HPLC-1 (5-35% MeCN); White solid (34.6 mg, 64%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 12.07 (s, 1H), 9.82 (br s, 1H), 8.(br s, 1H), 8.46 (br s, 1H), 8.31 (br s, 1H), 7.71 (s, 1H), 7.19 (s, 2H), 6.49 315 WO 2024/233900 PCT/US2024/028806 (br s, 1H), 4.44 (s, 2H), 3.98 (br s, 2H), 3.43 (s, 3H), 2.50 (br s, 3H), 2.15 (s, 6H).100 (R)-4-amino-N-(5-(azepan-2-yl)pyridin-3-yl)-l-(4-(methoxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(azepan-2-yl)pyridin-3-yl)-l-(4-(methoxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B22, Intermediate A30HPLC-1 (1-40% MeCN); White solid (20.5 mg, 55%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, CDCI3): 11.92 (s, 1H), 9.85 (d, 1H), 8.53 (d, 1H), 8.22 (d, 2H), 7.65 (s, 1H), 7.13 (s, 2H), 5.88 (d, 1H), 4.39 (s, 2H), 3.(t, 1H), 3.37 (s, 3H), 3.03-3.01 (m, 1H), 2.87-2.82 (m, 1H), 2.10 (s, 6H), 1.95-1.91 (m, 2H), 1.84-1.79 (m, 2H), 1.71-1.50 (m, 4H).101 4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2R,5S)-5- methylpyrrolidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5- ((2S,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4-amino-l-(4-(methoxymethyl)-2,6- dimethylphenyl)-N-(5-((2R,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6- oxo-l,6-dihydropyrimidine-5-carboxamide or 4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2S,5S)-5-methylpyrrolidin-2- yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B22, Intermediate A3 8HPLC-1 (10-40% MeCN); White solid (31.7 mg, 77%); LCMS m/z = 4[M+H]+; 1HNMR(400MHz, CDCI3): 1.31 (d, 3H), 1.63-1.79 (m, 1H), 2.02-2.15 (m, 1H), 2.19 (d, 6H), 2.24-2.34 (m, 1H), 2.35-2.46 (m, 1H), 3.(s, 3H), 3.67-3.82 (m, 1H), 4.48 (s, 2H), 4.64 (dd, 1H), 6.02 (d, 1H), 7.22 (s, 2H), 7.73 (s, 1H), 8.23-8.41 (m, 2H), 8.63 (d, 1H), 9.89 (d, 1H), 12.03 (s, 1H).102 4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2R,6S)-6- methylpiperidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5- ((2 S, 6R)-6-methylpiperi din-2-yl)pyri din-3 -yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamideor 4-amino-l-(4-(methoxymethyl)-2,6- 316 WO 2024/233900 PCT/US2024/028806 dimethylphenyl)-N-(5-((2R,6R)-6-methylpiperidin-2-yl)pyridin-3-yl)-6- oxo-l,6-dihydropyrimidine-5-carboxamide or 4-amino-l-(4- (methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2S,6S)-6-methylpiperi din-2- yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B22, Intermediate A34HPLC-3 (1-40% MeCN); White solid (33.9 mg, 61%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, CDCI3): 1.27 (d, 3H), 1.49 (d, 1H), 1.67-1.(m, 2H), 1.88-2.07 (m, 3H), 2.17 (s, 6H), 3.45 (s, 3H), 4.18 (d, 1H), 4.46 (s, 2H), 6.11 (d, 1H), 7.20 (s, 2H), 7.72 (s, 1H), 8.38 (s, 1H), 8.59 (s, 1H), 9.(d, 1H) 12.00 (s, 1H).103 4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2R,5S)-5- methylpyrrolidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5- ((2S,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4-amino-l-(4-(methoxymethyl)-2,6- dimethylphenyl)-N-(5-((2R,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6- oxo-l,6-dihydropyrimidine-5-carboxamide or 4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2S,5S)-5-methylpyrrolidin-2- yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B22, Intermediate A37HPLC-1 (1-40% MeCN); Yellow solid (57.9 mg, 85%); LCMS m/z = 4[M+H]+; 1HNMR(400MHz, CDCI3): 1.30 (d, 3H), 1.64-1.78 (m, 1H), 2.07-2.15 (m, 1H), 2.17 (d, 6H), 2.24-2.33 (m, 1H), 2.34-2.44 (m, 1H), 3.(s, 3H), 3.72-3.82 (m, 1H), 4.46 (s, 2H), 4.64 (d, 1H), 6.09 (d, 1H), 7.20 (s, 2H), 7.71 (s, 1H), 8.29 (d, 1H), 8.35 (s, 1H), 8.60 (d, 1H), 9.86 (d, 1H), 12.01 (s, 1H).104 (R)-4-amino-N-(5-(l-aminoethyl)pyridin-3-yl)-l-(4-ethoxy-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-aminoethyl )pyri din-3-yl)-l-(4-ethoxy-2,6-dimethylphenyl)- 6-oxo-1,6-dihydropyrimi dine-5 -carboxamideIntermediate B25, Intermediate A16HPLC-1 (5-35% MeCN); White solid (10.2 mg, 25%); LCMS m/z = 4[M+H]+; 1HNMR(400MHz, CDCI3): 11.99 (s, 1H), 9.74 (s, 1H), 8.51 (s, 317 WO 2024/233900 PCT/US2024/028806 1H), 8.20 (s, 2H), 7.67 (s, 1H), 6.65 (s, 2H), 6.08 (d, 1H), 4.15 (d, 1H), 3.(q, 2H), 2.05(d, 6H), 1.41-1.33 (m, 6H).105 4-amino-l-(4-(difluoromethyl)-2,6-dimethylphenyl)-N-(5- ((methylamino)methyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B17, Intermediate A56HPLC-1 (10-40% MeCN); White solid (60.9 mg, 92%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.99 (s, 1H), 9.93 (d, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 7.74 (s, 1H), 7.41 (s, 2H), 6.67 (t, 1H), 6.(d, 1H), 4.01 (s, 2H), 2.56 (s, 3H), 2.25 (s, 6H).106 (R)-4-amino-N-(5-(l-aminobutyl)pyridin-3-yl)-l-(4-(difluoromethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B17, Intermediate A7HPLC-1 (1-40% MeCN); White solid (28.2 mg, 41%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.94 (s, 1H), 9.82 (s, 1H), 8.50 (s, 1H), 8.34 (s, 1H), 8.25 (s, 1H), 7.71 (s, 1H), 7.38 (s, 2H), 6.84-6.47 (m, 1H), 6.42 (s, 1H), 4.14-4.02 (m, 1H), 2.23 (d, 6H, J = 8.4 Hz), 1.94-1.74 (m, 2H), 1.26 (br s, 2H), 0.86 (t, 3H).107 4-amino-l-(4-(difluoromethyl)-2,6-dimethylphenyl)-N-(5-((2R,6S)-6- methylpiperidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(4-(difluoromethyl)-2,6-dimethylphenyl)-N-(5- ((2 S, 6R)-6-methylpiperi din-2-yl)pyri din-3 -yl)-6-oxo-1,6- dihydropyrimidine-5-carboxamide or 4-amino-l-(4-(difluoromethyl)-2,6- dimethylphenyl)-N-(5-((2R,6R)-6-methylpiperidin-2-yl)pyridin-3-yl)-6- oxo-l,6-dihydropyrimidine-5-carboxamide or 4-amino-l-(4- (difluoromethyl)-2,6-dimethylphenyl)-N-(5-((2S,6S)-6-methylpiperidin-2- yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B17, Intermediate A31HPLC-1 (5-45% MeCN); White solid (44.6 mg, 98%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.93 (s, 1H), 10.00 (d, 1H), 8.65 (d, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 7.75 (s, 1H), 7.42 (s, 2H), 6.68 (t, 1H), 6.(d, 1H), 4.18 (t, 1H), 3.40 (d, 1H), 2.27 (s, 6H), 2.27-1.91 (m, 3H), 1.74- 1.71 (m, 2H), 1.51-1.47 (m, 1H), 1.29 (d, 3H). 318 WO 2024/233900 PCT/US2024/028806 108 4-amino-l-(4-(difluoromethyl)-2,6-dimethylphenyl)-N-(5-((2R,6S)-6- methylpiperidin-2-yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or 4-amino-l-(4-(difluoromethyl)-2,6-dimethylphenyl)-N-(5- ((2 S, 6R)-6-methylpiperi din-2-yl)pyri din-3 -yl)-6-oxo-1,6- dihydropyrimidine-5-carboxamide or 4-amino-l-(4-(difluoromethyl)-2,6- dimethylphenyl)-N-(5-((2R,6R)-6-methylpiperidin-2-yl)pyridin-3-yl)-6- oxo-l,6-dihydropyrimidine-5-carboxamide or 4-amino-l-(4- (difluoromethyl)-2,6-dimethylphenyl)-N-(5-((2S,6S)-6-methylpiperidin-2- yl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate Bl7, Intermediate A33HPLC-1 (5-35% MeCN); White solid (20.9 mg, 92%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, CDCI3): 11.93 (s, 1H), 10.09-9.90 (m, 1H), 8.64 (d, 1H), 8.43 (d, 1H), 8.35 (s, 1H), 7.74 (s, 1H), 7.42 (s, 2H), 6.91-6.(m, 1H), 6.11 (d, 1H), 4.24-4.13 (m, 1H), 3.42 (d, 1H), 2.26 (s, 6H), 1.95 (d, 3H), 1.84-1.67 (m, 2H), 1.57-1.44 (m, 1H), 1.30 (d, 3H).109 (S)-4-amino-l-(2,6-dichloro-4-(trifluoromethoxy)phenyl)-6-oxo-N-(5- (pyrrolidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide Intermediate B37, Intermediate A13HPLC-2 (10-40% MeCN); Yellow solid (10.1 mg, 60%); LCMS m/z = 5[M+H]+; 1HNMR(400MHz, CDCI3): 11.64 (s, 1H), 10.10 (s, 1H), 8.69 (d, 1H), 8.35 (d, 1H), 8.20 (t, 1H), 7.73 (s, 1H), 7.46 (d, 2H), 6.12 (d, 1H), 4.(t, 1H), 3.25-3.23 (m, 1H), 3.15-3.09 (m, 1H), 2.06-1.94 (m, 2H), 1.92-1.(m, 1H), 1.86-1.76 (m, 1H).110 (R)-4-amino-l-(2,6-dimethyl-4-(trifluoromethoxy)phenyl)-6-oxo-N-(5- (piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide Intermediate B38, Intermediate A4HPLC-1 (1-40% MeCN); White solid (21.2 mg, 66%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 1.26 (s, 1 H) ,1.48-1.58 (m, 1 H), 1.70-1.79 (m, 2 H), 1.85-1.96 (m, 2 H), 2.21 (d, 6 H), 2.81 (dd, 1 H), 3.(br.d, 1 H), 3.78 (dd, 1 H), 5.97 (br.d, 1 H), 7.10 (s, 2 H), 7.72 (s, 1 H), 8.29-8.35 (m, 2 H), 8.63 (d, 1 H), 9.97 (d, 1 H) ,11.83-11.93 (m, 1 H).ill 4-amino-l-(4-((R)-l,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-((R)- piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide or 4- 319 WO 2024/233900 PCT/US2024/028806 amino-1 -(4-((S)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5 -((R)- piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide Intermediate B40, Intermediate A4HPLC-3 (10-40% MeCN); White solid (22.8 mg, 50%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 1.47-1.64 (m, 1H), 1.77 (q, 2H), 1.87-2.02 (m, 3H), 2.23 (d, 6H), 2.71-2.92 (m, 1H), 3.19 (d, 1H), 3.71-3.(m, 1H), 4.49-4.88 (m, 2H), 5.58-5.87 (m, 1H), 5.99 (d, 1H), 7.26 (s, 2H), 7.73 (s, 1H), 8.29-8.38 (m, 1H), 8.41 (s, 1H), 8.58 (d, 1H), 9.95 (hr d, 1H), 11.92 (s, 1H).112 4-amino-N-(5 -((R)-azepan-2-yl)pyri din-3 -yl)-1 -(4-((S)-1,2-difluoroethyl)- 2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4- amino-N-(5-((R)-azepan-2-yl)pyridin-3-yl)-l-(4-((R)-l,2-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4-amino- N-(5-((S)-azepan-2-yl)pyridin-3-yl)-l-(4-((S)-l,2-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4-amino- N-(5-((S)-azepan-2-yl)pyri din-3 -yl)-1 -(4-((R)-1,2-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B40, Intermediate A29HPLC-1 (10-50% MeCN); White solid (28.9 mg, 44%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 1.57-1.82 (m, 4H), 1.88 (d, 2H), 2.(br d, 2H), 2.21 (s, 6H), 2.85-3.21 (m, 2H), 3.98 (s, 1H), 4.48-4.82 (m, 2H), 5.61-5.79 (m, 1H), 6.19 (d, 1H), 7.24 (s, 2H), 7.71 (s, 1H), 8.26-8.35 (m, 2H), 8.60 (s, 1H), 9.94 (br s, 1H), 11.92 (br s, 1H).113 4-amino-l-(4-((R)-l,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-((R)- piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide or 4- amino-1 -(4-((S)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5 -((R)- piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide Intermediate B41, Intermediate A4White solid (42 mg, 84%); LCMS m/z = 483 [M+H]+; 1H NMR (400 MHz, CDCh): 11.94 (s, 1H), 9.93 (d, 1H), 8.59 (s, 1H), 8.37 (d, 2H), 7.73 (s, 1H), 7.25 (s, 2H), 6.20 (d, 1H), 5.82-5.61 (m, 1H), 4.77-4.63 (m, 2H), 3.84 (dd, 1H), 3.19 (d, 1H), 2.81 (t, 1H), 2.22 (d, 6H), 2.00-1.84 (m, 3H), 1.79-1.(m, 2H), 1.62-1.48 (m, 1H). 320 WO 2024/233900 PCT/US2024/028806 114 4-amino-N-(5 -((R)-1 -aminoethyl )pyri din-3 -yl)-1 -(4-((S)-1,2-difluoroethyl)- 2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4- amino-N-(5-((R)-1 -aminoethyl)pyri din-3 -yl)-1 -(4-((R)-1,2-difluoroethyl)- 2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4- amino-N-(5-((S)-1 -aminoethyl )pyri din-3 -yl)-1 -(4-((S)-1,2-difluoroethyl)- 2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4- amino-N-(5-((S)-1 -aminoethyl )pyri din-3 -yl)-1 -(4-((R)-1,2-difluoroethyl)- 2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B41, Intermediate A16HPLC-3 (5-30% MeCN); White solid (11.1 mg, 31%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, CDCI3): 11.98 (s, 1H), 9.91 (s, 1H), 8.60 (s, 1H), 8.33 (br s, 3H), 7.74 (s, 1H), 7.26 (s, 2H), 6.25 (s, 1H), 5.88-5.61 (m, 1H), 4.82-4.74 (m, 1H), 4.73-4.68 (m, 1H), 4.67-4.63 (m, 1H), 4.61-4.(m, 1H), 4.30 (d, 1H), 2.23 (d, 6H), 1.53 (d, 3H).115 4-amino-N-(5 -((R)-azepan-2-yl)pyri din-3 -yl)-1 -(4-((S)-1,2-difluoroethyl)- 2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4- amino-N-(5-((R)-azepan-2-yl)pyridin-3-yl)-l-(4-((R)-l,2-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4-amino- N-(5-((S)-azepan-2-yl)pyridin-3-yl)-l-(4-((S)-l,2-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4-amino- N-(5-((S)-azepan-2-yl)pyri din-3 -yl)-1 -(4-((R)-1,2-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B41, Intermediate A29HPLC-1 (20-50% MeCN); White solid (22.1 mg, 41%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.92 (s, 1H), 9.98 (d, 1H), 8.65 (d, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 7.73 (s, 1H), 7.29 (s, 2H), 6.04 (d, 1H), 5.87- 5.59 (m, 1H), 4.81-4.52 (m, 2H), 3.98 (dd, 1H), 3.15 (td, 1H), 3.04 - 2.(m, 1H), 2.23 (s, 6H), 2.11-1.55 (m, 8H).116 (R)-4-amino-l-(2,6-dichloro-4-(l,2-difluoroethyl)phenyl)-N-(5- ((methylamino)methyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or (S)-4-amino-l-(2,6-dichloro-4-(l,2-difluoroethyl)phenyl)- N-(5-((methylamino)methyl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide 321 WO 2024/233900 PCT/US2024/028806 Intermediate B42, Intermediate A56HPLC-1 1-50% MeCN; White solid 40.8 mg, 88%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.72 (s, 1H), 9.98 (d, 1H), 8.57 (s, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 7.71 (s, 1H), 7.56 (s, 2H), 6.38-6.38 (m, 1H), 5.82-5.61 (m, 1H), 4.83-4.55 (m, 2H), 3.96 (s, 2H), 2.52 (s, 3H).117 (R)-4-amino-l-(2,6-dichloro-4-(l,2-difluoroethyl)phenyl)-N-(5- ((methylamino)methyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or (S)-4-amino-l-(2,6-dichloro-4-(l,2-difluoroethyl)phenyl)- N-(5-((methylamino)methyl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B43, Intermediate A56HPLC-1 (5-35% MeCN); White solid (27.8 mg, 61%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.72 (s, 1H), 10.05 (br d, 1H), 8.(d, 1H), 8.34 (br d, 2H), 7.73 (s, 1H), 7.58 (s, 2H), 6.16 (br d, 1H), 5.84- 5.63 (m, 1H), 4.85-4.71 (m, 1H), 4.71-4.58 (m, 1H), 3.91 (s, 2H), 2.51 (s, 3H).118 (S)-4-amino-l-(2,6-di chi oro-4-(tri fluoromethyl )phenyl)-6-oxo-N-(5- (pyrrolidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide Intermediate B23, Intermediate A13HPLC-1 (1-50% MeCN); White solid (22.1 mg, 50%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, DMSO-d6): 1.53-1.66 (m, 1H), 1.74-1.88 (m, 2H), 2.13-2.24 (m, 1H), 2.94-3.00 (m, 1H), 3.03-3.08 (m, 1H), 4.17 (br.t, 2H), 8.04 (t, 1H), 8.24 (s, 1H), 8.26 (br. s, 1H), 8.28 (d, 1H), 8.32 (s, 2H), 8.48 (s, 1H), 8.70 (d, 1H), 8.85 (br.d, 1H), 9.50-9.85 (m, 1H), 11.55-11.(m, 1H).119 (S)-4-amino-l-(2,6-di chi oro-4-(tri fluoromethyl )phenyl)-6-oxo-N-(5- (piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide Intermediate B23, Intermediate A5HPLC-1 (1-50% MeCN); White solid (14 mg, 31%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, DMSO-d6): 1.37-1.50 (m, 3 H), 1.60 (d, 1H), 1.70-1.85 (m, 2 H), 2.64-2.75 (m, 1 H), 3.09 (d, 1H), 3.68 (d, 1H), 8.08 (t, 1H), 8.27 (d, 1H), 8.24 (d, 1H), 8.33 (s, 2H), 8.48 (s, 1H), 8.67 (d, 1H), 8.(d, 1H), 9.69 (d, 1H), 11.71 (s, 1H). 322 WO 2024/233900 PCT/US2024/028806 120 4-amino-N-(5-(aminom ethyl )pyri din-3-yl)-l-(2,6-di chi oro-4- (trifluoromethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B23, Intermediate ASOHPLC-1 (1-30% MeCN); White solid (10.8 mg, 15%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, CDCI3): 11.65 (s, 1H), 10.11 (d, 1H), 8.62 (d, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 7.85 (s, 2H), 7.74 (s, 1H), 6.19 (d, 1H), 3.(s, 2H).121 (R)-4-amino-l-(2,6-dichloro-4-(trifluoromethyl)phenyl)-N-(5-(2-methoxy- -(methyl amino)ethyl)pyri din-3 -yl)-6-oxo-1, 6-dihydropyrimidine-5 - carboxamide or (S)-4-amino-l-(2,6-dichloro-4-(trifluoromethyl)phenyl)-N- (5-(2-methoxy-l-(methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6- dihydropyrimidine-5-carboxamideIntermediate B23, Intermediate A23HPLC-1 (25-55% MeCN); White solid (36.3 mg, 56%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 2.62 (s, 3H), 3.39 (s, 3H), 3.76 (dd, 1H), 3.96 (br dd, 1H), 4.28 (br dd, 1H), 6.26 (br d, 1H), 7.72 (s, 1H), 7.(s, 2H), 8.41 (br s, 1H) 8.60 (s, 1H), 8.67 (br s, 1H), 10.03 (br d, 1H), 11.(s, 1H).122 (R)-4-amino-l-(2,6-dichloro-4-(trifluoromethyl)phenyl)-N-(5-(2-methoxy- -(methyl amino)ethyl)pyri din-3 -yl)-6-oxo-1, 6-dihydropyrimidine-5 - carboxamide or (S)-4-amino-l-(2,6-dichloro-4-(trifluoromethyl)phenyl)-N- (5-(2-methoxy-l-(methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6- dihydropyrimidine-5-carboxamideIntermediate B23, Intermediate A22HPLC-3 (5-35% MeCN); White solid (24.4 mg, 53%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.64 (s, 1 H), 10.13 (br s, 1H), 8.(d, 1H), 8.35 (s, 1H), 8.22 (br s, 1H), 7.84 (s, 2H), 7.73 (s, 1H), 6.24 (br d, 1H), 4.26 (br d, 1H), 3.51-3.60 (m, 1H), 3.45-3.45 (m, 1H), 3.45 (br d, 1H), 3.41 (s, 3H).123 (S)-4-amino-l-(2,6-dichloro-4-(dimethylamino)phenyl)-6-oxo-N-(5- (piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide Intermediate B8, Intermediate A5 323 WO 2024/233900 PCT/US2024/028806 HPLC-1 (1-70% MeCN); Yellow solid (23.4 mg, 85%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.90 (s, 1H), 9.96 (br d, 1H), 8.(s, 1H), 8.39 (br d, 2H), 7.75 (s, 1H), 6.72 (s, 2H), 6.12 (br s, 1H), 3.85-3.(m, 1H), 3.14 (br d, 1H), 3.03 (s, 6H), 2.78 (dt, 1H), 1.98-1.92 (m, 1H), 1.(brt, 2H), 1.76 (br d, 1H), 1.74-1.63 (m, 2H), 1.55-1.48 (m, 1H).124 (S)-4-amino-l-(2,6-dichloro-4-isopropoxyphenyl)-6-oxo-N-(5-(piperidin-2- yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B31, Intermediate A5HPLC-2 (5-40% MeCN); White solid (34.1 mg, 75%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, DMSO-d6): 11.91 (s, 1H), 9.63 (d, 1H), 8.78- 8.72 (m, 2H), 8.43 (s, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.36 (s, 2H), 4.84 (td, 1H), 3.83 (d, 1H), 3.16 (d, 1H), 2.79 (t, 1H), 1.88-1.76 (m, 2H), 1.65 (s, 1H), 1.51 (d, 3H), 1.32 (d, 6H).125 (R)-4-amino-l-(2,6-dimethyl-4-propoxyphenyl)-6-oxo-N-(5-(piperidin-2- yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B26, Intermediate A4HPLC-1 (5-40% MeCN); Yellow solid (26 mg, 57%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 12.06 (s, 1H), 9.94 (br.d, 1H), 8.(d, 1H), 8.36 (d, 1H), 8.24 (t, 1H), 7.77 (s, 1H), 6.76 (s, 2H), 5.95 (br.d, 1H), 3.96 (t, 2H), 3.72 (dd, 1H), 3.21 (br.d, 1H), 2.80 (td, 1H), 2.15 (s, 6H), 1.93 (br.d, 1H), 1.87-1.83 (m, 2H), 1.67 (br.d, 2H), 1.60-1.47 (m, 1H), 1.(t, 3H).126 (R)-4-amino-N-(5-(l-aminoethyl)pyridin-3-yl)-l-(2,6-dimethyl-4- propoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-aminoethyl)pyridin-3-yl)-l-(2,6-dimethyl-4- propoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B26, Intermediate A16HPLC-1 (5-35% MeCN); White solid (18.5 mg, 76%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 0.97 (t, 3H), 1.39 (d, 3H), 1.64-1.(m, 2 H), 2.05 (d, 6H), 3.86 (t, 2H), 4.14 (d, 1H), 5.86-6.17 (m, 1H), 6.66 (s, 2H), 7.67 (s, 1H), 8.20 (d, 2H), 8.53 (s, 1H), 9.79 (d, 1H), 12.00 (s, 1H). 324 WO 2024/233900 PCT/US2024/028806 127 4-amino-l-(2,6-dimethyl-4-propoxyphenyl)-N-(5- ((methylamino)methyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B26, Intermediate A56HPLC-1 (1-40% MeCN); White solid (39 mg, 62%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, CDCI3): 12.11 (s, 1H), 9.88 (br.d, 1H), 8.(s, 1H), 8.39 (br.s, 1H), 8.31 (s, 1H), 7.75 (s, 1H), 6.73 (s, 2H), 6.12 (br.d, 1H), 3.97-3.87 (m, 4H), 2.48 (s,3H), 2.13 (s, 6H), 1.86-1.76 (m, 2H), 1.(br.t, 3H).128 (R)-4-amino-N-(5-(l-aminopropyl)pyridin-3-yl)-l-(4-(difluoromethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-aminopropyl)pyridin-3-yl)-l-(4-(difluoromethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate Bl7, Intermediate Al7HPLC-1 (1-30% MeCN); White solid (23.7 mg, 47%); LCMS m/z = 4[M+H]+; 1HNMR(400MHz, CDCI3): 0.66-0.86 (m, 3H), 1.64-1.93 (m, 2H), 2.14 (d, 6H), 3.91 (s, 1H), 6.35 (s, 1H), 6.57 (t, 1H), 7.30 (s, 2H), 7.(s, 1H), 8.17 (s, 1H), 8.24 (s, 1H), 8.45 (s, 1H), 9.76 (d, 1H), 11.85 (s, 1H).129 (R)-4-amino-N-(5-(l-aminopropyl)pyridin-3-yl)-l-(2,6-dichloro-4- (ethoxymethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)- 4-amino-N-(5 -(1 -aminopropyl )pyri din-3 -yl)-1 -(2,6-dichloro-4-(ethoxym ethyl )phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B28, Intermediate A8HPLC-1 (1-40% MeCN); White solid (11.3 mg, 30%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 0.83 (t, 3H), 1.29 (t, 3H), 1.76-1.(m, 2H), 3.61 (q, 2H), 3.94 (t, 1H), 4.53 (s, 2H), 6.49 (s, 1H), 7.51 (s, 2H), 7.70 (s, 1 H), 8.26 (d, 2H), 8.57 (d, 1H), 9.95 (d, 1H), 11.76 (s, 1 H).130 (R)-4-amino-N-(5-(l-aminoethyl)pyridin-3-yl)-l-(4-(ethoxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-aminoethyl )pyri din-3-yl)-l-(4-(ethoxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B29, Intermediate A16 325 WO 2024/233900 PCT/US2024/028806 HPLC-1 (10-30% MeCN); White solid (17.2 mg, 47%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.94 (s, 1H), 9.73 (d, 1H), 8.49 (s, 1H), 8.50-8.14 (m, 2H), 7.63 (s, 1H), 7.13 (s, 2H), 6.11 (d, 1H), 4.42 (s, 3H), 4.42-4.16 (m, 1H), 3.52 (q, 2H), 2.09 (d, 6H), 1.43 (s, 3H), 1.20 (t, 3H).131 (R)-4-amino-l-(4-(ethoxymethyl)-2,6-dimethylphenyl)-6-oxo-N-(5- (piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide Intermediate B29, Intermediate A4HPLC-3 (1-30% MeCN); White solid (50.9 mg, 80%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 1.28 (t, 3H), 1.46-1.59 (m, 1H), 1.63-1.80 (m, 2H), 1.83-1.98 (m, 3H), 2.17 (s, 6H), 2.77 (td, 1H), 3.14 (d, 1H), 3.60 (q, 2H), 3.76-3.86 (m, 1H), 4.50 (s, 2H), 6.21 (d, 1H), 7.21 (s, H), 7.71 (s, 1H), 8.32-8.40 (m, 2H), 8.58 (d, 1H), 9.90 (d, 1H), 12.02 (s, 1H).132 (R)-4-amino-N-(5-(azepan-2-yl)pyridin-3-yl)-l-(4-(ethoxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(azepan-2-yl)pyridin-3-yl)-l-(4-(ethoxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B29, Intermediate A30HPLC-1 (15-45% MeCN); White solid (10.7 mg, 39%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.93 (s, 1H), 9.84 (d, 1H), 8.53 (d, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 7.64 (s, 1H), 7.14 (s, 2H), 5.98 (d, 1H), 4.(s, 2H), 3.91 (t, 1H), 3.52 (q, 2H), 3.14-2.96 (m, 1H), 2.92-2.79 (m, 1H), 2.10 (s, 6H), 1.99-1.90 (m, 2H), 1.88-1.76 (m, 2H), 1.75-1.47 (m, 4H), 1.(t, 3H).133 (S)-4-amino-l-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-N-(5-(piperidin-2- yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B30, Intermediate A5HPLC-1 (5-45% MeCN); White solid (10.9 mg, 30%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.80 (s, 1H), 10.00 (d, 1H), 8.63 (s, 1H), 8.37 (br.s, 1H), 8.31 (s,lH), 7.72 (s, 1H), 7.04 (s, 2H), 6.15 (d, 1H), 4.09 (q, 2H), 3.79-3.74 (m, 1H), 3.19 (d, 2H), 2.83-2.75 (m, 1H), 2.03-1.87 326 WO 2024/233900 PCT/US2024/028806 (m, 2H), 1.87-1.82 (m, 1H), 1.80-1.75 (m, 1H), 1.73-1.68 (m, 2H), 1.46 (t, 3H).134 (R)-4-amino-N-(5-(l-amino-2-methoxyethyl)pyridin-3-yl)-l-(2,6-di chloro- 4-ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-amino-2-methoxyethyl)pyridin-3-yl)-l-(2,6-dichloro-4- ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B30, Intermediate A22HPLC-1 (15-45% MeCN); White solid (10.7 mg, 39%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, CDCI3): 11.80 (s, 1H), 10.00 (d, 1H), 8.63 (s, 1H), 8.37 (br.s, 1H), 8.31 (s,lH), 7.72 (s, 1H), 7.04 (s, 2H), 6.15 (d, 1H), 4.09 (q, 2H), 3.79-3.74 (m, 1H), 3.19 (d, 2H), 2.83-2.75 (m, 1H), 2.03-1.(m, 2H), 1.87-1.82 (m, 1H), 1.80-1.75 (m, 1H), 1.73-1.68 (m, 2H), 1.46 (t, 3H).135 (R)-N-(5-(l,4-oxazepan-3-yl)pyridin-3-yl)-4-amino-l-(2,6-dichloro-4- ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-N-(5- (l,4-oxazepan-3-yl)pyri din-3-yl)-4-amino-l-(2,6-di chi oro-4-ethoxyphenyl)- 6-oxo-1,6-dihydropyrimi dine-5 -carboxamideIntermediate B30, Intermediate A27HPLC-1 (1-40% MeCN); White solid (20.3 mg, 44%); LCMS m/z = 5[M+H]+; 1HNMR(400MHz, CDCI3): 11.81 (s, 1H), 10.00 (d, 1H), 8.70 (d, 1H), 8.31 (d, 1H), 8.21 (s, 1H), 7.73 (s, 1H), 7.05 (s, 2H), 6.12 (d, 1H), 4.12-4.03 (m, 3H), 4.01-3.91 (m, 2H), 3.89-3.81 (m, 1H), 3.62 (dd, 1H), 3.22 (td, 1H), 3.04 (ddd, 1H), 2.12-1.94 (m, 2H), 1.46 (t, 3H).136 (R)-4-amino-N-(5-(l-aminopropyl)pyridin-3-yl)-l-(2,6-di chi oro-4- ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-aminopropyl)pyridin-3-yl)-l-(2,6-dichloro-4-ethoxyphenyl)- 6-oxo-1,6-dihydropyrimi dine-5 -carboxamideIntermediate B30, Intermediate A8HPLC-3 (15-35% MeCN); White solid (33.7 mg, 92%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, CDCI3): 11.78 (s, 1H), 9.86 (d, 1H), 8.51 (s, 1H), 8.28-8.17 (m, 2H), 7.68 (s, 1H), 7.00 (s, 2H), 6.46 (d, 1H), 4.04 (q, 2H), 3.99-3.91 (m, 1H), 1.96-1.68 (m, 2H), 1.42 (t, 3H, J = 6.8 Hz), 0.80 (t, 3H). 327 WO 2024/233900 PCT/US2024/028806 137 (R)-4-amino-N-(5-(l-aminoethyl)pyri din-3-yl)-l-(2,6-di chi oro-4- ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-aminoethyl)pyridin-3-yl)-l-(2,6-dichloro-4-ethoxyphenyl)- 6-oxo-1,6-dihydropyrimi dine-5 -carboxamideIntermediate B30, Intermediate A16HPLC-1 (10-50% MeCN); White solid (21.9 mg, 65%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.87 (s, 1H), 9.63 (s, 1H), 8.77 (s, 1H), 8.72 (s, 1H), 8.41 (s, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.36 (s, 2H), 4.- 4.15 (m, 3H), 1.38-1.33 (m, 6H).138 4-amino-l-(2,6-dichloro-4-ethoxyphenyl)-N-(5-(((ethyl- d5)amino)methyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B30, Intermediate A53HPLC-1 (1-40% MeCN); White solid (32.1 mg, 88%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.84 (s, 1H), 10.00 (br d, 1H), 8.(d, 1H), 8.43 (br s, 1H), 8.34 (s, 1H), 7.74 (s, 1H), 7.06 (s, 2H), 6.07 (d, 1H), 4.10 (q, 2H), 3.96 (s, 2H), 1.48 (t, 3H).139 (R)-4-amino-N-(5-(amino(cyclopropyl)methyl)pyridin-3-yl)-l-(2,6- dichloro-4-ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(amino(cyclopropyl)methyl)pyridin-3-yl)-l-(2,6- dichloro-4-ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A9HPLC-1 (15-45% MeCN); Yellow solid (36.4 mg, 50%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.81 (s, 1H), 9.82 (br s, 1H), 8.(s, 1H), 8.39 (br s, 1H), 8.31 (br s, 1H), 7.71 (s, 1H), 7.02 (s, 2H), 6.53 (br s, 1H), 4.07 (q, 2H), 3.41 (br d, 1H), 1.45 (t, 3H), 1.30 (br d, 1H), 0.68 (br s, 1H), 0.57-0.48 (m, 2H), 0.27 (br d, 1H).140 (R)-4-amino-N-(5-(l-amino-2-ethoxyethyl)pyridin-3-yl)-l-(2,6-di chi oro-4- ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-amino-2-ethoxyethyl)pyridin-3-yl)-l-(2,6-dichloro-4- ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B30, Intermediate A10 328 WO 2024/233900 PCT/US2024/028806 HPLC-1 (10-40% MeCN); White solid (32.4 mg, 97%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.84 (s, 1H), 9.95 (d, 1H), 8.66 (d, 1H), 8.34 (d, 2H), 7.74 (s, 1H), 7.06 (s, 2H), 6.17 (s, 1H), 4.32 (dd, 1H), 4.10 (q, 2H), 3.63-3.66 (m, 1H), 3.56 (dd, 3H), 1.48 (t, 3H), 1.21 (t, 3H).141 (R)-4-amino-l-(2,6-dichloro-4-ethoxyphenyl)-N-(5-(2-methoxy-l- (methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or (S)-4-amino-l-(2,6-dichloro-4-ethoxyphenyl)-N-(5-(2- methoxy-l-(methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine- 5-carboxamideIntermediate B30, Intermediate A23HPLC-1 (25-65% MeCN); White solid (29.6 mg, 59%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 12.28 (s, 1H), 10.13 (d, 1H), 8.92- 9.16 (m, 1H), 8.86 (s, 1H), 8.52-8.79 (m, 1H), 7.96 (s, 1H), 7.50 (s, 2H), 6.36-6.46 (m, 1H), 4.54 (s, 1H), 4.31 (q, 2H), 4.12-4.22 (m, 1H), 3.98-4.(m, 1H), 3.61 (s, 3H), 2.86 (s, 3H), 1.69 (t, 1H).142 (R)-4-amino-N-(5-(l-aminoethyl)pyri din-3-yl)-l-(2,6-di chi oro-4- ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-aminoethyl)pyridin-3-yl)-l-(2,6-dichloro-4-ethoxyphenyl)- 6-oxo-1,6-dihydropyrimi dine-5 -carboxamideIntermediate B30, Intermediate A17HPLC-1 (10-40% MeCN); White solid (32.2 mg, 68%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.81 (s, 1H), 9.96 (br s, 1H), 8.(s, 1H), 8.32-8.26 (m, 2H), 7.74 (s, 1H), 7.06 (s, 2H), 6.23-6.15 (m, 1H), 4.27-4.12 (m, 1H), 4.10 (q, 2H), 3.62 -3.44 (m, 3H), 1.50-1.46 (m, 6H).143 (R)-4-amino-N-(5-(l-amino-3,3-difluoropropyl)pyridin-3-yl)-l-(2,6- dichloro-4-ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-( 1 -amino-3,3 -difluoropropyl )pyri din-3 -yl)-1 -(2,6- dichloro-4-ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A45HPLC-1 (10-40% MeCN); White solid (42.1 mg, 77%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.86 (s, 1H), 10.02 (d, 1H), 8.70 (d, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 7.75 (s, 1H), 7.07 (s, 2H), 6.09-5.76 (m, 2H), 4.25 (dd, 1H), 4.11 (q, 2H), 2.31-2.17 (m, 2H), 1.48 (t, 3H). 329 WO 2024/233900 PCT/US2024/028806 144 (R)-4-amino-N-(5-(l-aminoethyl)pyridin-3-yl)-l-(4-(2,2-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-aminoethyl )pyri din-3-yl)-l-(4-(2,2-difluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B32, Intermediate A16HPLC-1 (10-40% MeCN); White solid (22.2 mg, 81%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.90 (s, 1H), 9.84 (d, 1H), 8.54 (s, 1H), 8.29-8.06 (m, 2H), 7.66 (s, 1H), 7.06 (s, 2H), 6.08-5.71 (m, 2H), 4.(s, 1H), 3.83-3.74 (m, 2H), 3.07 (td, 2H), 2.10 (d, 6H), 1.38 (s, 3H).145 (R)-4-amino-l-mesityl-6-oxo-N-(5-(piperidin-2-yl)pyri din-3-yl)-l,6- dihydropyrimidine-5-carboxamideIntermediate B35, Intermediate A4HPLC-3 (15-40% MeCN); White solid (23.9 mg, 47%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 12.06 (s, 1H), 9.89 (br.d, 1H), 8.(br.s, 1H), 8.48 (s, 1H), 8.30 (s, 1H), 7.77 (s, 1H), 7.07 (s, 2H), 5.98 (d, 1H), 3.96 (d, 1H), 3.16 (d, 1H), 2.93-2.77 (m, 1H), 2.38 (s, 3H), 2.17 (d, 6H), 2.09-1.92 (m, 3H), 1.91-1.71 (m, 2H), 1.68-1.49 (m, 1H).146 (R)-4-amino-N-(5-(azepan-2-yl)pyri din-3 -yl)-1 -mesityl-6-oxo-1,6- dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(azepan-2- yl)pyri din-3-yl)-l-mesityl-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B35, Intermediate A29HPLC-1 (25-65% MeCN); White solid (31.3 mg, 63%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 12.06 (s, 1H), 9.73 (br.d, 1H), 8.(br.s, 1H), 8.43 (s, 1H), 8.24 (br.s, 1H), 7.66 (s, 1H), 6.96 (s, 2H), 5.(br.d, 1H), 4.08 (br.d, 1H), 3.10-2.89 (m, 2H), 2.28 (s, 3H), 2.25-2.(m,lH), 2.05 (d, 6H), 1.98-1.83 (m, 3H), 1.79-1.50 (m, 4H).147 (R)-4-amino-N-(5-(l-aminoethyl)pyridin-3-yl)-l-mesityl-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(l-aminoethyl )pyri din-3 -yl)-1 -mesityl-6-oxo-1,6-dihydropyrimidine-5 - carboxamideIntermediate B35, Intermediate A16HPLC-1 (1-35% MeCN); White solid (37.9 mg, 70%); LCMS m/z = 3[M+H]+; 1HNMR (400 MHz, CDCI3): 11.99 (s, 1H), 9.73 (d, 1H), 8.46 (d, 330 WO 2024/233900 PCT/US2024/028806 1H), 8.46-8.20 (m, 3H), 7.65 (s, 1H), 6.95 (s, 2H), 6.43-6.41 (m, 1H), 6.31- 6.26 (m, 1H), 6.39-6.17 (m, 1H), 4.19 (d, 1H), 2.26 (s, 3H), 2.04 (d, 6H,), 1.43 (d, 3H).148 (R)-4-amino-N-(5-(azepan-2-yl)pyridin-3-yl)-l-(4-ethyl-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(azepan-2-yl)pyridin-3-yl)-l-(4-ethyl-2,6-dimethylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxamideIntermediate B58, Intermediate A29HPLC-1 (15-45% MeCN); Pink solid (38.3 mg, 100%); LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, CDCI3): 1.19 (t, 3H) 1.50-1.63 (m, 2H) 1.64- 1.74 (m, 2H) 1.75-1.88 (m, 2H) 1.89-1.98 (m, 2H) 2.07 (s, 6H) 2.57 (q, 2H) 2.77-2.92 (m, 1H) 3.03 (d, 1H) 3.89 (t, 1H) 5.98 (d, 1H) 6.98 (s, 2H) 7.(s, 1H) 7.67 (s, 1H) 8.16-8.27 (m, 1H) 8.19-8.27 (m, 1H) 8.53 (d, 1H) 9.(d, 1H) 11.96 (s, 1H).149 (S)-4-amino-l-(2,6-dichloro-4-fluorophenyl)-6-oxo-N-(5-(pyrrolidin-2- yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B39, Intermediate A13HPLC-2 (5-35% MeCN); White solid (19.9 mg, 54%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.73 (s, 1H), 9.92 (br d, 1H), 8.(d, 1H), 8.41 (s, 2H), 7.70 (s, 1H), 7.31 (d, 2H), 6.25 (br d, 1H), 4.64-4.(m, 1H), 3.51-3.25 (m, 2H), 2.41 (dt, 1H), 2.28-2.17 (m, 2H), 2.16-2.02 (m, 1H).150 (R)-4-amino-N-(5-(l -aminobut-3 -yn-1 -yl)pyri din-3 -yl)-1 -(2,6-dichloro-4- ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l -aminobut-3 -yn-1 -yl)pyri din-3 -yl)-1 -(2,6-dichloro-4- ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B30, Intermediate A57BHPLC-1 (10-50% MeCN); White solid (11.8 mg, 27%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.86 (s, 1H), 10.04 (d, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 7.77 (s, 1H), 7.08 (s, 2H), 6.18-6.09 (m, 1H), 4.26 (t, 1H), 4.12 (q, 2H), 2.69-2.53 (m, 2H), 2.10 (s, 1H), 1.50 (t, 3H).151 (R)-4-amino-N-(5-(l -aminobut-3 -yn-1 -yl)pyri din-3 -yl)-1 -(2,6-dichloro-4- ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- 331 WO 2024/233900 PCT/US2024/028806 amino-N-(5-(l -aminobut-3 -yn-1 -yl)pyri din-3 -yl)-1 -(2,6-dichloro-4- ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideIntermediate B30, Intermediate A57AHPLC-1 (1-40% MeCN); White solid (21.8 mg, 35%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.84 (s, 1H), 10.06 (d, 1H), 8.72 (d, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 7.76 (s, 1H), 7.07 (s, 2H), 6.11 (d, 1H), 4.(t, 1H), 4.11 (q, 2H), 2.66-2.52 (m, 2H), 2.08 (s, 1H), 1.49 (t, 3H).152 (R)-4-amino-l-(3,5-dichloropyridin-4-yl)-6-oxo-N-(5-(piperidin-2- yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B52, Intermediate A4HPLC-2 (5-35% MeCN); White solid (46.6 mg, 43%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.60 (s, 1H), 9.71 (d, 1H), 8.98 (s, 2H), 8.88 (d, 1H), 8.63 (d, 1H), 8.47 (s, 1H), 8.24 (d, 1H), 8.05 (s, 1H), 3.60-3.52 (m, 1H), 3.02 (d, 1H), 2.68-2.58 (m, 1H), 1.78 (d, 1H), 1.69 (d, 1H), 1.55 (d, 1H), 1.49-1.35 (m, 2H), 1.34-1.22 (m, 1H).153 (R)-4-amino-N-(5-(l-aminopropyl)pyridin-3-yl)-l-(3,5-dichloropyridin-4- yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(l- aminopropyl)pyri din-3 -yl)-1 -(3,5-dichloropyridin-4-yl)-6-oxo-1,6- dihydropyrimidine-5-carboxamideIntermediate B52, Intermediate A60HPLC-15 (20-40% MeCN); White solid (12.5 mg, 30%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, DMSO-d6): 11.59 (s, 1H), 9.72 (br d, 1H), 8.99 (s, 2H), 8.88 (br d, 1H), 8.71 (d, 1H), 8.48 (s, 1H), 8.23 (d, 1H), 7.95 (t, 1H), 3.72 (t, 1H), 1.94 (br s, 2H), 1.65-1.50 (m, 2H), 0.78 (t, 3H).154 4-amino-l-(2,6-dichloro-4-(2-methoxyethyl)phenyl)-N-(5- ((ethylamino)methyl)pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B49, Intermediate A24HPLC-1 (1-40% MeCN); White solid (28.3 mg, 76%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.71 (s, 1H), 9.91 (br d, 1H), 8.(d, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 7.63 (s, 1H), 7.34 (s, 2H), 5.98 (br d, 1H), 3.89 (s, 2H), 3.58 (t, 2H), 3.30 (s, 3H), 2.84 (t, 2H), 2.79-2.70 (m, 2H), 1.12 (t, 3H). 332 WO 2024/233900 PCT/US2024/028806 155 (R)-4-amino-N-(5-(l-aminoethyl)pyridin-3-yl)-l-(4-(2-fluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-aminoethyl )pyri din-3-yl)-l-(4-(2-fluoroethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B33, Intermediate A16HPLC-7 (1-25% MeCN); White solid (18.5 mg, 40%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 12.04-12.00 (m, 1H), 9.83 (br s, 1H), 8.56 (br s, 1H),8.36-8.31 (m, 2H), 7.76 (d, 1H), 7.31 (d, 1H), 7.31-7.30 (m, 1H), 6.36 (br d, 1H), 6.09-5.73(m, 2H), 4.77-4.63 (m, 2H), 4.36-4.24 (m, 1H), 3.08-3.29 (m, 2H), 2.18 (d, 6H), 1.54-1.49 (m, 3H).156 4-amino-l-(4-(2,2-difluoroethyl)-2,6-dimethylphenyl)-N-(5- ((ethylamino)methyl )pyri din-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamideIntermediate B32, Intermediate A24HPLC-1 (20-60% MeCN); Yellow solid (18.9 mg, 69%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.99 (s, 1H), 9.91 (d, 1H), 8.57 (d, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.73 (s, 1H), 7.13 (s, 2H), 6.13-5.82 (m, 2H), 3.95 (s, 2H), 3.15 (dt, 2H), 2.84 (q, 2H), 2.17 (s, 6H), 1.18 (t, 3H).157 4-amino-N-(5-(l-aminocyclobutyl)pyridin-3-yl)-l-(4-(methoxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B22, Intermediate A51HPLC-7 (1-40% MeCN); White solid (23.6 mg, 57%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.92 (s, 1H), 9.89 (d, 1H), 8.65 (d, 1H), 8.34 (s, 1H), 8.05 (br s, 1H), 7.66 (s, 1H), 7.14 (s, 2H), 5.88 (d, 1H), 4.39 (s, 2H), 3.37 (s, 3H), 2.53-2.45 (m, 2H), 2.20-2.14 (m, 2H), 2.11 (s, 6H), 2.06-1.98 (m, 1H), 1.78-1.67 (m, 1H).158 (R)-4-amino-l-(2,6-dimethyl-4-((methylsulfonyl)methyl)phenyl)-6-oxo-N- (5-(piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B53, Intermediate A4HPLC-1 (15-40% MeCN); White solid (12 mg, 14%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, CDCI3): 11.95 (s, 1H), 9.61 (d, 1H), 8.57- 8.50 (m, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 7.64 (s, 1H), 7.23 (s, 2H), 5.90 (d, 1H), 4.24-4.16 (m, 2H), 4.05-3.94 (m, 1H), 3.26 (d, 1H), 2.94-2.87 (m, 1H), 333 WO 2024/233900 PCT/US2024/028806 2.84 (s, 3H), 2.13 (s, 3H), 2.10 (s, 3H), 2.05-1.85 (m, 4H), 1.81-1.67 (m, 1H), 1.62-1.44 (m, 1H).159 (R)-4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-(5- oxopiperazin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-(5- oxopiperazin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide Intermediate B22, Intermediate A74HPLC-1 (1-25% MeCN); White solid (14.2 mg, 52%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 12.05 (s, 1H), 9.84 (br d, 1H), 8.(s, 1H), 8.29 (br d, 2H), 7.66 (s, 1H), 7.14 (s, 2H), 6.10 (br d, 2H), 4.39 (s, 2H), 4.06 (br t, 1H), 3.67 (br d, 2H), 3.37-3.39 (m, 5H), 2.10 (s, 6H).160 (R)-4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-(5- oxopiperazin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-(5- oxopiperazin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide Intermediate B22, Intermediate A74HPLC-1 (1-30% MeCN); White solid (16.1 mg, 59%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 12.04 (s, 1H), 9.84 (br d, 1H), 8.(d, 1H), 8.32-8.25 (m, 2H), 7.66 (s, 1H), 7.14 (s, 2H), 6.09 (br s, 2H), 4.(s, 2H), 4.06 (t, 1H), 3.75-3.61 (m, 2H), 3.42-3.34 (m, 5H), 2.10 (s, 6H).161 (R)-4-amino-l-(4-fluoro-2,6-dimethylphenyl)-6-oxo-N-(5-(piperi din-2- yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide trifluoroacetate Intermediate B50, Intermediate A4HPLC-12 (10-40% MeCN); White solid (16.1 mg, 59%); LCMS m/z = 4[M+H]+; 1HNMR (500 MHz, DMSO-d6): 12.23 (s, 1H), 9.50 (d, 1H), 9.01- 8.85 (m, 2H), 8.75-8.64 (m, 1H), 8.61 (d, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 7.16 (d, 2H), 4.31 (t, 1H), 3.37 (d, 1H), 3.05 (q, 1H), 2.09 (s, 6H), 1.96 (d, 1H), 1.92-1.78 (m, 3H), 1.74-1.56 (m, 2H).162 (R)-4-amino-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-N-(5-(piperidin-2- yl)pyri din-3 -yl)-6-thioxo-1,6-dihydropyrimidine-5-carboxamide tri fluoroacetateIntermediate B56, Intermediate A4 334 WO 2024/233900 PCT/US2024/028806 HPLC-12 (10-40% MeCN); White solid (18.9 mg, 34%); LCMS m/z = 5[M+H]+; 1HNMR (500 MHz, CDCI3): 14.48 (s, 1H), 10.46 (s, 1H), 10.(s, 1H), 9.62 (s, 2H), 8.85 (s, 1H), 8.64 (s, 1H), 8.58 (s, 1H), 7.79 (s, 1H), 7.48 (s, 1H), 7.45 (s, 1H), 6.56 (s, 1H), 4.28 (d, 1H), 3.51 (d, 1H), 3.23 - 2.99 (m, 1H), 2.26 (s, 3H), 2.14 (s, 3H), 2.13-1.83 (m, 5H), 1.67 (q, 1H).163 (R)-4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-(piperi din-2- yl)pyridin-3 -yl)-6-thioxo-1,6-dihydropyrimidine-5-carboxamide tri fluoroacetateIntermediate B57, Intermediate A4HPLC-12 (10-40% MeCN); White solid (10.8 mg, 38%); LCMS m/z = 4[M+H]+; 1HNMR (500 MHz, DMSO-d6): 12.81 (s, 1H), 8.86 (d, 1H), 8.(s, 1H), 8.73 (q, 1H), 8.34 (s, 1H), 8.30 (s, 1H), 8.18 (s, 1H), 7.11 (s, 2H), 5.68 (s, 2H), 4.35 (s, 2H), 4.27 (t, 1H), 3.27 (s, 3H), 3.02 (t, 1H), 1.99 (s, 6H), 1.93-1.73 (m, 4H), 1.69-1.52 (m, 2H).164 4-amino-l-((S)-2-chloro-6-methylphenyl)-N-(3-methoxy-2-(2- (methylamino)ethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B3, Intermediate A64HPLC-14 (33-53% MeCN); Yellow solid (31.4 mg, 57%); LCMS m/z = 442 [M+H]+; 1HNMR (400 MHz, MeOH-d4): 11.69 (s, 1H), 8.08 (s, 1H), 7.57 (d, 1H), 7.54-7.48 (m, 1H), 7.46 (t, 1H), 7.43-7.38 (m, 1H), 7.29 (t, 1H), 6.87 (d, 1H), 3.88 (s, 3H), 3.16-3.10 (m, 2H), 3.08-3.00 (m, 2H), 2.(s, 3H), 2.26 (s, 3H).165 4-amino-l-(2,6-dichloro-4-ethoxyphenyl)-N-(5-(((2- (methylsulfonyl)ethyl)amino)methyl)pyridin-3-yl)-6-oxo-l,6- dihydropyrimidine-5-carboxamideIntermediate B30, Intermediate A66HPLC-12 (10-40% MeCN); White solid (41 mg, 51%); LCMS m/z = 5[M+H]+; 1HNMR (500 MHz, DMSO-d6): 12.01 (s, 1H), 9.57 (d, 1H), 9.(s, 2H), 8.86 (d, 1H), 8.79 (d, 1H), 8.43 (s, 1H), 8.38 (d, 1H), 8.29 (t, 1H), 7.35 (s, 2H), 4.26 (s, 2H), 4.18 (q, 2H), 3.53 (dd, 2H), 3.42 (s, 2H), 3.13 (s, 3H), 1.36 (t, 3H).166 (S)-4-amino-l-(2-methoxyphenyl)-N-(2-morpholino-3-(pyrrolidin-2-yl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-l- 335 WO 2024/233900 PCT/US2024/028806 (2-methoxyphenyl)-N-(2-morpholino-3-(pyrrolidin-2-yl)phenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamideIntermediate B59, Intermediate A75HPLC-16 (15-45% MeCN); Yellow solid (14.4 mg, 16%); LCMS m/z = 491 [M+H]+; 1H NMR (400 MHz, CDCI3): 12.21 (s, 1H), 10.03 (d, 1H), 8.15 (dd, 1H), 7.83 (s, 1H), 7.50-7.48 (m, 1H), 7.30 (dd, 1H), 7.23-7.20 (m, 2H), 7.10-7.08 (m, 2H), 5.76 (d, 1H), 4.51 (t, 1H), 3.95-3.92 (m, 2H), 3.(s, 3H), 3.70 (dd, 2H), 3.27-3.25 (m, 3H), 3.01-2.96 (m, 1H), 2.93 (d, 2H), 2.26-2.20 (m, 1H), 1.90-1.88 (m, 2H), 1.68-1.65 (m, 1H).167 (S)-4-amino-l-(2,6-dichlorophenyl)-N-(2-fluoro-3-(pyrrolidin-2-yl)phenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-l-(2,6- dichlorophenyl)-N-(2-fluoro-3-(pyrrolidin-2-yl)phenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamideIntermediate B9, Intermediate A76HPLC-1 (5-35% MeCN); Yellow solid (7.1 mg, 31%); LCMS m/z = 4[M+H]+; 1HNMR(400MHz, CDCI3): 11.83 (s, 1H), 10.08 (s, 1H), 8.30 (t, 1H), 7.73 (s, 1H), 7.55 (d, 2H), 7.46-7.42 (m, 1H), 7.16-7.09 (m, 2H), 6.(s, 1H), 4.52-4.50 (m, 1H), 3.22-3.14 (m, 2H), 2.27 (s, 1H), 1.96-1.80 (m, 3H).168 (S)-4-amino-l-(2,6-dichlorophenyl)-N-(2-fluoro-3-(pyrrolidin-2-yl)phenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-l-(2,6- dichlorophenyl)-N-(2-fluoro-3-(pyrrolidin-2-yl)phenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamideIntermediate B9, Intermediate A77HPLC-16 (30-60% MeCN); Yellow solid (3.4 mg, 16%); LCMS m/z = 4[M+H]+; 1HNMR(400MHz, CDCI3): 11.70 (s, 1H), 10.00 (s, 1H), 8.18 (t, 1H), 7.64 (s, 1H), 7.45 (d, 2H), 7.37-7.33 (m, 1H), 7.09-6.99 (m, 2H), 5.(s, 1H), 4.38-4.34 (m, 1H), 3.12-2.96 (m, 2H), 2.19-2.11 (m, 1H), 1.86-1.(m, 3H).169 (R)-4-amino-l-(2,6-dichlorophenyl)-N-(2-methoxy-3-(pyrrolidin-2- yl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-l- (2,6-di chi orophenyl)-N-(2-m ethoxy-3-(pyrrolidin-2-yl)phenyl)-6-oxo-1,6- dihydropyrimidine-5-carboxamide 336 WO 2024/233900 PCT/US2024/028806 Intermediate B9, Intermediate A81chiral SFC (Rilas Technologies, Regis Whelk 0-1 (S,S) 250 x 21 mm, 30% EtOH + 0.25% diethylamine in CO2)HPLC-1 (1-50% MeCN); White solid (15 mg); LCMS m/z = 474 [M+H]+; 1HNMR (500 MHz, DMSO-d6): 11.92 (s, 1H), 9.74 (d, 1H), 8.60 (d, 1H), 8.40 (s, 1H), 8.22 (dd, 1H), 7.77 (d, 2H), 7.64 (dd, 1H), 7.19 (dd, 1H), 7.(t, 1H), 4.27 (t, 1H), 3.63 (s, 3H), 3.07-2.97 (m, 1H), 2.87 (q, 1H), 2.11 (dq, 1H), 1.85 - 1.66 (m, 2H), 1.47-1.36 (m, 1H).170 4-amino-N-(3-(aminomethyl)-2-(difluoromethoxy)phenyl)-l-(2,6- dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide tri fluoroacetateIntermediate B9, Intermediate A84HPLC-12 (10-50% MeCN); White solid (3.4 mg, 5%); LCMS m/z = 4[M+H]+; 1HNMR (500 MHz, DMSO-d6): 11.95 (s, 1H), 9.62 (d, 1H), 8.(d, 1H), 8.42 (s, 1H), 8.37 (d, 1H), 8.16 (s, 3H), 7.77 (d, 2H), 7.64 (t, 1H), 7.41 (t, 1H), 7.28 (d, 1H), 7.01 (t, 1H), 4.05 (q, 2H).171 4-amino-N-(3 -(aminomethyl)-2-(trifluorom ethyl )phenyl)-1 -(2,6- dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide Intermediate B9, Intermediate A78HPLC-1 (10-40% MeCN); White solid (6.6 mg, 36%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, DMSO-d6): 11.61 (brd, 1H), 9.62 (br s, 1H), 8.67 (br s, 1H), 8.53-8.31 (m, 1H), 7.75 (d, 2H), 7.74-7.67 (m, 1H), 7.65- 7.60 (m, 1H), 7.55 (d, 1H), 3.90 (d, 2H).172 (R)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-N-(6-(piperidin-2- yl)pyridazin-4-yl)-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-l- (2,6-dichloro-4-methoxyphenyl)-6-oxo-N-(6-(piperidin-2-yl)pyridazin-4- yl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B10, Intermediate A79HPLC-2 (5-35% MeCN); Brown solid (13.7 mg, 51%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 12.07 (s, 1H), 9.89 (d, 1H), 9.17 (d, 1H), 8.10 (d, 1H), 7.75 (s, 1H), 7.07 (s, 2H), 6.28 (d, 1H), 4.14-4.07 (m, 1H), 3.89 (s, 3H), 3.31 (d, 1H), 2.96-2.87 (m, 1H), 2.03 (d, 1H), 1.94 (s, 1H), 1.72 (s, 1H), 1.66 (d, 1H), 1.63-1.55 (m, 2H). 337 WO 2024/233900 PCT/US2024/028806 173 (S)-4-amino-l-(2-chloro-6-hydroxyphenyl)-6-oxo-N-(5-(piperi din-2- yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamideIntermediate B60, Intermediate A5HPLC-1 (1-40% MeCN); Yellow oil (8.7 mg, 45%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, DMSO-d6): 12.09-12.04 (m, 1H), 9.53 (br d, 1H), 8.72-8.68 (m, 1H), 8.54 (br d, 1H), 8.28-8.26 (m, 2H), 8.12 (s, 1H), 7.37-7.31 (m, 1H), 7.08-7.01 (m, 2H), 3.80 (br d, 2H), 3.13 (br d, 1H), 2.80- 2.72 (m, 1H), 1.84-1.74 (m, 2H), 1.62 (br s, 1H), 1.49 (br d, 3H).
Example 174 and 175.Synthesis of 4-amino-N-(5-((R)-l-aminoethyl)pyridin-3-yl)-l-(4- ((R)-l-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((S)-l-aminoethyl)pyridin-3-yl)-l-(4-((R)-l-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((R)-l- aminoethyl)pyridin-3-yl)-l-(4-((S)-l-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((S)-l-aminoethyl)pyridin-3-yl)-l-(4- ((S)-l-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide. 338 WO 2024/233900 PCT/US2024/028806 Peak 2 339 WO 2024/233900 PCT/US2024/028806 Peak 1 Step 1.To a mixture of methyl 4-amino-l-(4-(l-methoxyethyl)-2,6-dimethylphenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxylate (Intermediate B51, 50 mg, 0.151 mmol) and tert-butyl (S)-(l-(5-aminopyridin-3-yl)ethyl)carbamate or tert-butyl (R)-(l-(5-aminopyridin-3-yl)ethyl)carbamate (Intermediate Al6, 53.7 mg, 0.226 mmol) in toluene (3 mL) was added AlMe3 (2 M in toluene, 0.226 mL) at 0°C and the mixture stirred at 40°C for 1 h under N2.The reaction mixture was diluted with 1M NaOH (20mL) and extracted with EtOAc (3x340 WO 2024/233900 PCT/US2024/028806 20mL). The combined organics were washed with brine (2x 10 mL), dried (Na2SO4) and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (50% EtOAc/PE) followed by prep-SFC (DAICEL CHIRALPAK IE, 250 x 30 mm, pm); 40% [Heptane-(4:1 IPA:MeCN)] in CO2) to afford Peak 1 as a white solid (10 mg, 12%) and Peak 2 as a white solid (10 mg, 12%) which were independently taken through to the next step.
Step 2a. Synthesis of 4-amino-N-(5-((R)-l-aminoethyl)pyridin-3-yl)-l-(4-((R)-l- methoxy ethyl)-2,6-dimethylphenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxamide or 4-amino- N-(5-((S)-l-aminoethyl)pyridin-3-yl)-l-(4-((R)-l-methoxyethyl)-2,6-dimethylphenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((R)-l-aminoethyl)pyridin-3-yl)-l- (4-((S)-l-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((S)-l-aminoethyl)pyridin-3-yl)-l-(4-((S)-l-methoxy ethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide.
The compound of Peak 1 (Part 1 Peak 1,10 mg, 18.64 pm 01) in DCM (2 mL) and TEA (mL) was stirred at 25°C for 0.5 h and the reaction mixture concentrated under N2 and under reduced pressure. The residue was purified by prep-HPLC-1 (1-50% MeCN) to give Example 174. White solid (4.2 mg, 46%). LCMS m/z = 437 [M+H]+; 1HNMR (400 MHz, CDCI3): 1.46 (d, 3H), 1.53 (br d, 3H), 2.19 (d, 6H), 3.31 (s, 3H), 4.31 (q, 2H), 6.26 (br d, 1H), 7.18 (br d, 2H), 7.75 (s, 1H), 8.33 (br d, 3H), 8.58 (s, 1H), 9.85 (br s, 1H), 12.03 (s, 1H).
Step 2b. Synthesis of 4-amino-N-(5-((R)-l-aminoethyl)pyridin-3-yl)-l-(4-((R)-l-methoxy ethyl)-2,6-dimethylphenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxamide or 4-amino- N-(5-((S)-l-aminoethyl)pyridin-3-yl)-l-(4-((R)-l-methoxyethyl)-2,6-dimethylphenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((R)-l-aminoethyl)pyridin-3-yl)-l- (4-((S)-l-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((S)-l-aminoethyl)pyridin-3-yl)-l-(4-((S)-l-methoxy ethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide The compound of Peak 2 (Part 1, Peak 2) was deprotected in an analogous manner as described for Peak 1 to give Example 175. White solid (4.2 mg, 46%). LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 1.37 (d, 3 H) 1.46 (br d, 3 H) 2.10 (d, 6 H) 3.21 (s, H) 4.13-4.33 (m, 2 H) 6.19 (br s, 1 H) 7.08 (s, 2 H) 7.65 (s, 1 H) 8.26 (br d, 2 H) 8.47 (s, H) 9.74 (br s, 1H) 11.93 (s, 1 H). 341 WO 2024/233900 PCT/US2024/028806 Example 176.Synthesis of (R)-4-amino-N-(5-(l-aminobutyl)pyridin-3-yl)-l-(4- (methoxymethyl)-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide.
Step 1. Synthesis of tert-butyl (R)-(l-(5-(4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)butyl)carbamate.
AlMe3 (2 M, 142 pL) was added dropwise to a solution of methyl 4-amino-l-(4- (methoxymethyl)-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B22, 30 mg, 0.095 mmol) and tert-butyl (R)-(l-(5-aminopyridin-3- yl)butyl)carbamate (Intermediate A7, 37.6 mg, 0.142 mmol) in toluene (2 mL) at 0°C and the mixture stirred at 40°C for 1 h under N2. The reaction mixture was quenched with IN NaOH aq. (2 mL) at 0°C and extracted with EtOAc (4x 5 mL). The combined organics were washed with brine (5 mL) and dried (Na2S04) and evaporated to dryness to afford the title compound as a yellow oil (50 mg, crude). LCMS m/z = 551 [M+H]+; Step 2. Synthesis of (R)-4-amino-N-(5-(l-aminobutyl)pyridin-3-yl)-l-(4-(methoxymethyl)- 2,6-dime thy Ipheny I)-6-oxo-1,6-dihydropyrimidine-5-carb oxamide.
Tert-butyl (R)-(l-(5-(4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)butyl)carbamate (Part 1, 50 mg, 0.091 mmol) was dissolved into DCM (1 mL) and TFA (1 mL) and the mixture stirred at 25°C for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue purified by prep-HPLC-8 (20-55% MeCN) to give the title compound as a pale yellow solid (12.3 mg, 27%). LCMS m/z = 451 [M+H]+; 1HNMR (400 MHz, CDCI3): 0.91 (t, 3H) 1.19-1.39 (m, 2H) 1.67 (d, 2H) 2.18 (s, 6 H) 3.45 (s, 3H) 3.94 (t, 1H) 4.46 (s, 2 H) 6.07 (br d, 1H) 7.21 (s, 2H) 7.73 (s, 1H) 8.12 (s, 1H) 8.26 (s, 1H) 8.67 (d, 1H) 9.97 (d, 1H) 12.01 (s, 1H). 342 WO 2024/233900 PCT/US2024/028806 Example 177.Synthesis of (S)-4-amino-N-(5-(l-amino-2-ethoxyethyl)pyridin-3-yl)-l-(4- (methoxymethyl)-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (R)- 4-amino-N-(5-(l-amino-2-ethoxyethyl)pyridin-3-yl)-l-(4-(methoxymethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide.
Step 1. Synthesis of tert-butyl (S)-(l-(5-(4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)-2-ethoxyethyl)carbamate or tert- butyl (R)-(l-(5-(4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)-2-ethoxyethyl)carbamate.
To a solution of methyl 4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B22, 50 mg, 0.158 mmol) and tert-butyl (S)- (l-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamate or tert-butyl (R)-(l-(5-aminopyridin-3- yl)-2-ethoxyethyl)carbamate (Intermediate All, 66.5 mg, 0.236 mmol) in toluene (3 mL) was added AlMe3 (2 M in toluene, 394 pL) at 0°C and the mixture stirred at 60°C for 1 h underN2. The reaction mixture was quenched by addition H20 (0.5 mL) and TFA (0.5 mL) at 0°C,filtered and concentrated under reduced pressure to give the title compound as a white solid (75 mg, 0.132 mmol, 84 %). LCMS m/z = 451 [M+H]+.
Step 2. Synthesis of (S)-4-amino-N-(5-(l-amino-2-ethoxyethyl)pyridin-3-yl)-l-(4- (methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4- 343 WO 2024/233900 PCT/US2024/028806 amino-N-(5-(l-amino-2-ethoxyethyl)pyridin-3-yl)-l-(4-(methoxymethyl)-2,6-dimethylphenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxamide.
A mixture of tert-butyl (S)-(l-(5-(4-amino-l-(4-(methoxymethyl)-2,6-dimethylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)-2-ethoxyethyl)carbamate or tert- butyl (R)-( 1 -(5-(4-amino-1 -(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)-2-ethoxyethyl)carbamate (Step 1, 70 mg, 0.124 mmol) in DCM (1 mL) and TFA (2 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under N2 and the residue purified by prep-HPLC-9 (10-45% MeCN) to afford the title compound as a brown solid (9.90 mg, 16%). LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.95 (s, 1H) 9.84 (d, 1H) 8.62 (d, 1H) 8.25 (s, 1H) 8.17 (s, 1H) 7.66 (s, 1H) 7.13 (s, 2H) 5.94 (d, 1H) 4.39 (s, 2 H) 4.18 (dd, 1H) 3.40-3.55 (m, H) 3.37 (s, 3H) 2.10 (s, 6H) 1.13 (t, 3H).
Example 178.Synthesis of 4-amino-l-(2,6-dichloro-4-ethoxyphenyl)-N-(5- ((ethylamino)methyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide.
AlMe3 (2M in toluene, 209 pL) was added to a mixture of methyl 4-amino-l-(2,6-dichloro-4- ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B30, 50 mg, 0.1mmol) and 5-((ethylamino)methyl)pyridin-3-amine (Intermediate A12, 31.7 mg, 0.209 mmol) in toluene (2 mL) and the mixture was stirred at 0°C for 5 min and then stirred at 100°C for 0.5 hr under N2. The reaction mixture was quenched by addition IN NaOH aq. (2 mL) at 0°C and extracted with EtOAc (4x 5 mL). The combined organics were washed with sat. aq.NaQ (5 mL), dried (Na2S04) and concentrated under reduced pressure. The residue was purified by prep-HPLC-8 (5-40% MeCN) to give the title compound as a white solid (45.mg, 61%,). LCMS m/z = 477 [M+H]+; 1H NMR (400 MHz, CDCI3): 11.84 (s, 1H), 9.96 (d, 1H), 8.58 (d, 1H), 8.47-8.41 (m, 2H), 8.32 (s, 1H), 7.72 (s, 1H), 7.04 (s, 2H), 6.20 (d, 1H), 4.08 (q, 2H), 3.97 (s, 2H), 2.83 (q, 2H), 1.46 (t, 3H), 1.26-1.15 (m, 3H).344 WO 2024/233900 PCT/US2024/028806 Example 179.Synthesis of 4-amino-N-(5-(l-aminocyclobutyl)pyridin-3-yl)-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide.
Step 1. Synthesis of tert-butyl (l-(5-(4-amino-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)cyclobutyl)carbamate.
AlMe3 (2 M, 262 uL) was added to a solution of methyl 4-amino-l-(2,6-dichloro-4- methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B10, 60.0 mg, 0.174 mmol) and tert-butyl (l-(5-aminopyridin-3-yl)cyclobutyl)carbamate (Intermediate A51, 51.0 mg, 0.192 mmol) in toluene (15 mL) at 0°C under N2 and the mixture heated at 80°C for h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3x mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, 50% EtOAc/PE) to afford the title compound as a yellow solid (30 mg, 30%). LCMS m/z = 575 [M+H]+.
Step 2. Synthesis of 4-amino-N-(5-(1 -aminocyclobutyl)pyridin-3-yl)-l-(2,6-dichloro-4- methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide.
A mixture of tert-butyl (l-(5-(4-amino-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)cyclobutyl)carbamate (30.0 mg, 52.1 umol) in hydrochioric/dioxane (4 M, 6 mL) was stirred at 25 °C for 10 min. The reaction mixture was concentrated under reduced pressure and the residue purified by prep-HPLC-1 (12-42% MeCN) to afford the title compound as a white solid (8.20 mg, 30% yield). LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, MeOH-d4): 8.81-8.77 (m, 1H), 8.53 (s, 1H), 8.40-8.35 (m, 1H), 8.22 (t, 1H), 8.08 (s, 1H), 7.23 (s, 2H), 3.90 (s, 3H), 2.73-2.62 (m, 2H), 2.46-2.38 (m, 2H), 2.23-2.12 (m, 1H), 1.96-1.82 (m, 1H).
Example 180.Synthesis of 4-amino-l-(2,6-dichlorophenyl)-N-(3-((2R,5R)-5- methylpyrrolidin-2-yl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4-amino-l- (2,6-dichlorophenyl)-N-(3-((2S,5S)-5-methylpyrrolidin-2-yl)phenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxami de. 345 WO 2024/233900 PCT/US2024/028806 A dry flask containing methyl 4-amino-l-(2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine- 5-carboxylate (Intermediate B9, 50.3 mg, 0.160 mmol) and rel-tert-butyl (2S,5S)-2-(3- aminophenyl)-5-methylpyrrolidine-l-carboxylate (Intermediate A72, 64.1 mg, 0.192 mmol) was evacuated and backfilled three times with nitrogen. Anhydrous toluene (3 mL) was added and the solution cooled to 0 °C and trimethylaluminum solution (2.0 M in toluene, 0.240 mL, 0.480 mmol,) was added. The flask was removed from the ice bath and the reaction stirred at it for 10 min and then heated to 100°C for l h. The reaction was cooled to it, quenched with methanol (2 mL) and TFA (0.2 mL), poured into water (30 mL) and extracted with DCM (4x 10 mL). The combined organics were washed with saturated aqueous sodium bicarbonate, water, and brine, dried (MgSO4) and evaporated to dryness in vacuo. The residue was dissolved in DCM (2 mL) and TFA (1 mL) and the solution stirred at it for 3 h. The reaction mixture was evaporated to dryness and the residue purified by prep- HPLC-10 (10-60%) followed by chiral SFC (Regis Whelk O-l (S,S) 4.6 x 100 mm, 3 pm;, 45% EtOH + 0.25% diethylamine in CO2) to afford: Peak 1, Example 180. 4-amino-l-(2,6-dichlorophenyl)-N-(3-((2R,5R)-5-methylpyrrolidin-2- yl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4-amino-l-(2,6-dichlorophenyl)- N-(3-((2S,5S)-5-methylpyrrolidin-2-yl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide (white powder, 17.9 mg). LCMS m/z = 458 [M+H]+; 1HNMR (500 MHz, DMSO-d6): 11.(s, 1H), 9.68 (d, 1H), 9.43 (s, 1H), 8.73 (d, 1H), 8.46 (s, 1H), 8.43-8.28 (m, 1H), 7.84 (dd, 1H), 7.77 (d, 2H), 7.71-7.58 (m, 2H), 7.40 (t, 1H), 7.15 (d, 1H), 4.68-4.55 (m, 1H), 3.81-3.(m, 1H), 2.40 (ddt, 1H), 2.25 (dq, 1H), 2.13 (dtd, 1H), 1.72 (dq, 1H), 1.34 (d, 3H).346 WO 2024/233900 PCT/US2024/028806 Example 181-186 The title compounds were prepared from the appropriate ester and the appropriate amine using an analogous 2-Step method as described for Example 179.
ExampleNoName, Structure, Starting Material (SM), Data 181 4-amino-N-(5-(l-aminocyclopropyl)pyridin-3-yl)-l-(2,6-di chi oro-4- methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideN NH2&Yo CI NIntermediate B10, Intermediate A40HPLC-1 (10-40% MeCN); White solid (9.7 mg, 24%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, MeOH-d4): 8.70 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 8.06-8.03 (m, 1H), 7.22 (s, 2H), 3.90 (s, 3H), 1.18-1.13 (m, 2H), 1.11-1.(m, 2H).182 4-amino-N-(5-(4-aminotetrahydro-2H-pyran-4-yl)pyridin-3-yl)-l-(2,6-dichloro- 4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide n !יa ji 0 0 ، y nh2MeO^^TI Intermediate B10, Intermediate A63HPLC-2 (9-39% MeCN); White solid (10.1 mg, 48%); LCMS m/z = 5[M+H]+; 1HNMR (400 MHz, DMSO־d6): 11.82 (s, 1H), 9.79-9.49 (m, 1H), 8.77 (s, 1H), 8.74-8.66 (m, 1H), 8.45 (s, 1H), 8.40 (d, 1H), 8.04 (d, 1H), 7.(d, 2H), 3.89 (s, 3H), 3.87-3.81 (m, 2H), 3.62 (d, 2H), 2.00-1.92 (m, 2H), 1.(d, 2H).183 4-amino-N-(5-(l-aminocyclobutyl)pyridin-3-yl)-l-(2,6-di chi oro-4-ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamideN NH2. AsxT> Me/ 0 CI N 347 WO 2024/233900 PCT/US2024/028806 Intermediate B30, Intermediate A51HPLC-5 (30-50% MeCN); White solid (20 mg, 80%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, MeOH-d4): 12.16 (s, 1H), 8.93 (s, 1H), 8.42 (s, 1H), 8.36 (s, 1H), 8.11 (s, 1H), 7.22 (s, 2H), 4.18-4.11 (m, 2H), 2.91-2.79 (m, 2H), 2.70-2.60 (m, 2H), 2.34-2.20 (m, 1H), 2.13-1.90 (m, 1H), 1.47-1.40 (t, 3H).184 4-amino-1 -(4-((R)-1 -fluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-((R)- piped din-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide or 4-amino- l-(4-((S)-l-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-((R)-piperidin-2- yl)pyri din-3-yl)-l,6-dihydropyrimidine-5-carboxamide r ^n!nh h n 0 0 ، JMe NF or !e jO 0 0 .Me NFIntermediate B54, Intermediate A4HPLC-13 (35-60% MeCN); Yellow solid (20.4 mg, 58%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.96 (s, 1H), 10.11-9.89 (m, 1H), 8.(d, 1H), 8.34 (d, 1H), 8.19 (s, 1H), 7.74 (s, 1H), 7.25 (s, 1H), 7.21 (s, 1H), 5.(d, 1H), 5.77-5.51 (m, 1H), 3.73-3.65 (m, 1H), 3.21 (d, 1H), 2.27-2.17 (m, 6H), 1.92 (d, 2H), 1.87-1.78 (m, 2H), 1.71 (d, 2H), 1.65 (d, 1H), 1.63-1.47 (m, 3H).185 4-amino-1 -(4-((R)-1 -fluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-((R)- piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide or 4-amino- l-(4-((S)-l-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-((R)-piperidin-2- yl)pyri din-3 -yl)-l,6-dihydropyrimidine-5 -carboxamide 348 WO 2024/233900 PCT/US2024/028806 r ^nt nh h n 0 0 VMe NF orNH2 ״ M ,NrYvMxyQ MeAA، 0 0 v y Me NFIntermediate B54, Intermediate A4HPLC-13 (30-60% MeCN); Grey solid (9.6 mg, 27%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.87 (s, 1H), 9.92 (d, 1H), 8.62 (d, 1H), 8.24 (d, 1H), 8.07 (s, 1H), 7.65 (s, 1H), 7.16 (s, 1H), 7.12 (s, 1H), 5.93 (d, 1H), 5.65-5.46 (m, 1H), 3.59-3.54 (m, 1H), 3.12 (d, 1H), 2.75-2.67 (m, 1H), 2.12 (d, 6H), 1.71 (s, 2H), 1.62 (d, 2H), 1.56 (d, 2H), 1.49-1.40 (m, 3H).186 (R)-4-amino-1 -(4-(l, 1 -difluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5- (piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide Y1fNYj fl p/[ Me N Intermediate B55, Intermediate A4HPLC-13 (25-65% MeCN); Grey solid (47.7 mg, 93%); LCMS m/z = 4[M+H]+; 1HNMR (400 MHz, CDCI3): 11.93 (s, 1H), 10.04 (d, 1H), 8.70 (d, 1H), 8.33 (s, 1H), 8.20 (s, 1H), 7.74 (s, 1H), 7.40 (s, 2H), 6.25 (d, 1H), 3.67 (d, 1H), 3.23 (d, 1H), 2.81 (t, 1H), 2.25 (s, 6H), 1.97 (t, 6H), 1.82 (d, 1H), 1.73- 1.65 (m, 1H), 1.61-1.49 (m, 3H).
Example 187 and 188.Synthesis of (R)-4-amino-N-(5-(3-aminotetrahydro-2H-pyran-3- yl)pyridin-3 -yl)-1 -(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5- carboxamide and (S)-4-amino-N-(5-(3-aminotetrahydro-2H-pyran-3-yl)pyridin-3-yl)-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide. 349 WO 2024/233900 PCT/US2024/028806 N NH2 n״nh 2 AlMe3 (2 M, 0.26 mL) was added to a mixture of methyl 4-amino-l-(2, 6-dichloro-4- methoxy-phenyl)-6-oxo-pyrimidine-5-carboxylate (Intermediate BIO, 60 mg, 0.174 mmol) and 5-(3-aminotetrahydro-2H-pyran-3-yl)pyridin-3-amine (Intermediate A55, 40.4 mg, 0.25 mmol) in toluene (2 mL) at 0°C under N2 and the mixture stirred at 100°C for 0.5 h under N2.The mixture reaction was quenched by H20 (0.2 mL) and TFA (0.2 mL) and the mixture purified by prep-HPLC-1 (5-40% MeCN). The residue further separated by SFC (DAICEL CHIRALCEL OX, 250 x 30 mm, 10 pm); 55% EtOH (+0.1% NH4OH)) to afford: Peak 1, Example 187.(R)-4-amino-N-(5-(3-aminotetrahydro-2H-pyran-3-yl)pyridin-3-yl)- 1-(2,6-dichioro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(3-aminotetrahydro-2H-pyran-3-yl)pyridin-3-yl)-l -(2,6-dichl oro-4- methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide. White solid (20.1 mg, 21%). LCMS m/z = 505 [M+H]+; 1HNMR (400 MHz, CDCI3): 11.70 (s, 1H), 9.98 (d, 1H), 8.70 (d, 1H), 8.48 (d, 1H), 8.23 (t, 1H), 7.66 (s, 1H), 6.99 (s, 2H), 5.96 (d, 1H), 3.86-3.80 (m, 4H), 3.67 (d, 1H), 3.53-3.46 (m, 2H), 2.06 (d, 1H), 1.91-1.82 (m, 1H), 1.74-1.71 (m, 1H), 1.54-1.47 (m, 1H).
Peak 2, Example 188.R)-4-amino-N-(5-(3-aminotetrahydro-2H-pyran-3-yl)pyridin-3-yl)-l- (2,6-dichloro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(3-aminotetrahydro-2H-pyran-3-yl)pyridin-3-yl)-l -(2,6-di chi oro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide. White solid (14.5 mg, 44%). %). LCMS m/z = 505 [M+H]+; 1HNMR (400 MHz, CDCI3): 11.81 (s, 1H), 10.09 (d, 1H), 8.81 (d, 1H), 8.58 (d, 1H), 8.33 (t, 1H), 7.77 (s, 1H), 7.10 (s, 2H), 6.05 (d, 1H), 3.96-3.91 (m, 4H), 3.77 (d, 1H), 3.63-3.59 (m, 2H), 2.17-2.12 (m, 1H), 2.03 (s, 1H), 1.85-1.81 (m, 1H), 1.64-1.58 (m, 1H).
Example 189 and 190.Synthesis of (R)-4-amino-l-(2,6-dichlorophenyl)-6-oxo-N-(3-(5- oxopiperazin-2-yl)phenyl)-1,6-dihydropyrimidine-5-carboxamide and (S)-4-amino-1 -(2,6-350 n״nh 2 WO 2024/233900 PCT/US2024/028806 dichlorophenyl)-6-oxo-N-(3-(5-oxopiperazin-2-yl)phenyl)-l,6-dihydropyrimidine-5- carboxamide The title compounds were prepared from methyl 4-amino-l-(2,6-dichlorophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B9) and 5-(3-aminophenyl)piperazin-2-one (Intermediate Al 8) using an analogous method to that described for Example 179 and 180.SFC (DAICEL CHIRALPAK IH-3, 50 x 4.6 mm, 3 pm); MeOH (+0.1% isopropylamine)) to afford: Peak 1, Example 189.(R)-4-amino-l-(2,6-dichlorophenyl)-6-oxo-N-(3-(5-oxopiperazin-2- yl)phenyl)-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-l-(2,6-dichlorophenyl)-6- oxo-N-(3-(5-oxopiperazin-2-yl)phenyl)-l,6-dihydropyrimidine-5-carboxamide. Yellow solid (59.5 mg, 74%). %). LCMS m/z = 473 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 11.78 (s, 1H), 9.74 (br d, 1H), 8.74-8.71 (m, 1H), 8.46 (s, 1H), 7.82-7.77 (m, 3H), 7.65-7.60 (m, 3H), 7.29 (t, 1H), 7.13 (br d, 1H), 3.90-3.88 (m, 1H), 3.36 (s, 3H), 3.31-3.27 (m, 2H), 3.13-3.15 (m, 1H), 2.96 (br s, 1H).
Peak 2, Example 190.(R)-4-amino-l-(2,6-dichlorophenyl)-6-oxo-N-(3-(5-oxopiperazin-2- yl)phenyl)-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-l-(2,6-dichlorophenyl)-6- oxo-N-(3-(5-oxopiperazin-2-yl)phenyl)-l,6-dihydropyrimidine-5-carboxamide. White solid (42.8 mg, 53%). LCMS m/z = 473 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 11.76 (s, 1H), 9.72 (br d, 1H), 8.69 (br d, 1H), 8.43 (s, 1H), 7.78-7.74 (m, 3H), 7.66-7.57 (m, 3H), 7.27 (t,1H), 7.10 (d, 1H), 3.88 (dd, 1H), 3.31-3.24 (m, 3H), 3.12-3.06 (m, 1H).
Example 191.Synthesis of 4-amino-l-(2,6-dichlorophenyl)-N-(3-((2R,5R)-5- (hydroxymethyl)pyrrolidin-2-yl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4- amino-l-(2,6-dichlorophenyl)-N-(3-((2S,5S)-5-(hydroxymethyl)pyrrolidin-2-yl)phenyl)-6- oxo-l,6-dihydropyrimidine-5-carboxamide.351 WO 2024/233900 PCT/US2024/028806 N NH2 Methyl 4-amino-l-(2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B9, 51 mg, 0.160 mmol) and tert-butyl 2-(3-aminophenyl)-5- (hydroxymethyl)pyrrolidine-l-carboxylate (Intermediate A65, 55.8 mg, 0.192 mmol) wasevacuated and backfilled three time with nitrogen. Anhydrous toluene (3 mL) was added and the solution cooled to 0°C. To this was added AlMe3 solution (2.0 M in toluene, 0.24 mL) and the reaction stirred at RT for 10 min and then at 100°C for l h. The reaction was cooled to RT and quenched with methanol (2 mL) and TFA (0.2 mL), poured into 30 mL water, and extracted with DCM (4x 10 mL). The combined organics were washed with saturatedaqueous sodium bicarbonate, water, brine, dried (MgSO4), and evaporated to dryness. The residue was dissolved in DCM (2 mL) and TFA (1 mL) and the solution stirred at RT for 3 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue purified by prep-HPLC-10 (10-60% MeCN) followed by chiral SFC (Rilas Technologies, Regis Whelk O-l (S,S) 21 x 250 mm, 45% EtOH + 0.25% diethylamine in CO2) to afford: Peak 1, Example 191.4-amino-l-(2,6-dichlorophenyl)-N-(3-((2R,5R)-5-(hydroxymethyl)pyrrolidin-2-yl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4- amino-l-(2,6-dichlorophenyl)-N-(3-((2S,5S)-5-(hydroxymethyl)pyrrolidin-2-yl)phenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxamide. White solid (16.6 mg), LCMS m/z = 4[M+H]+; 1HNMR (500 MHz, DMSO-d6): 11.67 (s, 1H), 9.73 (d, 1H), 8.64 (d, 1H), 8.42 (s, 1H), 7.76 (d, 2H), 7.64 (t, 1H), 7.56 (d, 1H), 7.46 (s, 1H), 7.21 (t, 1H), 7.06 (d, 1H), 4.45 (s,1H), 4.06 (t, 1H), 3.40-3.34 (m, 1H), 3.23-3.14 (m, 1H), 2.57 (q, 1H), 2.04 (dtd, 1H), 1.(dq, 1H), 1.58-1.37 (m, 2H), 1.03 (dt, 1H).
Example 192.Synthesis of 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5,6- dihydrospiro[cyclopenta[c]pyridine-7,2'-pyrrolidin]-4-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide. 352 n״nh 2 n״nh 2 WO 2024/233900 PCT/US2024/028806 To a solution of methyl 4-amino-l-(2,6-dichloro-4-methoxy-phenyl)-6-oxo-pyrimidine-5- carboxylate (Intermediate BIO, 30 mg, 0.087 mmol) and 5,6- dihydrospiro[cyclopenta[c]pyridine-7,2'-pyrrolidin]-4-amine (Intermediate A42, 26.4 mg, 0.139 mmol) in THE (1.5 mL) was added LiHMDS (1 M, 0.262 mL) at 0°C and the mixturewas stirred at 20°C for 12 h under N2. The reaction mixture was quenched by addition H(1 mL) at 0°C and concentrated under reduced pressure. The residue was purified by prep- HPLC-1 (5-40% MeCN) to give the title compound as a pale yellow solid (2.3 mg, 4.8%). LCMS m/z = 501 [M+H]+; 1HNMR (400 MHz, CDCI3): 11.56 (s, 1H), 10.05 (d, 1H), 9.27(s, 1H), 8.38 (s, 1H), 7.71 (s, 1H), 7.06 (s, 2H), 5.96 (d, 1H), 3.88 (s, 3H), 3.31-3.21 (m, 1H),3.20-3.12 (m, 1H), 3.11-3.00 (m, 1H), 2.93-2.80 (m, 1H), 2.30-2.21 (m, 2H), 2.19-2.05 (m, 3H), 2.05-1.99 (m, 2H).
Example 193.Synthesis of (S)-4-amino-l-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-N-(3-(pyrrolidin-2-yl)phenyl)-l,6-dihydropyrimidine-5-carboxamide.
Step 1. Synthesis of tert-butyl (S)-2-(3-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxamido)phenyl)pyrrolidine-l-carboxylate. 353 WO 2024/233900 PCT/US2024/028806 To a solution of methyl 4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-pyrimidine-5- carboxylate (Intermediate B6, 400 mg, 1.02 mmol) and tert-butyl (S)-2-(3- aminophenyl)pyrrolidine-l-carboxylate (Intermediate A61, 320 mg, 1.22 mmol) in toluene (mL) was added AlMe3 (2 M in toluene, 1.53 mL) at 0°C and the mixture was stirred at 100°C for l h under N2. The reaction mixture was quenched by addition saturated aqueous NaOH solution (5 mL) at 0°C and extracted with EtOAc (3x 7 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, 1-50% EtOAc/PE) to give the title compound as a white solid (180 mg, 28%). LCMS m/z = 622 [M+H]+.
Step 2. Synthesis of tert-butyl (S)-2-(3-(4-amino-l-(2,6-dichloro-4-hydroxyphenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxamido)phenyl)pyrrolidine-l-carboxylate To a solution of tert-butyl (S)-2-(3-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)phenyl)pyrrolidine-l-carboxylate (Step 1, 150 mg, 0.2mmol) in dioxane (3 mL) and H20 (1 mL) was added Pd2(dba)3 (22 mg, 0.024 mmol), t-Bu Xphos (20.4 mg, 0.048 mmol) and KOH (27 mg, 0.481 mmol) and the mixture was stirred at 100°C for l h under N2. The reaction mixture was concentrated under N2 and the residue purified by prep-HPLC-16 (35-65% MeCN) to give tert-butyl (R)-2-(3-(4-amino-l-(2,6- dichloro-4-hydroxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamido)phenyl)pyrrolidine- 1-carboxylate or tert-butyl (S)-2-(3-(4-amino-l-(2,6-dichloro-4-hydroxyphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)phenyl)pyrrolidine-l-carboxylate as a white solid (20 mg, 15%). LCMS m/z = 560 [M+H]+.
Step 3. Synthesis of tert-butyl (S)-2-(3-(4-amino-l-(2,6-dichloro-4-(difluoromethoxy)phenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxamido)phenyl)pyrrolidine-l-carboxylate To a solution of tert-butyl (S)-2-(3-(4-amino-l-(2,6-dichloro-4-hydroxyphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)phenyl)pyrrolidine-l-carboxylate (Step 2, 15 mg, 0.0mmol) and sodium 2-chloro-2,2-difluoroacetate (8.16 mg, 0.054 mmol) in DMF (0.5 mL) was added K2CO3 (4.07 mg, 0.029 mmol) and the mixture stirred at 60°C for 30 min . The reaction mixture was concentrated under reduced pressure and the residue was diluted with H20 (1 mL) and extracted with EtOAc (3x 2 mL). The combined organic layers were washed with brine (2x 1 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a white solid (15 mg, 92%). LCMS m/z = 610 [M+H]+. 354 WO 2024/233900 PCT/US2024/028806 Step 4. Synthesis of (S)-4-amino-l-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-N-(3- (pyrrolidin-2-yl)phenyl)-l,6-dihydropyrimidine-5-carboxamide.
A solution of tert-butyl (S)-2-(3-(4-amino-l-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxamido)phenyl)pyrrolidine-l-carboxylate (Step 3, 15 mg,0.025 mmol) in DCM (0.9 mL) and TFA (0.3 mL) was stirred at 25°C for 0.5 h. The reactionmixture was concentrated under reduced pressure and the residue was purified by prep- HPLC-2 (20-55% MeCN) to give the title compound as a white solid (3 mg, 22%). LCMS m/z = 510 [M+H]+; 1HNMR (400 MHz, CDCI3): 11.57 (s, 1H), 10.07 (br s, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.46 (br d, 1H), 7.35 (s, 2H), 7.29 (br s, 1H), 7.16 (br d, 1H), 6.79-6.42 (m,1H), 6.10 (brd, 1H), 4.42 (br d, 1H), 3.25 (br d, 2H), 2.32 (br d, 1H), 2.18-2.06 (m, 2H),2.06-2.00 (m, 1H).
Example 194.Synthesis of (S)-4-amino-l-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-N- (5-(pyrrolidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide.
Step 1. Synthesis of tert-butyl (S)-2-(5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)pyrrolidine-l-carboxylate.
To a solution of tert-butyl (S)-2-(5-aminopyridin-3-yl)pyrrolidine-l-carboxylate (Intermediate A13, 402 mg, 1.53 mmol) and methyl 4-amino-l-(4-bromo-2,6- dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B6, 400 mg, 1.02mmol) in toluene (5 mL) was added AlMe3 (2 M, 1.53 mL) at 0°C and the mixture stirred at 355 WO 2024/233900 PCT/US2024/028806 100°C for l h under N2. The reaction mixture was quenched by addition saturated aqueous NaOH solution (4 mL) at 0°C and extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure and the residue purified by MPLC (SiO2, 1-100% EtOAc/PE) to give the title compound as a white solid (350 mg, 55%). LCMS m/z = 625 [M+H]+.
Step 2. Synthesis of tert-butyl (S)-2-(5-(4-amino-l-(2,6-dichloro-4-cyclopropoxyphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)pyrrolidine-l-carboxylate.
To a mixture of tert-butyl (S)-2-(5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)pyrrolidine-l-carboxylate (Step 1, 15 mg, 0.024 mmol) and cyclopropanol (6.98 mg, 0.120 mmol) in toluene (2 mL) was added RockPhos Pd G3 (2.01 mg, 2.40 umol) and Cs2CO3 (11.74 mg, 36 umol) and the mixture was stirred at 110°C for 1 h under N2. The reaction mixture was filtered and concentrated under reduced pressure to give a residue to give the title compound as a yellow oil (25mg, crude). LCMS m/z = 601 [M+H]+.
Step 3. Synthesis of (S)-4-amino-l-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-N-(5- (pyrrolidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide.
A mixture of tert-butyl (S)-2-(5-(4-amino-l-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)pyrrolidine-l-carboxylate (Step 2, 25 mg, 0.042 mmol) in DCM (0.9 mL) and TEA (0.3 mL) was stirred at 25°C for 1 h. The reaction mixture was concentrated under N2 and the residue purified by prep-HPLC-6 (5-40% MeCN) to give the title compound as a brown oil (10.6 mg, 46%). LCMS m/z = 501 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 11.85 (s, 1H), 9.60 (d, 1H), 8.75 (d, 2H), 8.41 (s, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 7.44 (s, 2H), 4.25 (d, 1H), 4.06 (td, 1H), 3.58 (t, 1H), 3.17- 3.09 (m, 1H), 3.04 (s, 1H), 2.22 (d, 1H), 1.94-1.80 (m, 2H), 1.76-1.63 (m, 1H), 0.92-0.79 (m, 2H), 0.78-0.61 (m, 2H).
Example 195.Synthesis of (S)-4-amino-l-(2,6-dichloro-4-cyclopropoxyphenyl)-N-(5-(l- (methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (R)-4- amino-l-(2,6-dichloro-4-cyclopropoxyphenyl)-N-(5-(l-(methylamino)ethyl)pyridin-3-yl)-6- oxo-l,6-dihydropyrimidine-5-carboxamide. 356 WO 2024/233900 PCT/US2024/028806 Step 3 Step 1. Synthesis of (S)-4-amino-l-(4-bromo-2,6-dichlorophenyl)-N-(5-(l-(methylamino)ethyl)pyridin-3-yl)-6-oxo-l, 6-dihydropyrimidine-5-carboxamide or (R)-4-amino-l-(4-bromo-2,6-dichlorophenyl)-N-(5-(l-(methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide.
To a mixture of methyl 4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-pyrimidine-5- carboxylate (Intermediate B6, 190 mg, 0.483 mmol) and (S)-5-(l-(methylamino)ethyl)pyridin-3-amine or (R)-5-(l-(methylamino)ethyl)pyridin-3-amine 357 WO 2024/233900 PCT/US2024/028806 (Intermediate A14, 110 mg, 0.725 mmol) in toluene (13 mL) was added AlMez (2 M, 0.7mL) at 0°C and the mixture stirred at 60°C for 0.2 h under N2. The reaction mixture was diluted with H20 (5 mL) and TFA (5 mL) at 0°C and the mixture concentrated under reduced pressure to give the title compound as a yellow solid (350 mg, crude). LCMS m/z = 5[M+H]+.
Step 2. Synthesis of tert-butyl tert-butyl (S)-(l-(5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)- 6-oxo-l, 6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)ethyl)(methyl)carbamate or tert- butyl (R)-(l-(5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamido)pyridin-3-yl)ethyl)(methyl)carbamate To a solution of (S)-4-amino-l-(4-bromo-2,6-dichlorophenyl)-N-(5-(l- (methylamino)ethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (R)-4- amino-l-(4-bromo-2,6-di chi orophenyl)-N-(5-(l-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6- dihydropyrimidine-5-carboxamide (Step 1, 350 mg, 0.683 mmol) in THF (15 mL) and H(5 mL) was added NaHCO3 (115 mg, 1.37 mmol) and di-tert-butyl dicarbonate (149 mg, 0.683 mmol) and the mixture stirred at 25°C for l h. The reaction mixture was added to H(50 mL) at 0°C and extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound as a yellow solid (3mg, 88%). LCMS m/z = 613 [M+H]+.
Step 3. Synthesis of tert-butyl (S)-(l-(5-(4-amino-l-(2,6-dichloro-4-cyclopropoxyphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)ethyl)(methyl)carbamate or tert- butyl (R)-(1 -(5-(4-amino-l-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)ethyl)(methyl)carbamate To a solution of tert-butyl tert-butyl (S)-(l-(5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)ethyl)(methyl)carbamate or tert- butyl (R)-( 1 -(5-(4-amino-1 -(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5- carboxamido)pyridin-3-yl)ethyl)(methyl)carbamate (Step 2, 55 mg, 0.090mol) in toluene (mL) was added RockPhos Pd G3 (7.53 mg, 8.98 umol) and Cs2C03 (43.9 mg, 0.135 mmol) and cyclopropanol (26 mg, 0.449 mmol) and the mixture stirred at 110°C for 1.5 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with H20 (30 mL) and extracted with EtOAc (3x 20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-TLC 358 WO 2024/233900 PCT/US2024/028806 (50% EtOAc/PE) to give the title compound as a yellow solid (80 mg, 75%). LCMS m/z = 589 [M+H]+.
Step 4. Synthesis of (S)-4-amino-l-(2,6-dichloro-4-cyclopropoxyphenyl)-N-(5-(l- (methylamino)ethyl)pyridin-3-yl)-6-oxo-l, 6-dihydropyrimidine-5-carboxamide or (S)-4- amino-l-(2,6-dichloro-4-cyclopropoxyphenyl)-N-(5-(l-(methylamino)ethyl)pyridin-3-yl)-6- oxo-1,6-dihydropyrimidine-5-carboxamide.
A mixture of tert-butyl (S)-(l-(5-(4-amino-l-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)ethyl)(methyl)carbamate or tert-butyl (R)-(l-(5-(4-amino-l-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamido)pyridin-3-yl)ethyl)(methyl)carbamate (Step 3, 70 mg, 0.1189 mmol) in HCl/EtOAc (5 mL) was stirred at 25°C for l h. The reaction mixture was concentrated under N2 and the residue was purified by prep-HPLC-3 (5-40% MeCN) the title compound as a pale yellow solid (13.9 mg, 21%,). LCMS m/z = 489 [M+H]+; 1H NMR (400 MHz, CDCI3): 11.86 (s, 1 H), 10.00 (d, 1H), 8.66 (s, 1 H), 8.32 (d, 2H), 7.73 (s, 1 H), 7.21 (s, 2 H), 6.19 (d, 1H) 3.93 (d, 1H), 3.75-3.84 (m, 1 H), 2.38 (s, 3 H), 1.56 (d, 3H) 0.78-0.94 (m, 4 H).
Example 196.Synthesis of methyl (S)-4-(4-amino-6-oxo-5-((5-(piperidin-2-yl)pyridin-3- yl)carbamoyl)pyrimidin-l(6H)-yl)-3,5-dichlorobenzoate.
Step 1. Synthesis of tert-butyl (S)-2-(5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)piperidine-l-carboxylate. 359 WO 2024/233900 PCT/US2024/028806 To a solution of methyl 4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-pyrimidine-5- carboxylate (100 mg, 0.254 mmol) and tert-butyl (S)-2-(5-aminopyridin-3-yl)piperidine-l- carboxylate (Intermediate A5, 70.6 mg, 0.254 mmol) in toluene (3 mL) was added AlMe3 (M, 0.382 mL in toluene ) at 0°C and the mixture was stirred at 100°C for l h under N2. The reaction mixture was quenched by addition saturated aqueous NaOH (IM, 5 mL) at 0°C and then extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure and the residue was purified by prep-TLC (50% EtOAc/PE) to give the title compound as a white solid (118 mg, 72%). LCMS m/z = 6[M+H]+.
Step 2. Synthesis of (S)-4-(4-amino-5-((5-(l-(tert-butoxycarbonyl)piperidin-2-yl)pyridin-3- yl)carbamoyl)-6-oxopyrimidin-l(6H)-yl)-3,5-dichlorobenzoic acid To a solution of oxalic acid (116.5 mg, 1.29 mmol) in DMF (2 mL) was added tert-butyl (S)- 2-(5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamido)pyridin-3-yl)piperidine-l-carboxylate (Step 1, 118 mg, 0.185 mmol) , Pd(OAc)(4.15 mg, 0.018 mmol), Ac20 (56.6 mg, 0.555 mmol), DIPEA (71.7 mg, 0.555 mmol) and Xantphos (10.7 mg, 0.018 mmol) and the mixture was stirred at 100°C for 12 h under N2. The reaction mixture was concentrated under reduced pressure and the residue diluted with H20 (5 mL) and extracted with EtOAc (3x 5mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-TLC (10:1 EtOAc/MeOH) to give the title compound as a brown oil (70 mg, 63%). LCMS m/z = 603 [M+H]+.
Step 3. Synthesis of methyl (S)-4-(4-amino-6-oxo-5-((5-(piperidin-2-yl)pyridin-3- yl)carbamoyl)pyrimidin-1(6H)-yl)-3,5-dichlorobenzoate To a solution of (S)-4-(4-amino-5-((5-(l-(tert-butoxycarbonyl)piperidin-2-yl)pyridin-3- yl)carbamoyl)-6-oxopyrimidin-l(6H)-yl)-3,5-dichlorobenzoic acid (Step 2, 70 mg, 0.1mmol) in MeOH (I mL) was added SOC12 (55.2 mg, 0.464 mmol)at 0°C and the mixture stirred at 80°C for 2 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by prep-HPLC-1 (3-35% MeCN) to give the title compound as a white solid (20 mg, 30%). LCMS m/z = 517 [M+H]+; 1H NMR (400 MHz, CDCI3): 11.66 (s, 1H), 10.04 (d, 1H), 8.61 (d, 1H), 8.36 (s, 1H), 8.33- 8.34 (m, 1H), 8.19 (s, 2H), 7.71 (s, 1H), 6.18 (d, 1H), 4.00 (s, 3H), 3.81 (m, 1H), 3.21 (d, 1H), 1.77-2.00 (m, 4H), 1.68-1.74 (m, 2H), 1.51-1.61 (m, 1H). 360 WO 2024/233900 PCT/US2024/028806 Example 197.Synthesis of (R)-4-amino-N-(5-(l-amino-3-methoxypropyl)pyridin-3-yl)-l- (2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(l- amino-3-methoxypropyl)pyridin-3-yl)-l-(2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine- 5-carboxamide.
Step 1. Synthesis of tert-butyl (l-(5-(4-amino-l-(2,6-dichlorophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)-3-methoxypropyl)carbamate.
To a mixture of methyl 4-amino-l-(2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxylate (Intermediate B9, 20 mg, 0.064 mmol) and tert-butyl (l-(5-aminopyridin-3-yl)-3-methoxypropyl)carbamate (Intermediate A19, 19.7 mg, 0.070 mmol) in toluene (3 mL) was added AlMe3 (2M in toluene, 96 pL) at 0°C and the mixture stirred at 0°C for 5 min. The mixture was stirred at 40°C for 60 min under N2. The reaction mixture was diluted with H(0.2 mL) and TFA (0.2 mL) at 0°C and the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC-2 (30-60% MeCN) to give the titlecompound as a white solid (30 mg, 83%). LCMS m/z = 563 [M+H]+.
Step 2. Synthesis of tert-butyl (S)-(l-(5-(4-amino-l-(2,6-dichlorophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)-3-methoxypropyl)carbamate or tert-butyl 361 WO 2024/233900 PCT/US2024/028806 (R)-(l-(5-(4-amino-l-(2,6-dichlorophenyl)-6-oxo-l, 6-dihydropyrimidine-5- carboxamido)pyridin-3-yl)-3-methoxypropyl)carbamate. tert-butyl (l-(5-(4-amino-l-(2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamido)pyridin-3-yl)-3-methoxypropyl)carbamate (Step 1, 118.7 mg, 211 mmol) was purified by SFC separation (REGIS(S, S)WHELK-Ol, 250 x 25 mm, 10 pm); 45% EtOH (0.1% NH4OH) in CO2) to afford: Peak 2. tert-butyl (S)-(l-(5-(4-amino-l-(2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine- 5-carboxamido)pyridin-3-yl)-3-methoxypropyl)carbamate or tert-butyl (R)-(l-(5-(4-amino-l- (2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)-3- methoxypropyl)carbamate (yellow oil, 20 mg, 16%).
Step 3. Synthesis of (R)-4-amino-N-(5-(1 -amino-3-methoxypropyl)pyridin-3-yl)-l-(2,6- dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(l-amino- 3-methoxypropyl)pyridin-3-yl)-l-(2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide.
A mixture of tert-butyl (S)-(l-(5-(4-amino-l-(2,6-dichlorophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)-3-methoxypropyl)carbamate or tert-butyl (R)-(l-(5-(4-amino-l-(2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamido)pyridin-3-yl)-3-methoxypropyl)carbamate (Part 2, Peak 2, 10 mg, 0.018 mmol) in DCM (1.5 mL) and TEA (0.5 mL) was stirred at 25°C for 0.5 h under N2. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep- HPLC-2 (5-35% MeCN) to give the title compound as a white solid (1.3 mg, 14%). LCMS m/z = 463 [M+H]+; 1HNMR (400 MHz, DMSO-d6): 11.74-11.85 (m, 1H), 9.61-9.69 (m, 1H), 8.73-8.80 (m, 2H), 8.46 (s, 1H), 8.19-8.35 (m, 2H), 7.98-8.03 (m, 1H), 7.74-7.80 (m, 2H), 7.61-7.68 (m, 1H), 3.93-4.03 (m, 1H), 3.21-3.26 (m, 2H), 3.19 (s, 3H), 1.74-1.92 (m, 2H).
Example 198.Synthesis of methyl 4-(4-amino-5-((5-((ethylamino)methyl)pyridin-3- yl)carbamoyl)-6-oxopyrimidin-l(6H)-yl)-3,5-di chlorobenzoate. 362 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of tert-butyl ((5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate.
AlMe3 (2M in toluene, 1.91 mL) was added to a mixture of methyl 4-amino-l-(4-bromo-2,6- dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B6, 500 mg, 1.27mmol) and tert-butyl ((5-aminopyridin-3-yl)methyl)(ethyl)carbamate (Intermediate A24, 4mg, 1.91 mmol) in toluene (9 mL) at 0°C and the mixture stirred at 100°C for 0.5 h under N2. The reaction mixture was quenched by addition IM NaOH aqueous solution (50 mL) at 0°C and then extracted with EtOAc (3x 50 mL). The combined organics were dried (Na2S04), concentrated under reduced pressure and the residue purified by column chromatography(SiO2, 0-100% EtOAc/PE) to give the title compound as a yellow solid (2 g, 64%). LCMS m/z = 613 [M+H]+.
Step 2. Synthesis of 4-(4-amino-5-((5-(((tert-butoxycarbonyl)(ethyl)amino)methyl)pyridin-3- yl)carbamoyl)-6-oxopyrimidin-l(6H)-yl)-3,5-dichlorobenzoic acid.
To a solution of tert-butyl ((5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate (Step 1, 310 mg, 0.506 mmol) and oxalic acid (319 mg, 3.54 mmol) in DMF (2 mL) was added Pd(OAc)(11.4 mg, 0.051 mmol), Xantphos (29.3 mg, 0.051 mmol), Ac20 (155 mg, 1.52 mmol) and DIPEA (196 mg, 1.52 mmol) and the mixture was stirred at 100°C for 12 h under N2. Thereaction mixture was filtered and the filtrate concentrated under reduced pressure and the 363 WO 2024/233900 PCT/US2024/028806 residue purified by prep-HPLC-1 (30-60% MeCN) to give the title compound as a white solid (120 mg, 41%). LCMS m/z = 577 [M+H]+.
Step 3. Synthesis of methyl 4-(4-amino-5-((5-((ethylamino)methyl)pyridin-3-yl)carbamoyl)- 6-oxopyrimidin-l (6H)-yl)-3,5-dichlorobenzoate To a solution of 4-(4-amino-5-((5-(((tert-butoxycarbonyl)(ethyl)amino)methyl)pyridin-3- yl)carbamoyl)-6-oxopyrimidin-l(6H)-yl)-3,5-dichlorobenzoic acid (Part 2, 60 mg, 0.1mmol) in MeOH (1 mL) was added thionyl chloride (49.5 mg, 0.416 mmol) at 0°C and the mixture stirred at 80°C for 2 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by prep-HPLC-1 (3-35% MeCN) to give the title compound as a white solid (22.6 mg, 44%). LCMS m/z = 4[M+H]+; 1H NMR (400 MHz, CDCI3): 11.59 (s, 1H), 9.97 (d, 1H), 8.53 (d, 1H), 8.32-8.(m, 2H), 8.11 (s, 2H), 7.63 (s, 1H), 6.19 (d, 1H), 3.92 (s, 3H), 3.83 (s, 2H), 2.70 (q, 2H), 1.(t, 3H).
Example 199.Synthesis of ethyl 4-(4-amino-5-((5-((ethylamino)methyl)pyridin-3- yl)carbamoyl)-6-oxopyrimidin-l(6H)-yl)-3,5-dichlorobenzoate.
O The title compound was prepared as a white solid from methyl 4-amino-l-(4-bromo-2,6- dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B6) using an analogous 3-step method to that described for Example 198.LCMS m/z = 505 [M+H]+; 1H NMR (400 MHz, CDCI3): 11.70 (s, 1H), 10.08 (d, 1H), 8.65 (s, 1H), 8.32 (d, 2H), 8.22 (s, 2H), 7.74 (s, 1H), 6.22 (s, 1H), 4.48 (q, 2H), 3.92 (s, 2H), 2.78 (q, 2H), 1.47 (t, 3H), 1.(t,3H).
Example 200.Synthesis of 4-amino-l-(2,6-dichloro-4-(oxazol-5-yl)phenyl)-N-(5- ((ethylamino)methyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide. 364 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of tert-butyl ((5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate.
AlMe3 (2M in toluene, 1.91 mL) was added to a mixture of methyl 4-amino-l-(4-bromo-2,6- dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B6, 500 mg, 1.mmol) and tert-butyl ((5-aminopyridin-3-yl)methyl)(ethyl)carbamate (Intermediate A24, 4mg, 1.91 mmol) in toluene (9 mL) at 0°C and the mixture stirred at 100°C for 0.5 h under N2. The reaction mixture was quenched by addition IM NaOH aqueous solution (50 mL) at 0°C and then extracted with EtOAc (3x 50 mL). The combined organics were dried (Na2S04), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 0-100% EtOAc/PE) to give the title compound as a yellow solid (2 g, 64%). LCMS m/z = 613 [M+H]+.
Step 2. Synthesis of tert-butyl ((5-(4-amino-l-(2,6-dichloro-4-(oxazol-5-yl)phenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate.
A mixture of tert-butyl ((5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate (Part 1, 90 mg, 0.147 mmol) , 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)oxazole (57.33 mg, 0.2mmol), K3PO4 (62.4 mg, 0.294 mmol), [2-(2-aminophenyl)phenyl]-chloro- palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (23.13 mg, 0.0mmol) in dioxane (4 mL) and H20 (0.4 mL) was degassed and purged with N2 (x3) and the 365 WO 2024/233900 PCT/US2024/028806 mixture stirred at 110°C for 1 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (80 mg, 90%). LCMS m/z = 600 [M+H]+.
Step 3. Synthesis of 4-amino-l-(2,6-dichloro-4-(oxazol-5-yl)phenyl)-N-(5- ((ethylamino)methyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide.
To the mixture of tert-butyl ((5-(4-amino-l-(2,6-dichloro-4-(oxazol-5-yl)phenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate (Part 2, 60 mg, 0.100 mmol) in DCM (2 mL) and TFA (1 mL) and the mixture was stirred at 25°C for min. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC-1 (20-50% MeCN) to give the title compound as a yellow oil (8.2 mg, 16%). LCMS m/z = 500 [M+H]+; 1HNMR (400 MHz, DMSO-d6): 1.05 (t, 3H) 2.57 (d, 2H) 3.74 (d, 2H) 8.05 (s, 1H), 8.08 (s, 1H), 8.15 (s, 2H), 8.25 (s, 1H), 8.50 (s, 1H), 8.65 (s, 1H), 8.70 (br s, 1H), 8.85 (d, 1H), 9.69 (d, 1H), 11.78 (s, 1H).
Example 201.Synthesis of 4-amino-l-(2,6-dichloro-4-(oxazol-2-yl)phenyl)-N-(5- ((ethylamino)methyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide.
Step 1. Synthesis of tert-butyl ((5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate.
The title compound was prepared methyl 4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxylate (Intermediate B6) and tert-butyl ((5-aminopyridin-3- 366 WO 2024/233900 PCT/US2024/028806 yl)methyl)(ethyl)carbamate (Intermediate A24) using an analogous method to that described for Example 190, Step 1.
Step 2. Synthesis of tert-butyl ((5-(4-amino-l-(2,6-dichloro-4-(oxazol-2-yl)phenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate To a solution of tert-butyl ((5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate (Step 1, 50 mg, 0.082 mmol) in dioxane (1.5 mL) was added cataCXium® A Pd G2 (10.92 mg, 0.016 mmol) and 2-(tributylstannyl)oxazole (117 mg, 0.327 mmol) and the mixture stirred at 80°C for l h under N2. The reaction mixture was diluted with H20 (10mL) and extracted with EtOAc (3x mL). The combined organics were washed with brine (2x 1 mL), dried (Na2S04) and concentrated under reduced pressure. The residue was purified by prep-HPLC-8 (30-65% MeCN) to give the title compound as a yellow solid (20 mg, 41%). LCMS m/z = 6[M+H]+.
Step 3. Synthesis of 4-amino-l-(2,6-dichloro-4-(oxazol-2-yl)phenyl)-N-(5- ((ethylamino)methyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide.
The title compound was prepared from tert-butyl ((5-(4-amino-l-(2,6-dichloro-4-(oxazol-2- yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5 -carboxamido)pyridin-3 - yl)methyl)(ethyl)carbamate (Step 2) using an analogous method to that described for Example 200, Step 3. Prep-HPLC-1 (1-30% MeCN) to give the title compound as a white solid (5.1 mg, 14%). LCMS m/z = 500 [M+H]+; 1HNMR (400 MHz, CDCI3): 11.69 (s, 1H), 10.07-10.15 (m, 1H), 8.68 (d, 1H), 8.30 (s, 1H), 8.24(s, 2H), 8.15 (s, 1H), 7.84 (s, 1H), 7.(s, 1H), 7.36 (s, 1H), 6.06 (br dd, 1H), 3.83 (s, 2H), 2.70 (q, 2H), 1.15 (t, 3H).
Example 202.Synthesis of 4-amino-l-(2,6-dichloro-4-(2,2,2-trifluoroethyl)phenyl)-N-(5- ((ethylamino)methyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide. 367 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of (4-(4-amino-5-((5-(((tert-butoxycarbonyl)(ethyl)amino)methyl)pyridin-3- yl)carbamoyl)-6-oxopyrimidin-l(6H)-yl)-3,5-dichlorophenyl)boronic acid.
To a solution of tert-butyl ((5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamido)pyri din-3-yl)methyl)(ethyl)carbamate (Example 190, Step 1; 315 mg, 0.514 mmol) in dioxane (5.5 mL) was added Pd(dppf)C12.DCM (42 mg, 0.0mmol) andKOAc (101 mg, 1.03 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (653 mg, 2.57 mmol) and the mixture stirred at 80oC for 15 h under N2. The reaction mixture was filtered and concentrated under reduced pressure and the residue waspurified by prep-HPLC-8 (15-45% MeCN) to give the title compound as a white solid (1.3 g, 73%). LCMS m/z = 577 [M+H]+.
Step 2. Synthesis of tert-butyl ((5-(4-amino-l-(2,6-dichloro-4-(2,2,2-trifluoroethyl)phenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate.
A mixture of (4-(4-amino-5-((5-(((tert-butoxycarbonyl)(ethyl)amino)methyl)pyridin-3-yl)carbamoyl)-6-oxopyrimidin-l(6H)-yl)-3,5-dichlorophenyl)boronic acid (Part 1, 15 mg, 0.026 mmol), l,l,l-trifluoro-2-iodoethane (109 mg, 0.520 mmol), Pd2(dba)3 (2.38 mg, 2.umol), Xantphos (1.50 mg, 2.60 umol) and Cs2CO3 (33.9 mg, 0.104 mmol) in dioxane (mL) and H20 (0.1 mL) was degassed and purged with N2 (3x) and the mixture stirred at 80°C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to give the 368 WO 2024/233900 PCT/US2024/028806 title compound as a white solid (45 mg, 93%) which was without further purification. LCMS m/z = 615 [M+H]+.
Step 3. Synthesis of 4-amino-l-(2,6-dichloro-4-(2,2,2-trijluoroethyl)phenyl)-N-(5- ((ethylamino)methyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide.
The title compound was prepared as a white solid (5.1 mg, 13%) from tert-butyl ((5-(4- amino-l-(2,6-dichloro-4-(2,2,2-trifluoroethyl)phenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate (Step 2, 45 mg, 0.073 mmol) using an analogous method to that described for Example 200, Step 3. LCMS m/z = 515 [M+H]+; 1H NMR (400 MHz, CDCI3): 1.15-1.21 (m, 3H), 2.91 (q, 2H), 3.37 (q, 2H), 4.00 (s, 2H), 6.09 (d, 1H), 7.42 (s, 2H), 7.64 (s, 1H), 8.29 (s, 1H), 8.48 (d, 2H), 9.84 (d, 2H), 11.71 (s,lH).
Example 203.Synthesis of 4-amino-l-(2,6-dichloro-4-(2,2-difluoroethyl)phenyl)-N-(5- ((ethylamino)methyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide.
The title compound was prepared as a white solid from tert-butyl ((5-(4-amino-l-(4-bromo- 2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamido)pyridin-3- yl)methyl)(ethyl)carbamate (Example 190, Step 1) and l,l-difluoro-2-iodoethane using an analogous 3-Step method as described for Example 202. LCMS m/z = 497 [M+H]+; 1H NMR (400 MHz, CDCI3): 1.14-1.24 (m, 1H), 1.19 (d, 2H), 2.04 (d, 1H), 2.75 (d, 2H), 3.17- 3.31 (m, 2H), 3.88 (s, 2H), 5.86-6.25 (m, 1H), 6.07-6.15 (m, 1H), 7.48 (s, 2H), 7.74 (d, 1H), 8.16-8.37 (m, 1H), 8.25 (s, 1H), 8.33 (s, 1H), 8.66 (s, 1H), 10.06 (d, 1H), 11.73 (s, 1H).
Example 204.Synthesis of (R)-4-amino-N-(5-(l-amino-2,2-difluoroethyl)pyridin-3-yl)-l- (2,6-dichloro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-amino-2,2-difluoroethyl)pyridin-3-yl)-l-(2,6-dichloro-4-methoxyphenyl)-6- oxo-l,6-dihydropyrimidine-5-carboxamide. 369 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of (R)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-(I -(1,3- dioxoisoindolin-2-yl)-2,2-difluoroethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or (S)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-(l-(l,3-dioxoisoindolin- 2-yl)-2,2-difluoroethyl)pyridin-3-yl)-6-oxo-l, 6-dihydropyrimidine-5-carboxamide.
The title compound was prepared as a white solid (50 mg, 56%) from methyl 4-amino-l-(2,6- dichloro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B10) and (R)-2-(l-(5-aminopyridin-3-yl)-2,2-difluoroethyl)isoindoline-l,3-dione or (S)-2-(l-(5- aminopyridin-3-yl)-2,2-difluoroethyl)isoindoline-l,3-dione (Intermediate A48) using an analogous method to that described for Example 2. LCMS m/z = 615 [M+H]+.
Step 2. Synthesis of (R)-4-amino-N-(5-(l-amino-2,2-difluoroethyl)pyridin-3-yl)-l-(2,6- dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N- (5-(l-amino-2,2-difluoroethyl)pyridin-3-yl)-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamide To a solution of (R)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-(l-(l,3- dioxoisoindolin-2-yl)-2,2-difluoroethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide or (S)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-(l-(l,3- dioxoisoindolin-2-yl)-2,2-difluoroethyl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide (Step 1, 40 mg, 0.065 mmol) in EtOH (2 mL) was added hydrazine hydrate (15.31 mg, 0.260 mmol) and the mixture stirred at 70°C for l h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue was diluted 370 WO 2024/233900 PCT/US2024/028806 with H20 (3mL) and extracted with EtOAc (3x 3mL). The combined organics were washed with brine (2x 2 mL), dried (Na2S04) and concentrated under reduced pressure and the residue purified by prep-HPLC-3 (1-35% MeCN) to give the title compound as a brown solid (17.9 mg, 51%). LCMS m/z = 485 [M+H]+; 1HNMR (400 MHz, CDCI3): 11.86 (s, 1H), 10.01 (br d, 1H), 8.75 (d, 1H), 8.34 (d, 1H), 8.27 (t, 1H), 7.74 (s, 1H), 7.07 (s, 2H), 6.03 (br d, 1H), 5.95-5.65 (m, 1H), 4.24 (ddd, 1H), 3.88 (s, 3H).
Example 205.Synthesis of (R)-4-amino-l-(4-m ethoxy-2,6-dimethylphenyl)-6-oxo-N-(5- (piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide.
Step 1. Synthesis of tert-butyl (R)-2-(5-(4-amino-l-(4-bromo-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)piperidine-l-carboxylate.
The title compound was prepared from methyl 4-amino-l-(4-bromo-2,6-dimethylphenyl)-6- 0x0-1,6-dihydropyrimidine-5-carboxylate (Intermediate B34) and tert-butyl (R)-2-(5- aminopyridin-3-yl)piperidine-l-carboxylate (Intermediate A4) using an analogous method to that described for Example 2. LCMS m/z = 599 [M+H]+.
Step 2. Synthesis of tert-butyl (R)-2-(5-(4-amino-l-(4-methoxy-2,6-dimethylphenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)piperidine-l-carboxylate.
To the mixture of tert-butyl (R)-2-(5-(4-amino-l-(4-bromo-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)piperidine-l-carboxylate (Step 1, 250 mg, 0.418 mmol) in toluene (2 mL) and MeOH (2 mL) was added K3PO4 (133 mg, 0.628 mmol), 371 WO 2024/233900 PCT/US2024/028806 t-Bu Xphos (17.77 mg, 0.042 mmol) and Pd2(dba)3 (38.31 mg, 0.042 mmol) and the mixture stirred at 80°C for 2 h under N2. The mixture was filtered and concentrated under reduced pressure to give the title compound as a brown oil (500 mg). LCMS m/z = 594 [M+H]+.
Step 3. Synthesis of (R)-4-amino-l-(4-methoxy-2,6-dimethylphenyl)-6-oxo-N-(5-(piperidin-2- yl)pyridin-3-yl)-l, 6-dihydropyrimidine-5-carboxamide.
To the mixture of tert-butyl (R)-2-(5-(4-amino-l-(4-methoxy-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)piperidine-l-carboxylate (Step 2, 500 mg, 0.911 mmol) in DCM (4 mL) was added TFA (1.5 mL), the mixture was stirred at 20°C for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue waspurified by prep-HPLC-3 (5-45% MeCN) to give the title compound as a pale yellow solid (40.3 mg, 10%). LCMS m/z = 449 [M+H]+; 1HNMR (400 MHz, CDCI3): 12.09 (s, 1H), 9.(br d, 1H), 8.64 (s, 1H), 8.39 (s, 2H), 7.79 (s, 1H), 6.78 (s, 2H), 6.03 (br d, 1H), 3.87 (s, 3H), 3.83 (brd, 1H), 3.22 (br d, 1H), 2.86-2.79 (m, 1H), 2.18 (s, 6H), 1.99-1.85 (m, 3H), 1.73 (br d, 2H), 1.62-1.54 (m, 1H).
Example 206.Synthesis of 4-amino-N-((lR,3S)-3-(aminomethyl)cyclohexyl)-l-((S)-2- chloro-4-methoxy-6-methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4- amino-N-((lS,3R)-3-(aminomethyl)cy cl ohexyl)-l-((S)-2-chloro-4-m ethoxy-6- methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide. 372 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of 4-amino-l-((S)-2-chloro-4-methoxy-6-methylphenyl)-N-((lR,3S)-3- (((2,4-dimethoxybenzyl)amino)methyl) cyclohexyl)-6-oxo-1,6-dihydropyrimidine-5- carboxamide or 4-amino-l-( To a solution of (lS,3R)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexan-l-amine or (lR,3S)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexan-l-amine (Intermediate A58, 130.28 mg, 0.468 mmol) and methyl 4-amino-l-((S)-2-chloro-4-methoxy-6-methylphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B4, 101 mg, 0.312 mmol) in toluene 373 WO 2024/233900 PCT/US2024/028806 (2 mL) was added AlMe3 (2M in toluene, 0.47 mL) at 0°C under N2 and the mixture stirred at 100 °C for 1 h under N2. The reaction mixture was quenched by addition saturated aqueous NaOH solution (2 mL) at 0°C and the reaction mixture evaporated to dryness. The residue was purified by prep-TLC (10/1 EtOAc/MeOH) to give the title compound as a light yellow oil (70 mg, crude). LCMS m/z = 571 [M+H]+.
Step 2. Synthesis of tert-butyl (((lS,3R)-3-(4-amino-l-((S)-2-chloro-4-methoxy-6- methylphenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxamido)cyclohexyl)methyl) (2,4- dimethoxybenzyl)carbamate or tert-butyl (((lR,3S)-3-(4-amino-l-((S)-2-chloro-4-methoxy-6- methylphenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxamido)cyclohexyl)methyl) (2,4- dimethoxybenzyl)carbamate.
To a solution of 4-amino-l-((S)-2-chloro-4-methoxy-6-methylphenyl)-N-((lR,3S)-3-(((2,4- dimethoxybenzyl)amino)methyl)cyclohexyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or 4-amino-l-((S)-2-chloro-4-methoxy-6-methylphenyl)-N-((lS,3R)-3-(((2,4- dimethoxybenzyl)amino)methyl)cyclohexyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide (Step 1, 60 mg, 0.105 mmol) in MeOH (2 mL) was added di-tert-butyl dicarbonate (68.9 mg, 0.316 mmol) and the mixture stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure and the residue purified by prep-TLC (50% PE/EtOAc) to give the title compound as a light yellow oil (80 mg, crude). LCMS m/z = 671 [M+H]+.
Step 3. Synthesis of 4-amino-N-((lR,3S)-3-(aminomethyl)cyclohexyl)-l-((S)-2-chloro-4- methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N- ((IS, 3R)-3-(aminomethyl)cyclohexyl)-l-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-l, 6- dihydropyrimidine-5-carboxamide.
A solution of tert-butyl (((lS,3R)-3-(4-amino-l-((S)-2-chloro-4-methoxy-6-methylphenyl)-6- oxo-l,6-dihydropyrimidine-5-carboxamido)cyclohexyl)methyl)(2,4-dimethoxybenzyl)carbamate or tert-butyl (((lR,3S)-3-(4-amino-l-((S)-2-chloro-4-methoxy-6- methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamido)cyclohexyl)methyl)(2,4- dimethoxybenzyl)carbamate (Step 2, 70 mg, 0.104 mmol) in TEA (2 mL) was stirred at 80 °C for l h. The reaction mixture was concentrated under N2 and the residue purified by prep- HPLC-1 (1-50% MeCN) to give the title compound as a white solid (15.8 mg, 36%). LCMS m/z = 420 [M+H]+; 1HNMR (400 MHz, CDCI3): 0.87 (q, 2H), 1.10-1.22 (m, 1 H), 1.39 (q, H), 1.82 (br d, 3H), 1.98 (br d, 1H), 2.18 (s, 4H), 2.71 (br d, 2H), 3.83 (s, 4H), 6.17 (br d, 1H), 6.79 (d, 1H), 6.93 (d, 1H), 7.66 (s, 1H), 8.49 (br s, 1H), 9.59 (d, 1H), 9.99 (br d, 1H). 374 WO 2024/233900 PCT/US2024/028806 Example 207.Synthesis of (R)-2-(4-(4-amino-6-oxo-5-((5-(piperidin-2-yl)pyridin-3- yl)carbamoyl)pyrimidin-l(6H)-yl)-3,5-dimethylphenyl)acetic acid.
Step 1. Synthesis of tert-butyl (R)-2-(5-(I-(4-allyl-2,6-dimethylphenyl)-4-amino-6-oxo-l, 6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)piperidine-l-carboxylate.
To a solution of tert-butyl (R)-2-(5-(4-amino-l-(4-bromo-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)piperidine-l-carboxylate (Example 205, Step 1, 820 mg, 1.37 mmol) in DMF (5 mL) was added Pd(PPh3)4 (159 mg, 0.137 mmol) and allyltributylstannane (500 mg, 1.51 mmol) under N2 and the mixture stirred at 90°C for 3 hunder N2. The reaction mixture was quenched by addition saturated aqueous KF solution (mL) at 0°C and extracted with EtOAc (3x 20 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by MPLC 375 WO 2024/233900 PCT/US2024/028806 (SiO2, EtOAc) to give the title compound as a yellow oil (720 mg, 94%). LCMS m/z = 5[M+H]+ Step 2. Synthesis of tert-butyl (R)-2-(5-(4-amino-l-(4-(2-methoxy-2-oxoethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)piperidine-l- carboxylate.
Ozone (15 psi) was bubbled through a solution of tert-butyl (R)-2-(5-(l-(4-allyl-2,6- dimethylphenyl)-4-amino-6-oxo-l,6-dihydropyrimidine-5-carboxamido)pyri din-3- yl)piperidine-l-carboxylate or (Step 1, 280 mg, 0.501 mmol) in DCM (10 mL) and NaOH (2.5 M, 2.65 mL) in MeOH at -78°C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (296 mg, crude). LCMS m/z = 591 [M+H]+ Step 3. Synthesis of (R)-2-(4-(4-amino-5-((5-(l-(tert-butoxycarbonyl)piperidin-2-yl)pyridin- 3-yl) carbamoyl)-6-oxopyrimidin-l(6H)-yl)-3,5-dimethylphenyl)acetic acid.
To a solution of tert-butyl (R)-2-(5-(4-amino-l-(4-(2-methoxy-2-oxoethyl)-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)piperidine-l- carboxylate (Step 2, 296 mg, 0.501 mol) in MeOH (3 mL) and H20 (1 mL) was added NaOH (60 mg, 1.50 mmol) and the mixture stirred at 25°C for l h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue purified by prep-HPLC-13 (25-45% MeCN) to give the title compound as a white solid (68 mg, 23%). LCMS m/z = 577 [M+H]+ Step 4. Synthesis of methyl (R)-2-(4-(4-amino-6-oxo-5-((5-(piperidin-2-yl)pyridin-3- yl)carbamoyl)pyrimidin-1(6H)-yl)-3,5-dimethylphenyl)acetate.
To a solution of (R)-2-(4-(4-amino-5-((5-(l-(tert-butoxycarbonyl)piperidin-2-yl)pyridin-3- yl)carbamoyl)-6-oxopyrimidin-l(6H)-yl)-3,5-dimethylphenyl)acetic acid (Step 3, 68 mg, 0.118mol) in HCl/EtOAc (1 mL) was stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC-1 (5-35% MeCN) to give the title compound as a yellow gum (37 mg, 63 %). LCMS m/z = 4[M+H]+ Step 5. Synthesis of (R)-2-(4-(4-amino-6-oxo-5-((5-(piperidin-2-yl)pyridin-3- yl)carbamoyl)pyrimidin-1(6H)-yl)-3,5-dimethylphenyl)acetic acid. 376 WO 2024/233900 PCT/US2024/028806 To a solution of methyl (R)-2-(4-(4-amino-6-oxo-5-((5-(piperidin-2-yl)pyridin-3- yl)carbamoyl)pyrimidin-l(6H)-yl)-3,5-dimethylphenyl)acetate (Step 4, 32 mg, 0.065 mmol) in MeOH (I mL) and H20 (0.3 mL) was added NaOH (7.83 mg, 0.20 mmol) and the mixture stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure and the pH of the residue adjusted to pH 2-3 with 1M HCI. The residue was purified by prep- HPLC-1 (5-40% MeCN) to give the title compound as a white solid (9.1 mg, 26%). LCMS m/z = 477 [M+H]+; 1HNMR (400 MHz, DMSO-d3): 12.14 (s, 1H), 9.52 (d, 1H), 8.68 (d, 1H), 8.51 (d, 1H), 8.25 (d, 2H), 8.09 (s, 1H), 7.13 (s, 2H), 3.70 (d, 1H), 3.54 (s, 2H), 3.09 (d, 1H), 2.69 (d, 1H), 2.06 (s, 6H), 1.84-1.70 (m, 2H), 1.60 (d, 1H), 1.45 (s, 3H).
Example 208.Synthesis of (R)-4-amino-N-(5-(l-amino-2-methoxyethyl)pyridin-3-yl)-l- (2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-amino-2-methoxyethyl)pyridin-3-yl)-l-(2,6-dichloro-4-cyclopropoxyphenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxamide.
Step 1. Synthesis of tert-butyl (R)-(l-(5-(4-amino-l-(2,6-dichloro-4-cyclopropoxyphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)-2-methoxyethyl)carbamate or tert- butyl (S)-(l-(5-(4-amino-l-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)-2-methoxyethyl)carbamate.
To a solution of methyl 4-amino-l-[2, 6-dichloro-4-(cyclopropoxy)phenyl]-6-oxo- pyrimidine-5-carboxylate (Intermediate Bl 1, 30 mg, 81 umol) and tert-butyl (R)-(l-(5- 377 WO 2024/233900 PCT/US2024/028806 aminopyridin-3-yl)-2-methoxyethyl)carbamate or tert-butyl (S)-(l-(5-aminopyridin-3-yl)-2- methoxyethyl)carbamate (Intermediate A22, 32.5 mg, 0.122 mmol) in toluene (1.5 mL) and THF (0.5 mL) was added AlMe3 (2M in toluene, 0.122 mL) at 0°C and the mixture was stirred at 60°C for 1 h under N2. The reaction mixture was quenched by the addition of TFA (0.2 mL) at 0°C and the mixture concentrated under reduced pressure to the title compound as a brown oil (40 mg, 81%). LCMS m/z = 605 [M+H]+.
Step 2. Synthesis of (R)-4-amino-N-(5-(1 -amino-2-methoxyethyl)pyridin-3-yl)-l-(2,6- dichloro-4-cyclopropoxyphenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxamide or (S)-4- amino-N-(5-(l-amino-2-methoxyethyl)pyridin-3-yl)-l-(2,6-dichloro-4-cyclopropoxyphenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxamide.
To a solution of tert-butyl (R)-(l-(5-(4-amino-l-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)-2-methoxyethyl)carbamate or tert-butyl (S)-( 1 -(5-(4-amino-1 -(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5 - carboxamido)pyridin-3-yl)-2-methoxyethyl)carbamate (Step 1, 40 mg, 66 umol) in DCM (mL) was added TFA (1 mL) and the mixture stirred at 25°C for l h. The reaction mixture was concentrated under reduced pressure and the residue purified by prep-HPLC-1 (3-35% MeCN) to give the title compound as a pale yellow solid (9.9 mg, 27%). LCMS m/z = 5[M+H]+; 1H NMR (400 MHz, CDCI3): 11.78 (s, 1H), 10.12-9.95 (m, 1H), 8.70 (s, 1H), 8.(s, 1H), 8.20 (s, 1H), 7.73 (s, 1H), 7.22 (s, 2H), 6.08 (s, 1H), 4.28-4.17 (m, 1H), 3.79 (s, 1H), 3.52 (dd, 1H), 3.39 (s, 3H), 0.86 (d, 5H).
Example 209.Synthesis of (S)-4-amino-l-(4-(azetidin-l-yl)-2,6-dichlorophenyl)-6-oxo-N- (5-(piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide.
To a solution of tert-butyl (S)-2-(5-(4-amino-l-(4-bromo-2,6-dichlorophenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)piperidine-l-carboxylate (Example 196, Step 1; 40 mg, 0.063 mmol) in dioxane (3 mL) was added Pd2(dba)3 (5.74 mg, 0.0063 mmol), Xantphos (3.63 mg, 0.0063 mmol) and NaO’Bu (12 mg, 0.125 mmol) and the mixture stirred at 100°C for l h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (100% EtOAc) to give a 378 WO 2024/233900 PCT/US2024/028806 white solid which was dissolved in TFA (1 mL) and DCM (1 mL). The mixture was stirred at 25°C for l h. The reaction mixture was concentrated under N2 and the residue purified by prep-HPLC-1 (15-45% MeCN) to afford the title compound as a pale yellow solid (6.8 mg, 20%). LCMS m/z = 514 [M+H]+; 1HNMR (400 MHz, CDCI3): 11.89 (s, 1H), 9.98 (d, 1H),8.62 (d, 1H), 8.33 (s, 2H), 7.74 (s, 1H), 6.43 (s, 2H), 5.99 (d, 1H), 3.98 (t, 4H), 3.76 (dd, 1H),3.18 (d, 2H), 2.82-2.75 (m, 1H), 2.49-2.41 (m, 2H), 1.94-1.85 (m, 2H), 1.73-1.68 (m, 3H), 1.53-1.48 (m, 1H).
Example 210.Synthesis of (R)-N-(5-(l,4-oxazepan-3-yl)pyridin-3-yl)-4-amino-l-(2,6- dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-N-(5-(l,4-oxazepan-3-yl)pyridin-3 -yl)-4-amino-1 -(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.
Boc_N Step 4 N NH2 N NH2 Step 1. Synthesis of 3-(5-bromopyridin-3-yl)-l,4-oxazepane To a solution of the 3-((tributylstannyl)methoxy)propan-l-amine (1135 mg, 3.00 mmol) inDCM (15 mL) was added 5-bromonicotinaldehyde (558 mg, 3.0 mmol) and 4A molecular sieves (350 mg) under an inert atmosphere at ambient temperature. The reaction mixture was stirred for 2 h and filtered through a pad of Celite rinsing with DCM(50 mL). The filtrate was concentrated under reduced pressure to afford l-(5-bromopyridin-3-yl)-N-(3- ((tributylstannyl)methoxy)propyl)methanimine. Separately, anhydrous Copper(II)trifluoromethanesulfonate (1085 mg, 3.0 mmol) was added to a solution of 2,6-lutidine (0.mL) in l,l,l,3,3,3-hexafluoropropan-2-ol (12 mL) in a dry Schlenk flask and stirred at RT for l h, during which a homogeneous suspension formed. A solution of l-(5-bromopyridin-3- 379 WO 2024/233900 PCT/US2024/028806 yl)-N-(3-((tributylstannyl)methoxy)propyl)methanimine in DCM (48 mL) was added in one portion and the resulting mixture was allowed to stir at RT for 36 h. The reaction was quenched with a mixture of NaHCO3 (24 mL) and 10% aqueous NH4OH (12 mL) and stirred vigorously for 15 min. The layers were separated and the aqueous layer extracted with DCM (3x 10 mL). The combined organics were washed with water (3x 10 mL), brine (5 mL), dried (Na2S04) and evaporated to dryness in vacuo. Flash chromatography (ISCO, 24 g silica, 0- 15% MeOH/DCM) provided the title compound as an orange oil (337 mg, 44%). LCMS m/z = 257 [M+H]+.
Step 2. Synthesis of tert-butyl 3-(5-bromopyridin-3-yl)-l,4-oxazepane-4-carboxylate.
To a solution of 3-(5-bromopyridin-3-yl)-l,4-oxazepane (Step 1, 337 mg, 1.311 mmol) in DCM (2.6 mL) was added (Boc)2O (335 pl, 1.44 mmol), DMAP (8.0 mg, 0.066 mmol) and TEA (274 pl, 1.96 mmol) and the reaction stirred at RT for a 16 h. The mixture was poured into water (10 mL) and the aqueous layer extracted with DCM (3x 10 mL). The combined organics were washed with NH4OH (10 mL) and brine (10 mL), dried (Na2S04) and evaporated to dryness. The residue was purified by flash chromatography (ISCO, 24 g silica, 10-60% EtOAc/Hex) to afford the title compound as an off-white solid (249 mg, 53%). LCMS m/z = 395 [M+K]+.
Step 3. Synthesis of tert-butyl 3-(5-aminopyridin-3-yl)-l,4-oxazepane-4-carboxylate.
To a suspension of tert-butyl 3-(5-bromopyridin-3-yl)-l,4-oxazepane-4-carboxylate (Step 2, 248 mg, 0.694 mmol), Cs2CO3 (339 mg, 1.041 mmol), Pd2(dba)3 (31.8 mg, 0.035 mmol), and BINAP (43.2 mg, 0.069 mmol) in anhydrous toluene (2.75 mL) was added benzophenone imine (144 pL, 0.83 mmol) and the mixture sparged with N2 for 10 min and then heated to 80°C for 15 h. The reaction was filtered through Celite, washing with EtOAc and the filtrate evaporated to dryness. The residue was purified by flash chromatography (ISCO, 24 g silica, 0-60% EtOAc/Hex) to afford tert-butyl 3-(5-((diphenylmethylene)amino)pyridin-3-yl)-1,4- oxazepane-4-carboxylate intermediate as viscous yellow oil (322 mg, 91% yield) which was dissolved in MeOH (10.5 mL) and cooled to 0°C. Hydroxylamine hydrochloride (132 mg, 1.90 mmol) andNaOAc (260 mg, 3.17 mmol) were added and the reaction mixture stirred at RT for 2 h. The reaction mixture was poured into aqueous NH4C1 and extracted with EtOAc (3x 50 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated by rotary evaporation. The residue was purified by flash chromatography 380 WO 2024/233900 PCT/US2024/028806 (ISCO, 24g silica, 0-15% MeOH (w/10% NH40H)/DCM) to afford the title compound as a white solid (162 mg, 87%). LCMS m/z = 294 [M+H]+; Step 4. Synthesis of (R)-N-(5-(l, 4-oxazepan-3-yl)pyridin-3-yl)-4-amino-l-(2,6- dichlorophenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxamide or (S)-N-(5-(1,4-oxazepan-3- yl)pyridin-3-yl)-4-amino-l-(2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide.
Methyl 4-amino-l-(2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B9, 55 mg, 0.175 mmol) and tert-butyl 3-(5-aminopyridin-3-yl)-l,4-oxazepane- 4-carboxylate MEN-005-082 (Step 3, 61.6 mg, 0.210 mmol) were added to a dry flask and evacuated and backfilled (x3) with N2. Anhydrous toluene (3.5 mL) was added and the solution cooled to 0° C and AlMe3 solution (2M in toluene, 263 pL, 0.525 mmol) added dropwise. The reaction was stirred at ambient temperature for 10 min and at 100°C for 1.5 h. The reaction mixture was quenched with MeOH (2 mL), TFA (0.2 mL), poured into water (15 mL) and extracted with DCM (4x 10 mL). The combined organics were washed with sat aq sodium bicarbonate, water, brine, dried (Na2SO4) and evaporated to dryness. The residue was dissolved in DCM (1.7 mL) and TFA (43.8 pL, 0.191 mmol) added dropwise. The mixture was stirred at RT for 2 h and heated to 40°C for 16 h. The reaction mixture was evaporated to dryness in vacuo and the residue purified by flash chromatography (ISCO, 12 g silica, 0-15% MeOH (w/ 10% NH40H)/DCM) followed by chiral SFC (Regis Whelk O-l (S,S) 21 x 250 mm, 45% EtOH + 0.25% di ethylamine in CO2) provided Peak 1, Example 210.(R)-N-(3-(l,4-oxazepan-3-yl)phenyl)-4-amino-l-(2,6- dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-N-(5-(l,4-oxazepan-5- yl)pyridin-3 -yl)-4-amino-1 -(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5- carboxamide (white solid, 21 mg, 25%); LCMS m/z = 476 [M+H]+; 1HNMR (500 MHz, DMSO-d6): 11.84 (s, 1H), 9.71 (s, 1H), 8.91-8.70 (m, 2H), 8.52 (s, 1H), 8.32 (d, 1H), 8.05 (d, 1H), 7.83 (d, 2H), 7.71 (t, 1H), 4.03-3.81 (m, 3H), 3.76 (dt, 1H), 3.47-3.42 (m, 1H), 3.11 (d, 1H), 2.88 (dt, 1H), 1.91 (t, 2H).
Example 211.Synthesis of (R)-N-(3-(l,4-oxazepan-3-yl)phenyl)-4-amino-l-(2,6- dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-N-(3-(l,4-oxazepan-3- yl)phenyl)-4-amino-1 -(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5 -carboxamide. 381 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of 3-(3-nitrophenyl)-l,4-oxazepane.
The title compound was prepared as a white solid (152 mg, 45%) using an analogous method to that described for Example 210, Step 1. LCMS m/z = 223 [M+H]+.
Step 2. Synthesis of tert-butyl 3-(3-nitrophenyl)-l,4-oxazepane-4-carboxylate.
The title compound was prepared as a pale yellow oil (125 mg, 57%) using an analogous method to that described for Example 210, Step 2. LCMS m/z = 345 [M+Na]+.
Step 3. Synthesis of tert-butyl 3-(3-aminophenyl)-l,4-oxazepane-4-carboxylate.
To a mixture of tert-butyl 3-(3-nitrophenyl)-l,4-oxazepane-4-carboxylate (Step 2, 125 mg, 0.400 mmol) in THE (3 mL) and water (1.75 mL) was added Fe (112 mg, 2.00 mmol) and ammonium chloride (107 mg, 2.00 mmol) and the mixture heated to 60°C and stirred overnight. The reaction was cooled and filtered through celite, washed with EtOAc. The filtrate was washed with aqueous NaHCO3 (10 mL) and brine (10 mL), dried (Na2S04) and evaporated to dryness in vacuo to afford the title compound as a yellow solid (103 mg, 88%). LCMS m/z = 315 [M+Na]+.
Step 4. Synthesis of (R)-N-(3-(l, 4-oxazepan-3-yl)phenyl)-4-amino-l-(2,6-dichlorophenyl)-6- 0x0-1,6-dihydropyrimidine-5-carboxamide or (S)-N-(3-(l,4-oxazepan-3-yl)phenyl)-4-amino- l-(2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide The title compound was prepared as a white solid (11.1 mg, 12%) using an analogous method to that described for Example 210, Step 4. Chiral SFC (Regis Whelk O-l (S,S) 21 x 250 mm, 35% EtOH + 0.25% di ethylamine in CO2) provided: 382 WO 2024/233900 PCT/US2024/028806 Peak 1, Example 211.(R)-N-(3-(l,4-oxazepan-3-yl)phenyl)-4-amino-l-(2,6- dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-N-(3-(l,4-oxazepan-3- yl)phenyl)-4-amino-1 -(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5 -carboxamide (white solid, 11.1 mg, 12%); LCMS m/z = 474 [M+H]+; 1HNMR (500 MHz, DMSO-d6): 11.74 (s, 1H), 9.74 (s, 1H), 8.67 (s, 1H), 8.44 (d, 1H), 7.79 (d, 2H), 7.69-7.59 (m, 2H), 7.(d, 1H), 7.26 (t, 1H), 7.05 (d, 1H), 3.90-3.76 (m, 3H), 3.70 (dt, 1H), 3.06 (s, 1H), 2.81 (dt, 1H), 1.86 (q, 2H), 1.06 (d, 2H).
Example 212.Synthesis of (S)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5- (morpholin-3-yl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (R)-4-amino- l-(2,6-dichloro-4-methoxyphenyl)-N-(5-(morpholin-3-yl)pyridin-3-yl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxami de.
N NH2 Methyl 4-amino-1 -(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5- carboxylate (Intermediate B10, 60 mg, 0.175 mmol) and tert-butyl 3-(5-aminopyridin-3- yl)morpholine-4-carboxylate (Intermediate A68, 58.4 mg, 0.210 mmol) were added to a dry flask and evacuated and backfilled with N2 (3x). Anhydrous toluene (3.5 mL) was added and the solution cooled to 0°C and AlMe3 (2M in toluene; 262 pL, 0.525 mmol) added dropwise. The reaction was removed from the ice bath and stirred at it for 10 min and then at 100°C for 1.5 h. The reaction was cooled to it and quenched with MeOH (2 mL) and TFA (0.2 mL) poured into water (15 mL) and extracted with DCM (4x 10 mL). The combined organics were washed with sat. aq. NaHCO3, water, brine, dried (Na2SO4) and evaporated to dryness. The residue was dissolved in EtOAc (2.5 mL) and HCI (4M in dioxane, 218 pL, 0.872 mmol) added dropwise. The mixture was stirred at it for 18 h and evaporated to dryness in vacuo. The residue was purified by flash chromatography (ISCO, 12 g silica, 0-10% MeOH (w/ 10% NH40H) in DCM) followed by chiral SFC (ChiralPak AD-H 21 x 250 mm, 40% MeOH + 0.25% diethylamine in CO2) afforded: 383 N NH2Boc N.
WO 2024/233900 PCT/US2024/028806 Peak 1, Example 212.(S)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-(morpholin-3- yl)pyridin-3 -yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-1 -(2,6- dichloro-4-methoxyphenyl)-N-(5-(morpholin-3-yl)pyridin-3-yl)-6-oxo-l,6- dihydropyrimidine-5-carboxamide (white solid, 21.9 mg, 26%); LCMS m/z = 492 [M+H]+;1HNMR (500 MHz, DMSO-d6): 11.79 (s, 1H), 10.03 (s, 1H), 8.74 (d, 1H), 8.33 (d, 1H), 8.(s, 1H), 7.73 (s, 1H), 7.06 (s, 2H), 5.98 (s, 1H), 3.97 (dd, 1H), 3.91-3.79 (m, 5H), 3.66 (t, 1H), 3.41 (t, 1H), 3.20-3.06 (m, 1H), 3.01 (d, 1H).
Example 213.Synthesis of (S)-4-amino-N-(5-(azetidin-2-yl)pyridin-3-yl)-l-(2,6-dichloro-4- methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-N-(5-(azetidin-2-yl)pyridin-3-yl)-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine- 5-carboxamide.
Step 1 Step 1. Synthesis of tert-butyl 2-(5-aminopyridin-3-yl)azetidine-l-carboxylate.
A suspension of 5-bromopyridin-3-amine (77.1 mg, 0.45 mmol), l-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (214 mg, 0.90 mmol), C82CO3 (448 mg, 1.mmol), 4,4'-di-tert-butyl-2,2'-dipyridyl (18.4 mg, 0.068 mmol), NiC12 DME adduct (10.1 mg, 0.045 mmol) and [Ir[dF(CF3)ppy]2(dtbbpy)]PF6 (5.0 mg, 0.0045 mmol) in anhydrous DMF (15 mL) was purged with N2 for 20 min and then stirred at it for 72 h in a Penn PhD Mphotoreactor using 450 nM blue LED light. The reaction was filtered through Celite washedwith EtOAc (50 mL). The filtrate was washed with water (3x) and brine and evaporated to dryness. The residue was purified by flash chromatography (ISCO, 12g silica, 0-10% MeOH/DCM) provided the title compound as a yellow-orange oil (44.3 mg, 39%) which was used without further purification in Step 2.
Step 2. Synthesis of (S)-4-amino-N-(5-(azetidin-2-yl)pyridin-3-yl)-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxamide or (R)-4-amino-N-(5-(azetidin- 384 WO 2024/233900 PCT/US2024/028806 2-yl)pyridin-3-yl)-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide.
A dry vial containing methyl 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate BIO, 41.4 mg, 0.120 mmol) and tert-butyl 2- (5-aminopyridin-3-yl)azetidine-l-carboxylate (Step 1, 43.4 mg, 0.168 mmol) was evacuated and backfilled with N2 (3x). Anhydrous toluene (1.5 mL) was added and the mixture cooled on ice. To this solution was added dropwise AlMe3 solution (2.0 M in toluene, 0.180 mL). The reaction was stirred on ice for 5 min, rt for 5 minutes and then at 100°C for l h. The reaction was cooled, diluted with DCM (5 mL) and quenched with MeOH (1 mL) and TFA (0.2 mL). The mixture was poured into water and extracted with DCM (4x 10 mL). The combined organics were washed with sat aq NaHCO3, sat aq Rochelle salt, brine, dried (MgSO4) and concentrated by rotary evaporation. The residue was purified by prep-HPLC-(1-50% MeCN) followed by chiral-SFC (REGIS(S,S)WHELK-O1 250 x 25 mm, 10 pm; 50% MeOH (+0.1% NH4OH) in CO2)) to afford: Peak 1, Example 213;(S)-4-amino-N-(5-(azetidin-2-yl)pyridin-3-yl)-l-(2,6-dichloro-4- methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-N-(5- (azetidin-2-yl)pyridin-3-yl)-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine- 5-carboxamide as a white solid (4.7 mg, 27%). LCMS m/z = 461 [M+H]+; 1H NMR (4MHz, CDCI3): 11.82 (s, 1H), 10.02 (d, 1H), 8.66 (s, 1H), 8.29 (s, 2H), 7.73 (s, 1H), 7.07 (s, 2H), 6.07 (d, 1H), 5.09 (t, 1H), 3.88 (s, 3H), 3.87-3.81 (m, 1H), 3.50 (td, 1H), 2.69-2.58 (m, 1H), 2.47 (dd, 1H).
Example 214.Synthesis of 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,4R)-4- methylazetidin-2-yl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide formate or 4- amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,4S)-4-methylazetidin-2-yl)pyridin-3-yl)- 6-oxo-l,6-dihydropyrimidine-5-carboxamide formate.
Step 1 385 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of tert-butyl 2-(5-aminopyridin-3-yl)-4-methylazetidine-l-carboxylate trifluoroacetate.
The title compound was prepared from l-(tert-butoxycarbonyl)-4-methylazetidine-2- carboxylic acid as a mixture of diastereomers as a yellow oil (91 mg, 60%) using an analogous method to that described for Example 213, Step 1. Prep-HPLC-12 (10-40% MeCN). LCMS m/z = 264 [M+H]+.
Step 2. Synthesis of 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S, 4R)-4- methylazetidin-2-yl)pyridin-3-yl)-6-oxo-l, 6-dihydropyrimidine-5-carboxamide formate or 4- amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,4S)-4-methylazetidin-2-yl)pyridin-3-yl)- 6-oxo-1,6-dihydropyrimidine-5-carboxamide formate.
A suspension of tert-butyl 2-(5-aminopyridin-3-yl)-4-methylazetidine-l-carboxylate trifluoroacetate (88 mg, 0.240 mmol) and KCO3 (202 mg, excess) in MeCN (3 mL) was stirred at it for 20 min. The mixture was filtered, washed with MeCN and the filtrate evaporated to dryness. A mixture of the residue and methyl 4-amino-l-(2,6-dichloro-4- methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B10, 60 mg, 0.171 mmol) was evacuated and backfilled with N2 (3x). Anhydrous toluene (2.1 mL) was added and the mixture cooled on ice. To this was added dropwise AlMe3 solution (2.0 M in toluene, 0.514 mmol) and the reaction stirred on ice for 5 min, it for 5 min and at 100°C for h. The reaction was cooled, diluted with DCM (5 mL) and quenched with MeOH (1.0 mL) and TFA (0.1 mL). The mixture was poured into water and extracted with DCM (4x 15 mL). The combined organics were washed with sat aq NaHCO3, saturated aq Rochelle salt, brine, dried (MgSO4) and evaporated to dryness. The residue was dissolved in DCM (3 mL) and TFA (0.6 mL) and stirred at it for 2 h and evaporated to dryness in vacuo. The residue was purified by reverse-phase HPLC-12 (10-50% MeCN) to afford 4-amino-l-(2,6-dichloro-4- methoxyphenyl)-N-(5-(4-methylazetidin-2-yl)pyridin-3-yl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide trifluoroacetate as a light yellow solid as a 1:1 mixture of diastereomers (74.mg TFA salt). The TFA salt was dissolved in MeCN (4 mL) and sat aq NaHCO3 (0.5 mL) and the mixture stirred at it for 40 min. The solids were removed by filtration and the filtrate evaporated to dryness. The residue was separated by chiral SFC to afford the title compound as a pale-yellow solid (4 mg, 43%). LCMS m/z = 475 [M+H]+; 1H NMR (400 MHz, DMSO- d6): 11.89 (s, 1H), 9.73-9.63 (m, 1H), 8.82-8.73 (m, 1H), 8.68 (d, 1H), 8.46 (s, 1H), 8.29 (s, 386 WO 2024/233900 PCT/US2024/028806 1H), 8.19 (s, 1H), 7.43 (s, 2H), 4.94 (t, 1H), 3.94 (s, 3H), 3.84-3.72 (m, 1H), 2.32-2.26 (m, 2H), 1.44-1.37 (m, 3H).
Example 215.Synthesis of (R)-N-(5-(l,4-oxazepan-5-yl)pyridin-3-yl)-4-amino-l-(2,6- dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-N-(5-(l,4-oxazepan-5- yl)pyridin-3 -yl)-4-amino-1 -(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.
Methyl 4-amino-l-(2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B9, 55 mg, 0.175 mmol) and tert-butyl 5-(5-aminopyridin-3-yl)-l,4-oxazepane-4-carboxylate (Intermediate A28, 61.6 mg, 0.21 mmol) were added to a dry flask and evacuated and backfilled with N2 (3x). Anhydrous toluene (3.5 mL) was added and the solution was cooled to 0° C before AlMe3 solution (2M in toluene, 263 pL, 0.525 mmol) was added dropwise. The reaction was removed from the ice bath and stirred at ambient temperature for 10 min and at 100°C for 1.5 h. The reaction was cooled to it and quenchedwith MeOH (2 mL) and TFA (0.2 mL) poured into H20 (15 mL) and extracted with DCM (4x 10 mL). The combined organics were washed with sat aq NaHCO3, water, brine, dried (Na2S04) and evaporated to dryness. The residue was dissolved in DCM (1.7 mL) and TFA (13.49 pl, 0.175 mmol) added dropwise. The mixture was stirred at rt for 18 h and evaporated to dryness in vacuo. The residue was purified by flash chromatography (ISCO, 12g silica, 0-15% MeOH (+10% NH4OH)/DCM) to afford an off-white solid (32 mg, 38%). The racemate was separated by chiral-SFC (REGIS(S,S)WHELK-O1, 250 x 25 mm, 10 pm); 50% MeOH (0.1% NHOH) in CO2) to afford: 387 WO 2024/233900 PCT/US2024/028806 Peak 1, Example 215.(R)-N-(5-(l,4-oxazepan-5-yl)pyridin-3-yl)-4-amino-l-(2,6- dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-N-(5-(l,4-oxazepan-5- yl)pyridin-3 -yl)-4-amino-1 -(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5- carboxamide (off-white solid, 9.9 mg, 30%). LCMS m/z = 475 [M+H]+; 1HNMR (4MHz, CDCI3): 11.66 (s, 1H), 9.98 (br d, 1H), 8.61 (br s, 1H), 8.27 (br s, 1H), 8.11 (s, 1H), 7.66 (s, 1H), 7.49-7.47 (m, 2H), 7.41-7.39 (m, 1H), 5.99 (br d, 1H), 3.97 (br t, 1H), 3.90-3.(m, 4H), 3.11-3.06 (m, 1H), 3.01-2.95 (m, 1H), 2.07-2.04 (m, 2H).
Example 216.Synthesis of (R)-4-amino-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo- N-(5-(piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide.
Step 1. Synthesis of tert-butyl (R)-2-(5-(4-amino-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)piperidine-l-carboxylate.
To a mixture of methyl 4-amino-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B24, 1.1g 3.22 mmol) and tert-butyl (R)-2- (5-amino-3-pyridyl)piperidine-l-carboxylate (Intermediate A4, 983 mg, 3.55 mmol) in toluene (20 mL) was added AlMe3 (2M in toluene, 4.83 mL) at 0°C under N2. The reaction mixture was stirred at 100°C for l h under N2. The reaction mixture was quenched with 2M NaOH (50 ml) and extracted with EtOAc (3x 60 mL). The combined organics were dried (Na2S04) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to afford the title compound as a brown solid (1 g, 53%). LCMS m/z = 587 [M+H]+.
Step 2. Synthesis of (R)-4-amino-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-N-(5- (piperidin-2-yl)pyridin-3-yl)-l,6-dihydropyrimidine-5-carboxamide. 388 WO 2024/233900 PCT/US2024/028806 A mixture of tert-butyl (R)-2-(5-(4-amino-l-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo- l,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)piperidine-l-carboxylate (Step 1, 8mg, 1.36 mmol) in HCl/EtOAc (2 mL) and EtOAc (4 mL) was stirred at 25°C for l h. The reaction mixture was evaporated to dryness in vacuo and the pH of the residue adjusted to pH 9-10 with 0.25 M aqueous Na2CO3 solution. The solids were collected to afford the title compound as a white solid (560 mg, 84%). LCMS m/z = 487 [M+H]+; 1H NMR (400 MHz, CDCI3):11.77 (s, 1 H), 9.95 (d, 1H), 8.60 (d, 1H), 8.23 (d, 1H), 8.08 (t, 1H), 7.63 (s, 1 H), 7.44 (s, 2H), 6.12 (d, 1H), 3.52-3.61 (m, 1 H), 3.13 (d, 1H), 2.64-2.76 (m, 1 H), 2.18 (s, 6 H), 1.72-1.86 (m, 2 H), 1.55-1.61 (m, 1 H), 1.45-1.51 (m, 1 H), 1.36-1.45 (m, 2 H).
Example 217.Synthesis of (S)-4-amino-l-((S)-2-chloro-6-methylphenyl)-N-(2-fluoro-3- (pyrrolidin-2-yl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-l-((S)- 2-chloro-6-methylphenyl)-N-(2-fluoro-3-(pyrrolidin-2-yl)phenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxami de.
Step 1 Step 2 Step 1. Synthesis of tert-butyl (S)-2-(3-(4-amino-l-((S)-2-chloro-6-methylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)-2-fluorophenyl)pyrrolidine-l-carboxylate or tert-butyl (R)-2-(3-(4-amino-l-((S)-2-chloro-6-methylphenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamido)-2-fluorophenyl)pyrrolidine-l-carboxylate.
To the mixture of methyl 4-amino-l-((S)-2-chloro-6-methylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B3, 100 mg, 0.340 mmol) and tert-butyl (S)- 2-(3-amino-2-fluorophenyl)pyrrolidine-l-carboxylate or tert-butyl (R)-2-(3-amino-2- fluorophenyl)pyrrolidine-l-carboxylate (Intermediate A85, 124 mg, 0.443 mmol) in toluene (1.5 mL) was added AlMe3 (2 M, 0.51 mL) in toluene at 0 °C under N2 and the mixture stirred at 100 °C for 0.5 h under N2. The mixture reaction was quenched by adding into water (10 mL). The reaction mixture was concentrated under reduced pressure and the residue partitioned between DCM (20 mL) and aq. I M NaOH (15 mL) and the aqueous 389 WO 2024/233900 PCT/US2024/028806 phase extracted with DCM (3x 20 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue purified by prep-TLC (SiO2, 50% EtOAc/PE). The residue was further purified by chiral SFC (Diacel Chiralpak AD, 30 x 2mm, 10 pm; 33% IP A (0.1% NH4OH) in CO2) to afford: Peak 1, tert-butyl (S)-2-(3-(4-amino-l-((S)-2-chloro-6-methylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)-2-fluorophenyl)pyrrolidine-l-carboxylate or tert-butyl (R)-2-(3-(4-amino-l-((S)-2-chloro-6-methylphenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamido)-2-fluorophenyl)pyrrolidine-l-carboxylate (40 mg, 22%). LCMS m/z = 5[M+Na]+.
Step 2. Synthesis of (S)-4-amino-l-((S)-2-chloro-6-methylphenyl)-N-(2-jluoro-3-(pyrrolidin- 2-yl)phenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxamide or (R)-4-amino-l-((S)-2-chloro-6- methylphenyl)-N-(2-fluoro-3-(pyrrolidin-2-yl)phenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide. tert-butyl (S)-2-(3-(4-amino-1 -((S)-2-chloro-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine- 5-carboxamido)-2-fluorophenyl)pyrrolidine-l-carboxylate or tert-butyl (R)-2-(3-(4-amino-1- ((S)-2-chloro-6-methylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamido)-2- fluorophenyl)pyrrolidine-l-carboxylate (Step 1, 40 mg, 0.074 mmol) in HCl/EtOAc (2 mL) was stirred at 20 °C for 1 h. The mixture was concentrated under a flow of N2 and the residue purified by prep-HPLC-3 (10-50% MeCN) to give the title compound as a yellow solid (10.1 mg, 31%). LCMS m/z = 442 [M+H]+; 1HNMR (400 MHz, DMSO-d6): 12.10 (d, 1H), 9.61 (d, 1H), 8.62 (d, 1H), 8.32 (s, 1H), 8.27-8.24 (m, 1H), 7.58-7.56 (m, 1H), 7.52-7.(m, 2H), 7.25-7.22 (m, 1H), 7.14-7.10 (m, 1H), 4.34 (brt, 1H), 3.04-2.91 (m, 2H), 2.21-2.(m, 4H), 1.79-1.74 (m, 2H), 1.56-1.49 (m, 1H).
Example 218.Synthesis of (R)-4-amino-N-(5-(l-aminoethyl)pyridin-3-yl)-l-(4-ethyl-2,6- dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(l- aminoethyl)pyridin-3-yl)-l-(4-ethyl-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide. 390 WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of tert-butyl (R)-(l-(5-(4-amino-l-(4-ethyl-2,6-dimethylphenyl)-6-oxo-1,6- dihydropyrimidine-5-carboxamido)pyridin-3-yl)ethyl)carbamate or tert-butyl (S)-(l-(5-(4- amino-l-(4-ethyl-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamido)pyridin- 3-yl) ethyl) carbamate.
To a mixture of methyl 4-amino-l-(4-ethyl-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B58, 30 mg, 0.100 mmol) and tert-butyl (S)- (l-(5-aminopyridin-3-yl)ethyl)carbamate or tert-butyl (R)-(l-(5-aminopyridin-3- yl)ethyl)carbamate BP1491256 A6 (Intermediate A16, 30.71 mg, 0.129 mmol) in toluene (mL) was added AlMe3 (2 M in toluene, 0.149.33 mL) at 0°C and the mixture stirred at 0°C for 5 min and at 40°C for 40 min under N2. To the reaction mixture was added NaOH (2 M, mL) at 0°C and then extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a yellow solid (40 mg, 79%). LCMS m/z = 507 [M+H]+.
Step 2. Synthesis of (S)-4-amino-N-(5-(l-aminoethyl)pyridin-3-yl)-l-(4-ethyl-2,6- dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-N-(5-(l- aminoethyl)pyridin-3-yl)-l-(4-ethyl-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide.
To a solution of tert-butyl (S)-(l-(5-(4-amino-l-(4-ethyl-2,6-dimethylphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamido)pyri din-3-yl)ethyl)carbamate or tert-butyl (R)-(l-(5-(4- amino-l-(4-ethyl-2,6-dimethylphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamido)pyridin- 3-yl)ethyl)carbamate (Step 1, 35 mg, 0.069 mmol) in DCM (2 mL) was added TFA (2 mL) and the mixture stirred at 25°C for 20 min. The reaction mixture was concentrated under N391 WO 2024/233900 PCT/US2024/028806 and the residue purified by prep-HPLC-1 (10-45% MeCN) to give the title compound as a white solid (21.5 mg, 76%). LCMS m/z = 407 [M+H]+; 1H NMR (400 MHz, CDCI3): 11.(s, 1H), 9.75 (d, 1H), 8.49 (d, 1H), 8.23 (d, 2H), 7.66 (s, 1H), 6.97 (s, 2H), 6.13 (d, 1H), 4.(d, 1H), 2.57 (q, 2H), 2.06 (d, 6H), 1.43 (d, 3H), 1.19 (t, 3H).
Example 219.Synthesis of (R)-4-amino-N-(6-(l-aminoethyl)pyrazin-2-yl)-l-(2,6-dichloro- 4-ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(6-(l- aminoethyl)pyrazin-2-yl)-1 -(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5 - carboxamide The title compound was prepared as a yellow solid (16.3 mg, 23%) from methyl 4-amino-l- (2,6-dichloro-4-ethoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B30) and 6-(l-aminoethyl)pyrazin-2-amine (Intermediate A80) using an analogous method to that described for Example 2. HPLC-1 (10-40% MeCN). LCMS m/z = 464 [M+H]+; 1H NMR (400 MHz, CDCI3): 12.11 (s, 1 H) 9.97 (s, 1 H) 9.51 (s, 1 H) 8.27 (s, 1 H) 7.75 (s, 1 H) 7.04 (s, 2 H) 6.06 (s, 1 H) 4.22 (m, 1 H) 4.09 (m, 2 H) 1.44-1.49 (m, 6 H).
Example 220.Synthesis of 4-amino-N-(3-(aminomethyl)-2-ethoxyphenyl)-l-(2,6- dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide.
The title compound was prepared as a yellow solid (16.3 mg, 23%) from methyl 4-amino-l- (2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxylate (Intermediate B9) and 3- (aminomethyl)-2-ethoxyaniline (Intermediate A83) using an analogous method to that described for Example 2. HPLC-12 (10-50% MeCN); LCMS m/z = 448 [M+H]+; 1H NMR (500 MHz, DMSO-d6): 12.03 (s, 1H), 9.68 (d, 1H), 8.67 (d, 1H), 8.43 (s, 1H), 8.35 (dd, 1H), 8.08 (s, 3H), 7.77 (d, 2H), 7.64 (t, 1H), 7.24-7.13 (m, 2H), 4.03 (s, 2H), 3.81 (q, 2H), 1.26 (t, 3H). 392 WO 2024/233900 PCT/US2024/028806 Example 221.Synthesis of 4-amino-N-(3-(aminomethyl)-2-methoxyphenyl)-l-(2,6- dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide trifluoroacetate.
OMe 0 Step 1. Synthesis of (3-amino-2-methoxypheny!)methanol.
Anhydrous THE (20 mL) was added to LiAlH4 (484 mg, 12.5 mmol) under N2 and the mixture cooled on ice. To this was added dropwise over 15 minutes a suspension of 3- amino-2-m ethoxybenzoic acid (830 mg, 5.0 mmol) in anhydrous THE (30 mL) and the reaction mixture warmed to RT and heated to 60 °C for 3 h. The reaction was carefully quenched by dropwise addition of water. The mixture was diluted with EtOAc (10 mL) and saturated aqueous NH4C1 (1 mL) and stirred at RT for 1.5 h. The mixture was poured into aqueous NaHCO3 and extracted with EtOAc (4x 50 mL). The combined organics were washed with water (2x), brine, dried (MgSO4) and concentrated under reduced pressure. The reside was purified by column chromatography (ISCO 40g silica, 0-20% MeOH/DCM) to afford the title compound as a waxy solid (466 mg, 60%). LCMS m/z =154 [M+H]+.
Step 2. Synthesis of 4-amino-l-(2,6-dichlorophenyl)-N-(3-(hydroxymethyl)-2- methoxyphenyl)-6-oxo-l, 6-dihydropyrimidine-5-carboxamide trifluoroacetate Trimethylaluminum solution (2.0 M in toluene, 0.450 mmol) was added dropwise to an ice- cold mixture of methyl 4-amino-l-(2,6-dichlorophenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxylate (Intermediate B9, 49.1 mg, 0.150 mmol) and (3-amino-2-methoxyphenyl)methanol (Part 1, 34.5 mg, 0.225 mmol) in dry toluene (3 mL). The reaction mixture was stirred at RT for 10 min and then heated to 100 °C for 75 min. The cooled reaction mixture was diluted with DCM (5 mL) and quenched with MeOH (2 mL) and TEA (0.2 mL). The mixture was poured into water and extracted with DCM (4x 10 mL). The combined organics were washed with saturated aqueous sodium bicarbonate, water, brine,dried (MgSO4) and evaporated to dryness. The residue was purified by prep-HPLC-12 (10- 393 WO 2024/233900 PCT/US2024/028806 60% MeCN) to afford the title compound as a white powder (26.5 mg, 32%). LCMS m/z = 435 [M+H]+.
Step 3. Synthesis of 4-amino-N-(3-(aminomethyl)-2-methoxyphenyl)-l-(2,6-dichlorophenyl)- 6-oxo-l,6-dihydropyrimidine-5-carboxamide trifluoroacetate.
A solution of 4-amino-l-(2,6-dichlorophenyl)-N-(3-(hydroxymethyl)-2-methoxyphenyl)-6- oxo-1,6-dihydropyrimidine-5-carboxamide trifluoroacetate (Step 2, 24.4 mg, 0.044 mmol), DIPEA (11.5 pL, 0.066 mmol), CBr4 (24.1 mg, 0.072 mmol) and PPh3 (19.0 mg, 0.0mmol) in DMF (0.8 mL) and DMSO (0.2 mL) was stirred at RT for 45 min. To this was added NaN3 (5.7 mg, 0.088 mmol) and the mixture heated to 60 °C for 3 h. The reaction was diluted with EtOAc (20 mL) and washed with water (3x), brine, dried (MgSO4) and concentrated by rotary evaporation.
PPh3 (28.1 mg, 0.107 mmol) and water (20.0 pL, 1.10 mmol) were added to the residue dissolved in THF (0.80 mL) and stirred at RT overnight. The reaction mixture was concentrated and the residue purified by prep-HPLC-12 (10-50% MeCN) to afford the title compound as a colourless film (0.7 mg, 2%). LCMS m/z = 434 [M+H]+; 1H NMR (4MHz, DMSO-d6): 12.05 (s, 1H), 9.70 (d, 1H), 8.70 (d, 1H), 8.48-8.37 (m, 2H), 8.09 (s, 3H), 7.78 (d, 2H), 7.65 (t, 1H), 7.20 (t, 1H), 7.15 (d, 1H), 4.05 (q, 2H), 3.70 (s, 3H).
Example 222.Synthesis of (R)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(3-fluoro-5- (piperidin-2-yl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-l-(2,6- dichloro-4-methoxyphenyl)-N-(3-fluoro-5-(piperidin-2-yl)phenyl)-6-oxo-l,6- dihydropyrimi di ne-5 -carb oxami de.
N״NH2 n^nh 2 n^nh 2 394 Ck ,CI WO 2024/233900 PCT/US2024/028806 Step 1. Synthesis of tert-butyl 2-(3-(4-amino-l-(2,6-dichlor o-4-methoxyphenyl)-6-oxo-1,6- dihydropyrimidine-5-carboxamido)-5-fluorophenyl)piperidine-l-carboxylate.
Trimethylaluminum solution (2.0 M in toluene, 0.110 mL, 0.214 mmol) was added dropwise to an ice-cold solution of methyl 4-amino-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxylate (Intermediate B10, 24.5 mg, 0.071 mmol) and tert-butyl 2- (3-amino-5-fluorophenyl)piperidine-l-carboxylate (Intermediate A85, 33 mg, 0.107 mmol) in dry toluene (1.4 mL). The reaction was stirred at RT for 10 min and then heated to 100 °C for l h. The reaction mixture was cooled, diluted with DCM (5 mL) and quenched with MeOH (2 mL) and TFA (0.2 mL). The mixture was poured into water and extracted with DCM (4x 10 mL). The combined organics were washed with saturated aqueous sodium bicarbonate, water, brine, dried (MgSO4) and evaporated to dryness to afford the title compound. LCMS m/z = 628 [M+Na]+.
Step 2. (R)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(3-fluoro-5-(piperidin-2- yl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-l-(2,6-dichloro-4- methoxyphenyl)-N-(3-fluoro-5-(piperidin-2-yl)phenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamide.
Tert-butyl 2-(3-(4-amino-l-(2,6-dichloro-4-methoxyphenyl)-6-oxo-l,6-dihydropyrimidine-5- carboxamido)-5-fluorophenyl)piperidine-l-carboxylate (Step 1) was dissolved in DCM (mL) and TFA (0.5 mL) and stirred at RT for 3 h. The solvents were removed by rotary evaporation and th residue purified by prep-HPLC-12 (10-50% MeCN) followed by chiral SFC (Rilas Technologies, Regis Whelk O-l (S,S) 21 x 250 mm, 30% EtOH + 0.25% diethylamine in CO2), to afford 70 mL/min) afforded: Peak 1,Example 222. (R)-4-amino-l-(2,6-dichloro-4-methoxyphenyl)-N-(3-fluoro-5- (piperidin-2-yl)phenyl)-6-oxo-l,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-l-(2,6- dichloro-4-methoxyphenyl)-N-(3-fluoro-5-(piperidin-2-yl)phenyl)-6-oxo-l,6- dihydropyrimidine-5-carboxamide (white solid, 6.3 mg). LCMS m/z = 506 [M+H]+; 1H NMR (500 MHz, DMSO-d6): 12.16 (s, 1H), 9.57 (s, 1H), 8.90 (s, 1H), 8.77 (s, 1H), 8.56 (s, 1H), 8.43 (s, 1H), 7.85 (d, 1H), 7.37 (s, 2H), 7.35 (s, 1H), 7.02 (d, 1H), 4.26-4.17 (m, 1H), 3.89 (s, 3H), 3.07-2.95 (m, 1H), 1.97-1.52 (m, 6H). 395 WO 2024/233900 PCT/US2024/028806 Biological Example 1. In vitro Enzymatic Activity Assay Full length human GSK3a or GSK3p expressed as N-terminal GST fusion proteins in baculovirus host were purchased from Carna Biosciences (Japan). The kinase was pre- incubated with ATP (adenosine-5'-triphosphate) for 45 min, then incubated with tested compounds for another 45 min in assay buffer that contains 100 mM HEPES (N-2- hydroxyethylpiperazine-N'-2-ethanesulfonic acid), pH 7.5, 10 mM MgCl, 1.0 mM DTT, and 0.015% Briji-35. Serial dilution of compound was prepared in DMSO (dimethyl sulfoxide and transferred to 384-well plates (Greiner BioOne) by Mosquito (SPT Labtech). The final reaction mixture containing 0.2 nM GSK3a or GSK3p kinase, 1.0 mM ATP (measured Km for ATP is 10-15 uM), and 1.0 pM peptide substrate (5-FAM-KRREILSRRPpSYR-COOH (SEQ ID NO: 1), ProfilerPro Peptide 15, Perkin Elmer) was initiated by addition of substrate peptide and incubated for 120 minutes at 25 °C. Reaction was terminated by the addition of excess EDTA. Substrate and product were separated, and fluorescence intensities of the substrate and product peaks were determined by Labchip EZ Reader II (Caliper Life Sciences, Hopkinton, MA). Percent inhibition was plotted against compound concentration to generate 10-point dose response curve with 3-fold serial dilution starting from 10 pM. ICvalue was determined from the 4-parameter logistic curve fitting.
Biological Example 2. In vitro Cellular Activity Assay Cellular target engagement, or cellular binding of the testing compounds were measured in NanoBRETTM assays, which is based on binding competition between the testing compounds and a bioluminescent tracer in human embryonic kidney cells (HEK-293 cell line). In the assay, HEK293 cells stably expressing either Nanoluc-GSK3 A or Nanoluc-GSK3B were maintained in culture media and seeded, using a multidrop dispenser, at a density of 5x1cells per well in 384-well white plates with 100 ng/ml doxycycline (Sigma) overnight.Compound was first diluted in DMSO to generate a 9-point serial dilution then diluted to lOx final concentration in Opti-MEM™M (Gibco). After overnight incubation, cell medium was aspirated from the seeded cells using a microplate automatic washer, then 27 pL of pre- warmed Opti-MEM™ with kinase tracer (K-8) and 3 pL of Opti-MEM™ diluted DMSO or compounds were added per well. Plates were protected from light, mixed in an orbital shaker for 3 min at RT and incubated at 37 °C, 5% CO2 in a humidified incubator for 2 hours. After acclimation at RT for 15 min, 15 pL of 3x complete NanoBRET™ Nano-Gio Substrate/Inhibitor (Promega) was added per well. Plates were mixed in an orbital shaker for 396 WO 2024/233900 PCT/US2024/028806 3 min at RT and incubated for an additional 30 min. Donor emission at 460 nm and acceptor emission at 647 nm were measured in EnVision multilabel plate reader (Perkin Elmer).
Biological assay data of exemplary compounds are provided in Table 1 below.
Table 1 EXAMPLE EnzymeGSKa (nM)EnzymeGSK3p (nM)NanoBRETGSK3a IC50 (nM)NanoBRETGSK3p IC50 (nM) 1 3.6 167.9 3.6 2437 399.4 4.9 328.96.6 344.4 5 395.23.7 186.8 1.4 109.38.3 378.1 6.2 382.77.2 292.4 6.5 3527.5 336.8 7.1 480.34.8 204.3 3.3 169.19.5 661.3 7.4 429.98.8 395 6.9 370.514.4 647.6 4.1 252.23.8 199.2 2.4 140.817.7 1006.8 9.8 502.66.4 318.4 4 230.74.5 208 2.2 118.64.1 254.7 1.9 132.37.8 339.6 3.8 270.611.9 621.5 7.1 428.93.2 231.7 3.5 179.814 685.1 7.2 396.53.2 216.6 2.6 145.28.4 389.3 5.6 334.15 342.7 4.3 239.34.1 297.8 2.8 146.913.9 691.8 7.5 714.9 397 WO 2024/233900 PCT/US2024/028806 26 5.5 327.2 4.4 268.72.4 54.2 1.7 42.59.6 320.4 9 698.892.2 3799.7 79.2 2500063.9 1949 72.2 15760.86.9 404.8 5 417.86.3 269 2.6 157.86.4 343.1 8.3 460.76.5 344.4 3.7 268.114.7 693.4 6.2 411.67.3 301.9 4.4 289.88.4 388 7.6 431.44.6 282.3 3.6 229.92.6 106.9 2.1 128.610.1 418 5.8 430.512.1 604.8 5.9 385.94.8 297.5 2.9 257.14.9 283 5.4 284.74.7 381.8 7.6 5188.5 384.4 6.6 364.710.5 489.3 7.3 3953.2 227.3 2.9 173.95.2 343.4 4.7 297.92.5 160.6 2.8 144.516.5 708.3 7.4 438.92.8 141.9 2.2 123.54.4 208.8 2.5 131.512.9 625.3 6.8 356.25.4 345.2 5.4 340.39.1 430.1 6.5 483.35.7 323.4 4.8 272.87.9 382.2 5.4 276.8 398 WO 2024/233900 PCT/US2024/028806 58 2.1 152.5 2.8 146.63.1 224.3 2.5 1876.5 333.8 3 199.56.4 465.5 3.7 284.42 123 2.4 155.44.5 209.4 4.4 23411.7 621.3 6.5 489.45.1 302 3.1 2176 348.8 2.9 2062.1 105.1 1.4 73.42.6 167.3 1.9 219.612.5 536 7 513.32.9 145.3 2.4 201.46.3 383.4 4.8 3537.5 468.3 5.1 378.66.7 318 5.8 3749.6 464.8 6.6 363.42.4 106.1 3.6 186.216 854 9.4 591.42.2 152.1 3.5 195.911.4 958.4 7.7 703.44.3 316.9 2.4 169.82.5 269.9 2.9 270.75.9 313.7 2.3 116.64.5 247.6 4 269.37 490.1 4.1 336.33.8 253.8 2.5 179.39.4 551 4.2 373.86.6 413.7 4.2 320.917.9 1127.3 7.6 542.815.4 1015.7 8.1 453.610.2 668.9 6.4 484.6 399 WO 2024/233900 PCT/US2024/028806 90 15.6 1065.2 6.5 700.16 299.1 3.7 200.716.4 1027 6.8 58431.7 1949.2 9.3 914.47.6 598.4 6.6 383.59.8 464.6 4.3 289.616.4 705.8 6.7 640.23.6 229.7 1.8 120.84.6 253.5 2.5 133.520.5 1023.6 7.4 565.2100 8.2 347.8 3.9 293.1101 19.6 941.3 7.8 799.7102 16.5 683.8 5 584103 13.2 581 6.6 532.5104 16.2 746.2 7.9 520.9105 19.3 1126.7 7.2 576.6106 4.5 278.9 2.8 195.5107 10 671.4 3.9 434.5108 24.6 998.1 8.7 688.4109 15.6 802.9 8.4 567110 9.9 567.8 3.7 334.9ill 3 163.3 2 139.9112 10.5 493.5 5.1 348.5113 3 132.9 1.7 107114 12.1 506.7 4.4 251.9115 7.6 362.2 4.7 280.7116 2.9 125.1 1.8 101.4117 2.2 104.1 1.4 81.1118 11.2 449.8 9.4 566.3119 8.1 414.1 8.1 502.1120 9.4 442.2 4.4 274.3121 3.8 306.5 3.4 395.4 400 WO 2024/233900 PCT/US2024/028806 122 5.3 327 5 313.8123 4.8 266.2 3.3 202.6124 7 393.4 7.8 404.3125 4.9 296.5 2.7 162.6126 14.7 701.8 7.9 505.9127 18.6 767.4 9.6 649.6128 19 1175.6 7.7 545.9129 2.1 104.8 1.2 81.7130 13.5 591 5.3 461.4131 4.9 201.7 2.3 159132 5.5 228 2 180.7133 9.7 508.2 6.1 349.5134 3.4 212.1 3.2 204135 3.2 184.2 4.5 264.3136 2.9 205.7 1.8 118.1137 1.9 129.4 1.7 87.1138 6.4 321.7 2.9 211.7139 10.9 559.7 5.1 281.2140 24.2 1235.7 9.2 615.8141 4.1 232 2.9 317.7142 9.8 420.6 4.7 349.8143 4.9 207.2 4.1 280.1144 11 472.4 5 375.4145 3 129.3 1 96.2146 7.7 355.3 3.7 339.8147 8.8 392 3.8 354148 7.2 316.5 4.3 349149 13.4 552.5 8.6 518.6150 1.1 44.2 1 49.5151 14.9 500.9 7.1 405.8152 2.7 119.8 2.4 173.6153 7.8 345.8 6.4 490.9 401 WO 2024/233900 PCT/US2024/028806 154 7 245.5 3.2 258.9155 9.9 373.5 3.7 278.8156 34.9 1252.1 8.1 956.6157 32.5 1315.6 11.3 1155158 9.3 355.1 37.3 531.9159 90.6 2082.4 76.9 5788.8160 161.4 2316.7 196.9 11315.6161 7.2 378.8 3 287.3162 5.6 218.3 5.4 300.5163 5.6 250 2.8 205164 29.4 1849.6 9.7 1165.9165 10.8 434.3 9.3 1119.1166 285.1 9383.3 176.6 16079.1167 45.4 1814.1 27.2 1864168 49.3 1526.6 27.1 1469.9169 4.2 105.2 2 103.4170 21.8 520 16.4 525.6171 44.8 1278.1 30.1 851.3172 6.3 259.9 3.5 98.8173 1883.3 10000 1510.8 25000174 28 705.1 8.7 559.8175 32.6 803.3 8.1 580.7176 5.1 272.3 2.6 190177 4 199.7 2.8 283178 7.2 335.2 4.8 259.7179 3.7 256.8 3.3 178.6180 6.4 297.5 4.7 321.6181 7.9 535.6 7 490.7182 17.4 914.6 8.2 643.1183 7.9 576 5 299.9184 3.9 175.3 2.1 166.7185 3.5 147.8 1.6 128 402 WO 2024/233900 PCT/US2024/028806 186 4.4 169.2 2.1 151.9187 8.4 356.6 5.6 421.1188 10.4 460.4 3.9 345.1189 133 2164.3 69.4 4579.9190 37.6 971.5 26.7 3300.4191 5.7 229.5 4.7 304.3192 1.8 14.7 1.4 18.8193 9.2 480.6 6.8 487.1194 6.2 302.2 5.1 329.8195 11 632.1 5.4 462.5196 6.6 399.7 4.2 242.2197 15 849.5 7.2 402.6198 5.6 331.5 3.7 208.8199 3.3 202.7 2.4 118200 14.4 813.5 7.6 451.1201 13.7 607.8 7.4 430.2202 8.7 431.6 5.9 385.4203 8 318.1 3.7 293.2204 13.5 706.3 8.8 781.9205 5 238 3.7 204.5206 9.4 259.8 3.1 139.1207 5.3 233.8 965.5 25000208 2.4 203 2.4 166.2209 5.2 383 5.9 300.4210 3.9 204.5 4 227.7211 15.9 887.5 8.6 797.4212 4.7 272.2 7.6 519.8213 33.2 1759.9 7.8 992.2214 17.3 930 8.9 640215 7.2 500.3 8.5 689.9216 5.6 292.6 3.4 172.8217 7.8 305 8 424.3 403 WO 2024/233900 PCT/US2024/028806 Biological Example 3. Efficacy in MC38 Syngeneic Colorectal Cancer Model 218 10.8 420.6 5.6 401.3219 5.4 270.6 3.8 187.4220 11.7 307.8 8.1 258.6221 15.6 399.9 7.3 235.5222 2.1 99.2 4.6 147.6 Murine MC38 colorectal carcinoma cells were cultured in DMEM medium supplemented with 10% fetal bovine serum, 100 U/mL Penicillin and 100 ug/mL Streptomycin at 37C in an atmosphere of 5% CO2. Cells with viability > 90% were harvested and counted for subcutaneous inoculation. Female C57BL/6 mice, 8-9 weeks old, (Beijing Vital River Laboratory Animal Technology Co), weighing approximately 18-22g, were acclimated for 1 week and then inoculated subcutaneously with MC38 cell suspension (1X106 cells) in 100 pL PBS into the right flank. Body weight of individual mice and tumor volume were used as randomization parameter for allocating of animals into treatment groups. Treatment started when tumor size reached an average of 90 mm3 (range 80-1mm3). Compound in vehicle (20% (w/w) HP־P־CD in 50 mM citrate buffer, pH 3) was prepared fresh daily and administered via oral gavage. Anti-PD-Ll injection solution was administered twice weekly by an initial intravenous loading dose of 5 mg/kg followed by intraperitoneal maintenance doses of 2.5 mg/kg BIW. Animals were monitored daily for clinical symptoms and detection of adverse effects. The volume of engrafted MC38 tumors was measured twice weekly using caliper. Tumor and body weight measurements were recorded for analysis. Figure 1 shows tumor volume in an MC38 mouse model of colorectal cancer with treatment with anti-PD-Ll antibody, Compound 178 or a combination of anti- PD-L1 antibody and Compound 178. 404

Claims (31)

WO 2024/233900 PCT/US2024/028806 CLAIMS What is claimed is:
1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein ؛s a sing1e bond or a double bond; X1isCR3orN; X2 is selected from the group consisting of CR7, N, and NRd; X3 is selected from the group consisting of CR12, N, and NRd; X4 is selected from the group consisting of CR13, N, and NRd; Z is O or S; R1 is selected from the group consisting of halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to groups each independently selected from the group consisting of halo, OH and CN; R2 is selected from the group consisting of H, D, halo, C1-C4alkyl, and C3-C10cycloalkyl; R3 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, -(C(Ra)2)n-ORb, - (C(Ra)2)״-C(O)ORb, -(C(Ra)2)n-SO2-Rb, -N(Ra)2, C3-C10cycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12-membered heteroaryl, wherein the C1-C4alkyl, C3-C10cycloalkyl, and 4 to 12-membered aryl are each optionally 405 WO 2024/233900 PCT/US2024/028806 substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl and 4 to 12- membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; R4 is selected from the group consisting of H, D, halo, C1-C4alkyl, and C3-Ciocycloalkyl; R5 is selected from the group consisting of halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to groups each independently selected from the group consisting of halo, OH and CN; R6 is H or D; R7 is selected from the group consisting of H, D, halo, C1-C4alkyl, C1-C4alkoxy, C3- Ciocycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12- membered heteroaryl, wherein the C1-C4alkyl, C1-C4alkoxy, C3-C10cycloalkyl, and to 12-membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; R8 is selected from the group consisting of H, D, halo, C1-C4alkyl, and C3-Ciocycloalkyl; R9 are each independently selected from the group consisting of H, D, C1-C4alkyl, C2- C4alkenyl, C2-C4alkynyl, -(C(Ra)2)n-ORb, C3-C10cycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12-membered heteroaryl, wherein the C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C10cycloalkyl, and 4 to 12-membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; or R7 and R9 are taken together with the carbon atoms to which they are attached to form Ring A, wherein Ring A is C3-C10cycloalkyl or 4 to 12-membered heterocyclyl, wherein the C3-C10cycloalkyl is optionally substituted with 1 to 4 Rc, wherein the 4 to 12- membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 4 Rc; or406 WO 2024/233900 PCT/US2024/028806 R8 and R9 are taken together with the carbon atom to which they are attached to form Ring B, wherein Ring B is C3-C10cycloalkyl or 4 to 12-membered heterocyclyl, wherein the C3-C10cycloalkyl is optionally substituted with 1 to 4 Rc, wherein the 4 to 12- membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 4 Rc; or R8 and R9 are taken together form a =0; R10 is selected from the group consisting of H, D, C1-C4 alkyl, -(C(Ra)2)n-ORb, -(C(Ra)2)n- SO2Rb, C3-C10cycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and to 12-membered heteroaryl, wherein the C1-C4alkyl, C3-C10cycloalkyl, and 4 to 12- membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12- membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; or R9 and R10 are taken together with the carbon atom and the nitrogen atom to which they are attached, respectively, to form Ring C, wherein Ring C is a 4 to 12-membered heterocyclyl having 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 4 Rc; or R7 and R9 are taken together with the carbon atoms to which they are attached to form Ring A, and R8 and R10 are taken together with the carbon atom and the nitrogen atom to which they are attached, respectively, to form Ring C, wherein Ring A and Ring C are each optionally substituted on a ring carbon by 1 to 4 Rc; R11 is selected from the group consisting of H, D, C1-C4alkyl, C1-C4haloalkyl, and C3- Ciocycloalkyl; R12 is selected from the group consisting of H, D, halo, C1-C4alkyl, and C3-C10cycloalkyl; or R11 and R12 are taken together with the nitrogen atom and the carbon atom to which they are attached, respectively, to form Ring D, wherein Ring D is selected from the group consisting of a 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl, wherein the 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl have 407 WO 2024/233900 PCT/US2024/028806 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd, and then are each optionally substituted on a ring carbon by 1 to 4 Rc; R13 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, C1-C4alkoxy, C3- Ciocycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12- membered heteroaryl, wherein the C1-C4alkyl, C1-C4alkoxy, C3-C10cycloalkyl, and to 12-membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; R14 is selected from the group consisting of H, D, and C1-C4alkyl; Each Ra is independently selected from the group consisting of H, D, halo, CN, C1-C4alkyl, and C1-C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN; Each Rb is independently selected from the group consisting of H, D, C1-C4alkyl, C3- Ciocycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12- membered heteroaryl, wherein the C1-C4alkyl, C3-C10cycloalkyl, and 4 to 12- membered aryl are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN, wherein the 4 to 12- membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are optionally substituted on a ring carbon with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN; Each Rc is independently selected from the group consisting of H, D, halo, OH, CN, C1- C4alkyl, and C1-C4alkoxy, or two Rc, attached to the same atom, form a =0, wherein said C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN; Each Rd is independently selected from the group consisting of H, D, C1-C4alkyl, and C(O)C1- 4alkyl; and n is 0, 1, 2, or 3. 408 WO 2024/233900 PCT/US2024/028806
2. The compound of claim 1, wherein the compound is of Formula (II), (Ila), (11b), (III), (Illa), (Illb), (IV), (IVa), (IVb), (V), (Va) or (Vb) : (11b), 409 WO 2024/233900 PCT/US2024/028806 410 WO 2024/233900 PCT/US2024/028806 411 WO 2024/233900 PCT/US2024/028806 or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1, wherein the compound is of Formula (IVc) or (IVd): or a pharmaceutically acceptable salt thereof, wherein Ring C is a 4 to 10-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from the groupconsisting of 0, S,and NRd, and then is optionally substituted on a ring carbon by 1 to 2 Rc.
4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein(i) Ring C is piperidine, 1,4-oxazepane, azetidine, morpholine, pyrrolidine, piperazine, piperazine-2-one, octahydrocyclopenta[c]pyrrole, or azepane, each of which is optionally substituted on a ring carbon by 1 to 2 Rc; or (ii) Ring C is represented by 412 WO 2024/233900 PCT/US2024/028806 5 each of which is optionally substituted with 1 or 2 Rc; and each Rc is independently C1-C3alkyl optionally substituted with halo or OH.
5. The compound of claim 1, wherein the compound is of Formula (VI): or a pharmaceutically acceptable salt thereof. 10
6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein X1isCR3orN; X2isCR7orN; X3isCR12 orN; X4isCR13 orN; 15 Z is O or S; 413 WO 2024/233900 PCT/US2024/028806 R1 is selected from the group consisting of halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C1- C4haloalkyl; R2 is selected from the group consisting of H, D, C1-C4alkyl, and C3-C10cycloalkyl; R3 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, -(C(Ra)2)n-ORb, - (C(Ra)2)״-C(O)ORb, -(C(Ra)2)n-SO2-Rb, -N(Ra)2, C3-C10cycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12-membered heteroaryl, wherein the C1-C4alkyl, C3-C10cycloalkyl, and 4 to 12-membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl and 4 to 12- membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; R4 is selected from the group consisting of H, D, C1-C4alkyl, and C3-C10cycloalkyl; R5 is selected from the group consisting of halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C1- C4haloalkyl; R6 is H or D; R7 is selected from the group consisting of H, D, halo, C1-C4alkyl, C1-C4alkoxy, C3- Ciocycloalkyl, and 4 to 12-membered heterocyclyl, wherein the C1-C4alkyl, C1- C4alkoxy, and C3-C10cycloalkyl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; R8 is selected from the group consisting of H, D, C1-C4alkyl, and C3-C10cycloalkyl; R9 are each independently selected from the group consisting of H, D, C1-C4alkyl, C2- C4alkenyl, C2-C4alkynyl, -(C(Ra)2)n-ORb, C3-C10cycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12-membered heteroaryl, wherein the C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C10cycloalkyl, and 4 to 12-membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; or 414 WO 2024/233900 PCT/US2024/028806 R7 and R9 are taken together with the carbon atoms to which they are attached to form Ring A, wherein Ring A is C3-C10cycloalkyl or 4 to 12-membered heterocyclyl, wherein the C3-C10cycloalkyl is optionally substituted with 1 to 4 Rc, wherein the 4 to 12- membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 4 Rc; and/or R8 and R9 are taken together with the carbon atom to which they are attached to form Ring B, wherein Ring B is C3-C10cycloalkyl or 4 to 12-membered heterocyclyl, wherein the C3-C10cycloalkyl is optionally substituted with 1 to 4 Rc, wherein the 4 to 12- membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 4 Rc; or R8 and R9 are taken together form a =0; R10 is selected from the group consisting of H, D, C1-C4 alkyl, -(C(Ra)2)n-ORb, -(C(Ra)2)n- SO2Rb, C3-C10cycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and to 12-membered heteroaryl, wherein the C1-C4alkyl, C3-C10cycloalkyl, and 4 to 12- membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12- membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; or R9 and R10 are taken together with the carbon atom and the nitrogen atom to which they are attached, respectively, to form Ring C, wherein Ring C is a 4 to 12-membered heterocyclyl having 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 4 Rc; R11 is selected from the group consisting of H, D, C1-C4alkyl, and C3-C10cycloalkyl; R12 is selected from the group consisting of H, D, halo, C1-C4alkyl, and C3-C10cycloalkyl; R13 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, C1-C4alkoxy, C3- Ciocycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12- membered heteroaryl, wherein the C1-C4alkyl, C1-C4alkoxy, C3-C10cycloalkyl, and to 12-membered aryl are each optionally substituted with 1 to 4 Rc, wherein the 4 to415 WO 2024/233900 PCT/US2024/028806 12-membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 4 Rc; R14 is selected from the group consisting of H, D, and C1-C4alkyl; Each Ra is independently selected from the group consisting of H, D, halo, CN, C1-C4alkyl, and C1-C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN; Each Rb is independently selected from the group consisting of H, D, C1-C4alkyl, C3- Ciocycloalkyl, 4 to 12-membered heterocyclyl, 4 to 12-membered aryl, and 4 to 12- membered heteroaryl, wherein the C1-C4alkyl, C3-C10cycloalkyl, and 4 to 12- membered aryl are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN, wherein the 4 to 12- membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are optionally substituted on a ring carbon with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN; Each Rc is independently selected from the group consisting of H, D, halo, OH, CN, C1- C4alkyl, and C1-C4alkoxy, or two Rc, attached to the same atom, form a =0, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN; Each Rd is independently selected from the group consisting of H, D, C1-C4alkyl, and C(O)C1- 4alkyl; and n is 0, 1, 2, or 3.
7. The compound of claim 5 or 6, or a pharmaceutically acceptable salt thereof, wherein X1isCR3orN; X2isCR7orN; X3isCR12 orN; X4isCR13 orN; 416 WO 2024/233900 PCT/US2024/028806 Z is O; R1 is selected from the group consisting of halo, OH, C1-C4alkyl, C1-C4alkoxy, and C1- C4haloalkyl; R2 is selected from the group consisting of H, D, and C1-C4alkyl; R3 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, -(C(Ra)2)n-ORb, - (C(Ra)2)״-C(O)ORb, -(C(Ra)2)n-SO2-Rb, -N(Ra)2, C3-C8cycloalkyl, 4 to 10-membered heterocyclyl, 4 to 10-membered aryl, and 4 to 10-membered heteroaryl, wherein the C1-C4alkyl, C3-C8cycloalkyl, and 4 to 10-membered aryl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 10-membered heterocyclyl and 4 to 10- membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 3 Rc; R4 is selected from the group consisting of H, D, and C1-C4alkyl; R5 is selected from the group consisting of halo, OH, C1-C4alkyl, C1-C4alkoxy, and C1- C4haloalkyl; R6 is H or D; R7 is selected from the group consisting of H, D, halo, C1-C4alkyl, C1-C4alkoxy, C3- Cscycloalkyl, and 4 to 10-membered heterocyclyl, wherein the C1-C4alkyl, C1- C4alkoxy, and C3-C8cycloalkyl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are each optionally substituted on a ring carbon with 1 to 3 Rc; R8 is selected from the group consisting of H, D, and C1-C4alkyl; R9 are each independently selected from the group consisting of H, D, C1-C4alkyl, C2- C4alkenyl, C2-C4alkynyl, -(C(Ra)2)n-ORb, C3-C8cycloalkyl, and 4 to 10-membered heterocyclyl, wherein the C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, and C3- Cscycloalkyl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 10- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are each optionally substituted on a ring carbon with 1 to 3 Rc; or 417 WO 2024/233900 PCT/US2024/028806 R7 and R9 are taken together with the carbon atoms to which they are attached to form Ring A, wherein Ring A is C3-C8cycloalkyl or 4 to 10-membered heterocyclyl, wherein the C3-C8cycloalkyl is optionally substituted with 1 to 3 Rc, wherein the 4 to 10- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 3 Rc; and/or R8 and R9 are taken together with the carbon atom to which they are attached to form Ring B, wherein Ring B is C3-C8cycloalkyl or 4 to 10- membered heterocyclyl, wherein the C3-C8cycloalkyl is optionally substituted with 1 to 3 Rc, wherein the 4 to 10- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 3 Rc; or R8 and R9 are taken together form a =0; R10 is selected from the group consisting of H, D, C1-C4 alkyl, -(C(Ra)2)n-ORb, -(C(Ra)2)n- SO2Rb, C3-C8cycloalkyl, 4 to 10-membered heterocyclyl, 4 to 10-membered aryl, and to 10-membered heteroaryl, wherein the C1-C4alkyl, C3-C8cycloalkyl, and 4 to 10- membered aryl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 10- membered heterocyclyl and 4 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are each optionally substituted on a ring carbon with 1 to 3 Rc; or R9 and R10 are taken together with the carbon atom and the nitrogen atom to which they are attached, respectively, to form Ring C, wherein Ring C is a 4 to 10-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 3 Rc; R11 is selected from the group consisting of H, D, and C1-C4alkyl; R12 is selected from the group consisting of H, D, halo, and C1-C4alkyl; R13 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, and C1-C4alkoxy,wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to Rc; 418 WO 2024/233900 PCT/US2024/028806 R14 is selected from the group consisting of H, D, and C1-C4alkyl; Each Ra is independently selected from the group consisting of H, D, halo, CN, C1-C4alkyl, and C1-C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH and CN; Each Rb is independently selected from the group consisting of H, D, C1-C4alkyl, C3- C8cycloalkyl, 4 to 10-membered heterocyclyl, 4 to 10-membered aryl, and 4 to 10- membered heteroaryl, wherein the C1-C4alkyl, C3-C8cycloalkyl, and 4 to 10- membered aryl are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH and CN, wherein the 4 to 10- membered heterocyclyl and 4 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, N, and NRd and then are optionally substituted on a ring carbon with 1 to 3 groups each independently selected from the group consisting of halo, OH and CN; Each Rc is independently selected from the group consisting of H, D, halo, OH, CN, C1- C4alkyl, and C1-C4alkoxy, or two Rc, attached to the same atom, form a =0, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH and CN; Each Rd is independently selected from the group consisting of H, D, C1-C4alkyl, and C(O)C1- 4alkyl; and n is 0, 1, 2, or 3.
8. The compound of claim 1 or 5, wherein the compound is of Formula (Via), (VIb), (Vic), (Vid), (Vie), (VIf), (Vig), or (Vlh): 419 WO 2024/233900 PCT/US2024/028806 420 WO 2024/233900 PCT/US2024/028806 or a pharmaceutically acceptable salt thereof. 5
9. The compound of claim 1, wherein the compound is of Formula (VII), (Vila) or (VIIb): 421 WO 2024/233900 PCT/US2024/028806 5 or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 or 9, or a pharmaceutically acceptable salt thereof, wherein X1isCR3orN; X4 is selected from the group consisting of CR13, N, and NRd; R1 is selected from the group consisting of halo, C1-C4alkyl, and C1-C4haloalkyl; 10 R2 is selected from the group consisting of H, D, and C1-C4alkyl;422 WO 2024/233900 PCT/US2024/028806 R3 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, -(C(Ra)2)n-ORb, - (C(Ra)2)״-C(O)ORb , -(C(Ra)2)n-SO2-Rb, -N(Ra)2, C3-C8cycloalkyl, and 4 to 10- membered heterocyclyl, wherein the C1-C4alkyl and C3-C10cycloalkyl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 10-membered heterocyclyl has to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are optionally substituted on a ring carbon with 1 to 3 Rc; R4 is selected from the group consisting of H, D, and C1-C4alkyl; R5 is selected from the group consisting of halo, C1-C4alkyl, and C1-C4haloalkyl; R6 is H or D; R7 is selected from the group consisting of H, D, halo, C1-C4alkyl, and C1-C4alkoxy, C3- C6cycloalkyl, and 4 to 7-membered heterocyclyl, wherein the C1-C4alkyl, C1- C4alkoxy, and C3-C6cycloalkyl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 7-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are each optionally substituted on a ring carbon with 1 to 3 Rc; R8 is selected from the group consisting of H, D, and C1-C4alkyl; R9 are each independently selected from the group consisting of H, D, C1-C4alkyl, C2- C4alkynyl, -(C(Ra)2)n-ORb, C3-C8cycloalkyl, and 4 to 10-membered heterocyclyl, wherein the C1-C4alkyl, C2-C4alkynyl, and C3-C8cycloalkyl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are optionally substituted on a ring carbon with 1 to 3 Rc; or R8 and R9 are taken together with the carbon atom to which they are attached to form Ring B, wherein Ring B is C3-C8cycloalkyl or 4 to 10- membered heterocyclyl, wherein the C3-C8cycloalkyl is optionally substituted with 1 to 3 Rc, wherein the 4 to 10- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 3 Rc; or R8 and R9 are taken together form a =0; 423 WO 2024/233900 PCT/US2024/028806 R10 is selected from the group consisting of H, D, C1-C4 alkyl, -(C(Ra)2)n-ORb, -(C(Ra)2)n- SO2Rb,C3-C8cycloalkyl, and 4 to 10-membered heterocyclyl, wherein the C1-C4 alkyl and C3-C8cycloalkyl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are optionally substituted on a ring carbon with 1 to 3 Rc; or R9 and R10 are taken together with the carbon atom and the nitrogen atom to which they are attached, respectively, to form Ring C, wherein Ring C is a 4 to 10-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 3 Rc; R11 is selected from the group consisting of H, D, and C1-C4alkyl; R12 is selected from the group consisting of H, D, halo, and C1-C4alkyl; R13 is selected from the group consisting of H, D, halo, CN, and C1-C4alkyl; R14 is selected from the group consisting of H, D, and C1-C4alkyl; Each Ra is independently selected from the group consisting of H, D, and C1-C4alkyl; Each Rb is independently selected from the group consisting of H, D, C1-C4alkyl, C1- C4alkoxy, C3-C8cycloalkyl, and 4 to 10-membered heterocyclyl, wherein the C1- C4alkyl and C3-C8cycloalkyl are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH and CN, wherein the to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are optionally substituted on a ring atom with 1 to 3 groups each independently selected from the group consisting of halo, OH and CN; Each Rc is independently selected from the group consisting of D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, or two Ra, attached to the same atom, form a =0, wherein the C1- C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH and CN; Each Rd is independently selected from the group consisting of H, D, C1-C4alkyl, and C(O)C1- 4alkyl; and 424 WO 2024/233900 PCT/US2024/028806 n is 0, 1, 2, or 3.
11. The compound of claim 1 or 9, wherein the compound is of Formula (Ville), (VIIIf), (Vlllg) or (Vlllh): 5 R4 (VIIIf), (Vlllg), or 425 WO 2024/233900 PCT/US2024/028806 R8 R9 (Vlllh), or a pharmaceutically acceptable salt thereof.
12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein: (i) R1 is halo, -OH, C1-C4alkyl, or C1-C4alkoxy; or (ii) R1 is -CH3, -Cl, -OH, or-OMe.
13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein: (i) R2 is H, D, halo, or C1-C4alkyl; or (ii) R2 is H.
14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein: (i) R3 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, -(C(Ra)2)n-ORb, -(C(Ra)2)n-C(O)ORb, -(C(Ra)2)n-SO2-Rb, -N(Ra)2, C3-C6cycloalkyl, 4 to 7- membered heterocyclyl, phenyl, and 4 to 6-membered heteroaryl, wherein the C1-C4alkyl, C3-C6cycloalkyl, and phenyl are each optionally substituted with 1 to 4 Rc, wherein the to 7-membered heterocyclyl and 4 to 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from the group consisting of 0, S,N, and NRd and then areeach optionally substituted on a ring carbon with 1 to 3 Rc; (ii) R3 is selected from thegroup consisting of-CH2CH3, -CH2OCH3, -CF3, -OCH3, H, -CN, -CHF2, -CHFCH3, - CHF-CHF, -CH(CH3)OMe, -OCHF2, Cl, -OCH.CH3, F, -CH3, -O-cyclopropyl, -0- CH2CH2CH3, -O-CF3, -N(CH3)2, -O-CH(CH3)2, -CH2OCH2CH3, -CH2CHF2, -CH2CH2F, - CH2SO2CH3, -CF2Me, -C(=O)OCH3, -C(=O)OCH2CH2CH3, -CH2CF3, and -CH2CO2H,or is represented by one of the following structures: (iii) R3 is -CH2CH3, -CH2OCH3, -CF3, or -OCH3.
15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, 426 WO 2024/233900 PCT/US2024/028806 wherein: (i) R4 is H, D, halo, or C1-C4alkyl; (ii) R4 is H.
16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein: (i) R5 is halo, OH, C1-C4alkyl, C1-C4haloalkyl or C1-C4alkoxy; or (ii) R5 is Me, Cl, -OH, -CHF2 or -OCH3.
17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein: (i) R7 is H, D, halo, C1-C4alkyl, C1-C4alkoxy, or 4 to 7-membered heterocyclyl, wherein the C1-C4alkyl, and C1-C4alkoxy are each optionally substituted with 1 to 3 Rc, wherein the 4 to 7-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are each optionally substituted on a ring carbon with 1 to 3 Rc; (ii) R7 is H, morpholin-N-yl, -CF3, -F, - OCHF2, -OCH2CH3, or -OCH3; or (iii) R7 is H.
18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein: (i) R8 is H, D, halo, or C1-C4alkyl; (ii) R8 is H or -CH3; or (ii) R8 is H.
19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein: (i) R9 is each independently H, D, C1-C4alkyl, C2-C4alkynyl, -(C(Ra)2)n-ORb, or C3-C8cycloalkyl, wherein the C1-C4alkyl, C2-C4alkynyl, and C3-C8cycloalkyl are each optionally substituted with 1 to 3 Rc; (ii) R9 is each independently H, Me, -CH2OCHCH3, -CH2CH2CH3, -CH2CH3, -CHOCH3, -CHCHF2, cyclopropyl, -CH2C=CH, - CH2CH2OCH3, or -CHF2; or (iii) R9 is is each independently H, Me, -CHOCH.CH3, - CH2CH2CH3, -CH2CH3, or -CHOCH3.
20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein: (i) R10 is H, D, C1-C4 alkyl, -(C(Ra)2)n-ORb, -(C(Ra)2)n-SO2Rb, or C3- C8cycloalkyl, wherein the C1-C4 alkyl and C3-C8cycloalkyl are each optionally substituted with 1 to 3 Rc; (ii) R10 is H, -CH3, -CHCH3, -CHCHCH3, -CH,CHSO2CH3, -CD,CD3, -CHCHOH, -CH2CH2OCH3, -CH(CH3)2, or -CD3; or (iii) R10 is H, -CH3, or -CHCH3
21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein: (i) R11 is H, D, halo, or C1-C4alkyl; or (ii) R11 is H.
22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein: (i) R12 is H, D, halo or C1-C4alkyl; (ii) R12 is H, D, or halo; (iii) R12 is H or F; or 427 WO 2024/233900 PCT/US2024/028806 (iv) R12 is H.
23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein: (i) R is H, D, halo or C1-C4alkyl; (ii) R is H, D, or halo; (iii) R is H or F; or (iv) R is H.13 13 5
24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof,wherein R14 is H.
25. The compound of claim 1, wherein the compound is of Formula (IXa) or (IXb): (IXa), 10 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of halo, C1-C4alkyl, and C1-C4haloalkyl; R3 is selected from the group consisting of H, D, halo, CN, C1-C4alkyl, -(C(Ra)2)n-ORb, -(C(Ra)2)״-C(O)ORb , -(C(Ra)2)n-SO2-Rb, -N(Ra)2, C3-C8cycloalkyl, and 4 to 10-membered heterocyclyl, wherein the C1-C4alkyl and C3-C8cycloalkyl are eachoptionally substituted with 1 to 3 Rc, wherein the 4 to 10-membered heterocyclyl hasto 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are optionally substituted on a ring carbon with 1 to 3 Rc; R5 is selected from the group consisting of halo, C1-C4alkyl, and C1-C4haloalkyl; 428 WO 2024/233900 PCT/US2024/028806 R8 is selected from the group consisting of H, D, and C1-C4alkyl; R9 is selected from the group consisting of H, D, C1-C4alkyl, -(C(Ra)2)n-ORb, C3- C8cycloalkyl, and 4 to 10-membered heterocyclyl, wherein the C1-C4alkyl and C3- C8cycloalkyl are each optionally substituted with 1 to 3 Rc, wherein the 4 to 10- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are optionally substituted on a ring carbon with 1 to 3 Rc; R10 is selected from the group consisting of H, D, C1-C4 alkyl, C3-C10cycloalkyl, and 4 to 12- membered heterocyclyl, wherein the C1-C4 alkyl and C3-C10cycloalkyl are each optionally substituted with 1 to 4 Rc, wherein the 4 to 12-membered heterocyclyl has to 4 ring heteroatoms each independently selected from the group consisting of O, S, and NRd and then are optionally substituted on a ring carbon with 1 to 4 Rc; or R9 and R10 are taken together with the carbon atom and the nitrogen atom to which they are attached, respectively, to form Ring C, wherein Ring C is a 4 to 10-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, and NRd, and then is optionally substituted on a ring carbon by 1 to 3 Rc; R11 is selected from the group consisting of H, D, and C1-C4alkyl; R13 is selected from the group consisting of H, D, halo, CN, and C1-C4alkyl; Each Ra is independently selected from the group consisting of H, D, and C1-C4alkyl; Each Rb is independently selected from the group consisting of H, D, C1-C4alkyl, and C1- C4alkoxy; Each Rc is independently selected from the group consisting of D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, or two Ra, attached to the same atom, form a =0; and Each Rd is independently selected from the group consisting of H, D, and C1-C4alkyl; and n is 0, 1, or 2.
26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R1 is halo or C1-C3alkyl; 429 WO 2024/233900 PCT/US2024/028806 R3 is C1-C3alkyl or -(C(Ra)2)n-ORb, wherein n is 0, and Rb is C1-C3alkyl, wherein the C1- C3alkyl is optionally substituted with 1 to 3 Rc, wherein Rc is independently halo or C1-C3alkoxy; R5 is halo or C1-C3alkyl; R8 is H; R9 is C1-C3alkyl or -(C(Ra)2)n-ORb, wherein n is 0, and Rb is C1-C3alkyl, wherein the C1- C3alkyl is optionally substituted with 1 to 3 Rc, wherein Rc is independently halo or C1-C3alkoxy; R10 is H or C1-C3alkyl; or R9 and R10 are taken together with the carbon atom and the nitrogen atom to which they are attached, respectively, to form Ring C, wherein Ring C is a 4 to 6-membered heterocyclycl; R11 is H; and R13 is H.
27. The compound of claim 25, or a pharmaceutically acceptable salt thereof, whereinR1 is -CH3 or -Cl;R3 is -CHCH3, -CHOCH3, -CF3 or-OCH3;R5 is -CH3 or -Cl;R8 is H;R9 is H, -CH3, -CH2OCH2CH3, -CHCHCH3, -CHCH3, or -CHOCH3;R10 is H, -CH3, or -CHCH3; orR9 and R10 are taken together with the carbon atom and the nitrogen atom to which they are attached, respectively, to form Ring C, wherein Ring C is represented by R11 is H; andR13 is H. 430 WO 2024/233900 PCT/US2024/028806
28. A pharmaceutical composition comprising: i) the compound of any one of claims 1-27 or a pharmaceutically acceptable salt thereof; and ii) a pharmaceutically acceptable carrier, excipient or diluent.
29. A method of treating a subject with a disease or disorder responsive to inhibition ofglycogen synthase kinase 3 (GSK3) activity, comprising administering to the subject an effective amount of the compound of claims 1-27 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 28.
30. The method of claim 29, wherein the disease or disorder is diabetes, cancer, viral infections or a CNS disorder. 10
31. The method of claim 29, wherein the disease or disorder is cancer. 431
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