Pyrrolo-isoquinoline compounds and their use in therapy

Abstract

Provided herein are compounds of formula (I): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L, R1, R2, R3, R4, R5, R6, R7, R15, R16, X, p, and q are as defined elsewhere herein. Also provided are methods of preparing compound of formula (I). Also provided herein are methods of inhibiting a MK2 and methods of treating a disease or condition mediated by MK2 in an individual in need thereof.

Description

[0001]Attorney Docket No.: 308642000140 PYRROLO-ISOQUINOLINE COMPOUNDS AND THEIR USE IN THERAPY CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority benefit of United States Provisional Patent Application No.63 / 595,193 filed November 1, 2023, which is hereby incorporated herein by reference in its entirety. FIELD OF THE INVENTION Aspects of the invention generally relate to pyrrolo-isoquinoline compounds, pharmaceutical compositions, kits comprising the same, their use for inhibiting mitogen- activated protein (MAP) kinase-activated protein kinase 2 (MAPKAPK2, MK2), and their use in the treatment of a disease or condition, such as an inflammatory disorder. BACKGROUND OF THE INVENTION Inflammatory disorders impact a substantial number of patients and often involve situations where the patient’s biological response to a stimulus results in the immune system attacking the body’s own cells or tissues. This can lead to abnormal inflammation and result in chronic pain, redness, swelling, stiffness, and / or damage to normal tissues. Inflammatory disorders can be characterized according to whether they are acute or chronic. Common inflammatory disorders affecting a significant number of patients annually include inflammatory bowel disease, asthma, rheumatoid arthritis, ulcerative colitis, and Crohn's disease. Common treatments currently available for treating inflammatory disorders include nonsteroidal anti-inflammatory drugs (such as aspirin, ibuprofen, or naproxen), corticosteroids (such as prednisone), and various biologic drugs such as abatacept, adalimumab, certolizumab, etanercept, infliximab, golimumab, rituximab, and tocilizumab. Compounds having inhibitory activity towards mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2 or MK2) have also been reported in literature for use in treating certain inflammatory disorders. See, e.g., U.S. Patent Application Publication No.2016 / 0075720, U.S. Patent Application Publication No.2022 / 0251105, U.S. Patent Application Publication No.2023 / 0255979 and international patent publications WO 2020 / 236636 and WO 2022 / 020562.ny-28088891 Attorney Docket No.: 308642000140 Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2 or MK2) has been reported in the literature to mediate multiple p38 MAPK-dependent cellular responses. See, e.g., U.S. Patent Application 2016 / 0075720. MK2 has also been reported to be an important intracellular regulator of the production of cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and interferon gamma (IFNγ), each of which are involved in several acute and chronic inflammatory diseases. MK2 has also been implicated in heart failure, brain ischemic injury, regulation of stress resistance, and the production of TNF-α. See, e.g., Deak et al., EMBO.17:4426-4441 (1998); Shi et al., Biol. Chem.383:1519-1536 (2002); Staklatvala., Curr. Opin. Pharmacol.4:372-377 (2004); and Shiroto et al., J. Mol. Cardiol. 38:93-97 (2005). Existing treatments for inflammatory disorders may not be effective for a significant percentage of patients and / or have undesirable adverse effects. Thus, new therapies are needed for treating inflammatory disorders. BRIEF SUMMARY OF THE INVENTION In one aspect, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is -C(R17)(R18)-, -C(O)-, -O-, -NR10-, or -S(O)n-; R1and R2are independently H, D, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, or C2-4 haloalkynyl, wherein the C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, and C2-4haloalkynyl are independently optionally substituted with -OR10or -N(R10)(R10); or R1and R2are taken together with the carbon atom to which they are attached to form a C3-6 cycloalkyl or a 4-6 membered heterocyclyl, wherein the C3-6cycloalkyl and 4-6 membered heterocyclyl are optionally substituted with one or more R2a;ny-28088892 Attorney Docket No.: 308642000140 R3and R4are independently H, D, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, C2-4 haloalkynyl, -OR10, -N(R10)(R10), C3-6 cycloalkyl, or 4-6 membered heterocyclyl, wherein the C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, and C2-4haloalkynyl are independently optionally substituted with -OR10, -N(R10)(R10), C3-6 cycloalkyl, or 4-6 membered heterocyclyl, and the C3-6cycloalkyl and the 4-6 membered heterocyclyl of R3and R4are optionally substituted with one or more R4a; or R3and R4are taken together with the carbon atom to which they are attached to form a C3-6 cycloalkyl or a 3-6 membered heterocyclyl, wherein the C3-6cycloalkyl or the 3-6 membered heterocyclyl are optionally substituted with one or more R4a; R5is H, C1-2 alkyl, C1-2 haloalkyl, or C3-5 cycloalkyl; R6is H, C1-2alkyl, C1-2haloalkyl, or C3-5cycloalkyl; R7is 5-6 membered heteroaryl or partially unsaturated 8-14 membered heterocyclyl, wherein a carbon atom adjacent to a heteroatom on the 5-6 membered heteroaryl or 8-14 membered heterocyclyl is substituted by R8, the 5-6 membered heteroaryl is optionally further substituted with one or more R9, and the 8-14 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of oxo and R9; R8is halo or -S(O)n(R13); each R9is independently halo, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, C2-4 haloalkynyl, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), -O- C(O)-R12, -C(O)-R12, -S(O)n(R12), C3-6cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein the C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, and C2-4 haloalkynyl are independently optionally substituted with one or more R9a; the C3-6cycloalkyl and 4-6 membered heterocyclyl are independently optionally substituted with one or more R9b; and the phenyl and 5-6 membered heteroaryl are each independently optionally substituted with one or more R9c; each R9ais independently D, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), - C(O)-R12, -S(O)n(R12), C3-6 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-6 membered heteroaryl, wherein,ny-28088893 Attorney Docket No.: 308642000140 the C3-6cycloalkyl is optionally substituted by one or more R14, and the 4-10 membered heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of oxo, halo, and R14; each R9bis independently halo, -OR10, -N(R10)(R10), C1-4alkyl, C1-4haloalkyl, or oxo; or each R9cis independently halo, -CN, -OR10, -N(R10)(R10), C1-4 alkyl, or C1-4 haloalkyl; each R10is independently H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkenyl, C1-4 alkynyl, C3-4 cycloalkyl, or 3-8 membered heterocyclyl; wherein the C1-4 alkyl, C1-4 haloalkyl, C1-4 alkenyl, or C1-4 alkynyl is optionally substituted by one or more R10a, and the C3-4cycloalkyl or 3-8 membered heterocyclyl is optionally substituted by one or more R10b; and each R10ais independently D, -OR14, or C3-4 cycloalkyl; each R2a, R4a, and R10bis independently halo, C1-4alkyl, C1-4haloalkyl, C1-4alkyl-(OR14), C1-4haloalkyl-(OR14), -OR14, or -N(R14)(R14); X is N, or CR11; R11is H, halo, C1-4 alkyl, C1-4 haloalkyl, or -CN; each R12is independently C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, C2-4 haloalkynyl, C3-6 cycloalkyl, -OR14, -N(R14)(R14), or 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted by halo, C1-4 alkyl, or C1-4 haloalkyl; R13is C1-4 alkyl or C1-4 haloalkyl; each R14is independently H, C1-4 alkyl, C1-4 haloalkyl, or C3-6 cycloalkyl; n is independently at each occurrence 0, 1, or 2; indicates a single or double bond, wherein when is a single bond, p and q are each 2, and when is a double bond, p and q are each 1; each R15and R16is independently H, D, or C1-4 alkyl; R17is H, -CH3, -CF3, halo, or -OH; and R18is H, -CH3, -CF3, or halo, or R17and R18are taken together with the carbon to which they are attached to form a cyclopropyl, provided that when L is -O-, each of R1-R6is H, R7is 2-chloropyrimidin-4-yl, X is CF, is a single bond, and each R15and R16is H, then R9is not ethoxymethyl.ny-28088894 Attorney Docket No.: 308642000140 In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is -C(R17)(R18)-, -C(O)-, -O-, -NR10-, or -S(O)n-; R1and R2are independently H, D, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, or C2-4 haloalkynyl, wherein the C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, and C2-4 haloalkynyl are independently optionally substituted with -OR10or -N(R10)(R10); or R1and R2are taken together with the carbon atom to which they are attached to form a C3- 6cycloalkyl or a 4-6 membered heterocyclyl, wherein the C3-6 cycloalkyl and 4-6 membered heterocyclyl are optionally substituted with one or more R2a; R3and R4are independently H, D, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, C2-4 haloalkynyl, -OR10, -N(R10)(R10), C3-6cycloalkyl, or 4-6 membered heterocyclyl, wherein the C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, and C2-4haloalkynyl are independently optionally substituted with -OR10, -N(R10)(R10), C3-6 cycloalkyl, or 4-6 membered heterocyclyl, and the C3-6cycloalkyl and the 4-6 membered heterocyclyl of R3and R4are optionally substituted with one or more R4a; or R3and R4are taken together with the carbon atom to which they are attached to form a C3-6cycloalkyl or a 3-6 membered heterocyclyl, wherein the C3-6cycloalkyl or the 3-6 membered heterocyclyl are optionally substituted with one or more R4a; R5is H, C1-2 alkyl, C1-2 haloalkyl, or C3-5 cycloalkyl; R6is H, C1-2alkyl, C1-2haloalkyl, or C3-5cycloalkyl; R7is 5-6 membered heteroaryl or partially unsaturated 8-14 membered heterocyclyl, wherein a carbon atom adjacent to a heteroatom on the 5-6 membered heteroaryl or 8-14 membered heterocyclyl is substituted by R8, the 5-6 membered heteroaryl is optionally further substituted with one or more R9, and the 8-14 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of oxo and R9; R8is halo or -S(O)n(R13); each R9is independently halo, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, C2-4 haloalkynyl, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), -O-ny-28088895 Attorney Docket No.: 308642000140 C(O)-R12, -C(O)-R12, -S(O)n(R12), C3-6cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein the C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, and C2-4haloalkynyl are independently optionally substituted with one or more R9a; the C3-6 cycloalkyl and 4-6 membered heterocyclyl are independently optionally substituted with one or more R9b; and the phenyl and 5-6 membered heteroaryl are each independently optionally substituted with one or more R9c; each R9ais independently D, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), - C(O)-R12, -S(O)n(R12), C3-6cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-6 membered heteroaryl, wherein, the C3-6 cycloalkyl is optionally substituted by one or more R14, and the 4-10 membered heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of oxo and R14; each R9bis independently halo, -OR10, -N(R10)(R10), C1-4 alkyl, C1-4 haloalkyl, or oxo; or each R9cis independently halo, -CN, -OR10, -N(R10)(R10), C1-4 alkyl, or C1-4 haloalkyl; each R10is independently H, C1-4alkyl, C1-4haloalkyl, or C3-4cycloalkyl; wherein the C1-4 alkyl or C1-4 haloalkyl is optionally substituted by one or more R10a, and the C3-4 cycloalkyl is optionally substituted by one or more R10b; and each R10ais independently D, -OR14, or C3-4cycloalkyl; each R2a, R4a, and R10bis independently halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyl-(OR14), C1-4 haloalkyl-(OR14), -OR14, or -N(R14)(R14); X is N, or CR11; R11is H, halo, C1-4alkyl, C1-4haloalkyl, or -CN; each R12is independently C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, C2-4haloalkynyl, C3-6cycloalkyl, -OR14, or -N(R14)(R14); R13is C1-4alkyl or C1-4haloalkyl; each R14is independently H, C1-4 alkyl, or C1-4 haloalkyl; n is independently at each occurrence 0, 1, or 2; indicates a single or double bond, wherein when is a single bond, p and q are each 2, and when is a double bond, p and q are each 1; each R15and R16is independently H, D, or C1-4alkyl;ny-28088896 Attorney Docket No.: 308642000140 R17is H, -CH3, -CF3, halo, or -OH; and R18is H, -CH3, -CF3, or halo, or R17and R18are taken together with the carbon to which they are attached to form a cyclopropyl, provided that when L is -O-, each of R1-R6is H, R7is 2-chloropyrimidin-4-yl, X is CF, is a single bond, and each R15and R16is H, then R9is not ethoxymethyl. Any embodiments provided herein of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, apply where applicable to any other formula detailed herein, the same as if each and every embodiment were specifically and individually listed. Thus, it is understood and described that each embodiment provided herein of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, such as embodiments related to L, R1, R2, R2a, R3, R4, R4a, R5, R6, R7, R8, R9, R9a, R9b, R9c, R10, R10a, R10b, R11, R12, R13, R14, R15, R16, n, p, q, and X apply to formulas (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I- e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the same as if each and every embodiment were specifically and individually listed. It is also understood and described that all such embodiments may be used in any of the pharmaceutical compositions, methods, kits, uses, or other aspects detailed herein. In one aspect, provided is a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. This aspect in some embodiments may employ a compound of any of formulas (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, provided is a method for treating a disease or condition mediated by MK2, comprising administering to a subject in need thereof a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or any-28088897 Attorney Docket No.: 308642000140 pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. This aspect in some embodiments may employ a compound of any of formulas (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e-1), (I-e-2), (I-f), (I- g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, provided herein is a method of inhibiting the activity of a MK2, comprising contacting a MK2 with an effective amount of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. This aspect in some embodiments may employ a compound of any of formulas (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I- n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, provided herein is a method of covalently modifying a MK2, comprising contacting a MK2 with an effective amount of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. This aspect in some embodiments may employ a compound of any of formulas (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, provided herein is a covalently modified MK2 formed by contacting a MK2 with an effective amount of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. This aspect in some embodiments may employ a compound of any of formulas (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c- 1), (I-c-2), (I-d-1), (I-d-2), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1- 32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any-28088898 Attorney Docket No.: 308642000140 pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in the treatment of a disease or condition mediated by MK2. This aspect in some embodiments may employ a compound of any of formulas (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45- 189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, provided herein is the use of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, in the manufacture a medicament for the treatment of a disease or condition mediated by MK2. This aspect in some embodiments may employ a compound of any of formulas (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, provided herein is a kit, comprising (i) a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an MK2-mediated disease or condition in an individual in need thereof. This aspect in some embodiments may employ a compound of any of formulas (I- a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I- k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing All pharmaceutical compositions, methods, kits, uses, or other aspects described herein with reference to formula (I), or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are also hereby described and embraced for any one of the other formulas detailed herein such as formula (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selectedny-28088899 Attorney Docket No.: 308642000140 from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, the same as if each and every embodiment were specifically and individually listed. DETAILED DESCRIPTION OF THE INVENTION “Individual” refers to mammals and includes humans and non-human mammals. Examples of individuals include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, individual refers to a human. As used herein, “about” a parameter or value includes and describes that parameter or value per se. For example, “about X” includes and describes X per se. “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired results may include one or more of the following: decreasing one or more symptom resulting from the disease or condition; diminishing the extent of the disease or condition; slowing or arresting the development of one or more symptom associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition); and relieving the disease, such as by causing the regression of clinical symptoms (e.g., ameliorating the disease state, enhancing the effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival). As used herein, “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and / or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition. As used herein, the term “therapeutically effective amount” or “effective amount” intends such amount of a compound of the disclosure or a pharmaceutically salt thereof sufficient to effect treatment when administered to an individual. As is understood in the art, an effective amount may be in one or more doses, e.g., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.ny-280888910 Attorney Docket No.: 308642000140 As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient, or compound, which may be in a pharmaceutically acceptable carrier. As used herein, by “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects. The term “alkyl”, as used herein, refers to an unbranched or branched saturated univalent hydrocarbon chain. As used herein, alkyl has 1-20 carbons (i.e., C1-20 alkyl), 1-16 carbons (i.e., C1-16alkyl), 1-12 carbons (i.e., C1-12alkyl), 1-10 carbons (i.e., C1-10alkyl), 1-8 carbons (i.e., C1-8alkyl), 1-6 carbons (i.e., C1-6alkyl), 1-4 carbons (i.e., C1-4alkyl), or 1-3 carbons (i.e., C1-3alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, iso-propyl, n- butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, iso-pentyl, neo-pentyl, hexyl, 2-hexyl, 3- hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “butyl” includes n-butyl, sec-butyl, iso-butyl, and tert-butyl; and “propyl” includes n-propyl and iso-propyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkyl” group, may be referred to as an “alkylene”. The term “alkenyl”, as used herein, refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon double bond. As used herein, alkenyl has 2-20 carbons (i.e., C2-20 alkenyl), 2-16 carbons (i.e., C2-16 alkenyl), 2-12 carbons (i.e., C2-12 alkenyl), 2-10 carbons (i.e., C2-10alkenyl), 2-8 carbons (i.e., C2-8alkenyl), 2-6 carbons (i.e., C2-6alkenyl), 2-4 carbons (i.e., C2-4alkenyl), or 2-3 carbons (i.e., C2-3alkenyl). Examples of alkenyl include, but are not limited to, ethenyl, prop-1-enyl, prop-2-enyl 1,2-butadienyl, and 1,3- butadienyl. When an alkenyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “propenyl” includes prop-1-enyl and prop-2-enyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkenyl” group, may be referred to as an “alkenylene”. The term “alkynyl”, as used herein, refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon triple bond. As used herein, alkynylny-280888911 Attorney Docket No.: 308642000140 has 2-20 carbons (i.e., C2-20alkynyl), 2-16 carbons (i.e., C2-16alkynyl), 2-12 carbons (i.e., C2-12alkynyl), 2-10 carbons (i.e., C2-10 alkynyl), 2-8 carbons (i.e., C2-8 alkynyl), 2-6 carbons (i.e., C2-6 alkynyl), 2-4 carbons (i.e., C2-4alkynyl), or 2-3 carbons (i.e., C2-3alkynyl). Examples of alkynyl include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, and but-3-ynyl. When an alkynyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “propynyl” includes prop-1-ynyl and prop-2-ynyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkynyl” group, may be referred to as an “alkynylene”. The term “alkoxy”, as used herein, refers to an -O-alkyl moiety. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert- butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. The term “aryl”, as used herein, refers to a fully unsaturated carbocyclic ring moiety. The term “aryl” encompasses monocyclic and polycyclic fused-ring moieties. As used herein, aryl encompasses ring moieties comprising, for example, 6 to 20 annular carbon atoms (i.e., C6-20 aryl), 6 to 16 annular carbon atoms (i.e., C6-16aryl), 6 to 12 annular carbon atoms (i.e., C6-12aryl), or 6 to 10 annular carbon atoms (i.e., C6-10 aryl). Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl. The term “cycloalkyl”, as used herein, refers to a saturated or partially unsaturated carbocyclic ring moiety. The term “cycloalkyl” encompasses monocyclic and polycyclic ring moieties, wherein the polycyclic moieties may be fused, branched, or spiro. Cycloalkyl includes cycloalkenyl groups, wherein the ring moiety comprises at least one annular double bond. Cycloalkyl includes any polycyclic carbocyclic ring moiety comprising at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, cycloalkyl includes rings comprising, for example, 3 to 20 annular carbon atoms (i.e., a C3-20cycloalkyl), 3 to 16 annular carbon atoms (i.e., a C3-16cycloalkyl), 3 to 12 annular carbon atoms (i.e., a C3-12 cycloalkyl), 3 to 10 annular carbon atoms (i.e., a C3-10 cycloalkyl), 3 to 8 annular carbon atoms (i.e., a C3-8 cycloalkyl), 3 to 6 annular carbon atoms (i.e., a C3-6 cycloalkyl), or 3 to 5 annular carbon atoms (i.e., a C3-5cycloalkyl). Monocyclic cycloalkyl ring moieties include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbonyl, decalinyl, 7,7-dimethyl -bicyclo [2.2.1]heptanyl, and the like. Still further,ny-280888912 Attorney Docket No.: 308642000140 cycloalkyl also includes spiro cycloalkyl ring moieties, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro [5.5]undecanyl. The term “halo”, as used herein, refers to atoms occupying groups VIIA of The Periodic Table and includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo). Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C1-4 haloalkyl” is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like. Terms such as “haloalkenyl” are meant to include monohaloalkenyl and polyhaloalkenyl. For example, the term “C1-4 haloalkenyl” is meant to include 4,4,4-trifluorobut-1-en-1-yl, 1-fluoroprop-1-en-1-yl, 1,3,3- trichloroprop-1-en-1-yl, and the like. Terms such as “haloalkynyl” are meant to include monohaloalkynyl and polyhaloalkynyl. For example, the term “C1-4haloalkynyl” is meant to include fluoroethynyl, 1,1-difluoroprop-2-yn-1-yl, 1-chloro-1-fluorobut-2-yn-1-yl, and the like. The term “heteroaryl”, as used herein, refers to an aromatic (fully unsaturated) ring moiety that comprises one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heteroaryl” includes both monocyclic and polycyclic fused-ring moieties. As used herein, a heteroaryl comprises, for example, 5 to 20 annular atoms (i.e., a 5-20 membered heteroaryl), 5 to 16 annular atoms (i.e., a 5-16 membered heteroaryl), 5 to 12 annular atoms (i.e., a 5-12 membered heteroaryl), 5 to 10 annular atoms (i.e., a 5-10 membered heteroaryl), 5 to 8 annular atoms (i.e., a 5-8 membered heteroaryl), or 5 to 6 annular atoms (i.e., a 5-6 membered heteroaryl). Any monocyclic or polycyclic aromatic ring moiety comprising one or more annular heteroatoms is considered a heteroaryl, regardless of the point of attachment to the remainder of the molecule (i.e., the heteroaryl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heteroaryl moiety). Examples of heteroaryl groups include, but are not limited to, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and pyridazinyl. The term “heterocyclyl”, as used herein, refers to a saturated or partially unsaturated cyclic moiety that encompasses one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes both monocyclic and polycyclic ring moieties, wherein the polycyclic ring moieties may be fused, bridged, or spiro. Any non-aromatic monocyclic or polycyclic ring moiety comprising at least one annular heteroatom is considered a heterocyclyl, regardless of the point of attachment to the remainder of the molecule (i.e., the heterocyclyl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heterocyclyl moiety).ny-280888913 Attorney Docket No.: 308642000140 Further, the term heterocyclyl is intended to encompass any polycyclic ring moiety comprising at least one annular heteroatom wherein the polycyclic ring moiety comprises at least one non- aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, a heterocyclyl comprises, for example, 3 to 20 annular atoms (i.e., a 3-20 membered heterocyclyl), 3 to 16 annular atoms (i.e., a 3-16 membered heterocyclyl), 3 to 12 annular atoms (i.e., a 3-12 membered heterocyclyl), 3 to 10 annular atoms (i.e., a 3-10 membered heterocyclyl), 3 to 8 annular atoms (i.e., a 3-8 membered heterocyclyl), 3 to 6 annular atoms (i.e., a 3-6 membered heterocyclyl), 3 to 5 annular atoms (i.e., a 3-5 membered heterocyclyl), 5 to 8 annular atoms (i.e., a 5-8 membered heterocyclyl), or 5 to 6 annular atoms (i.e., a 5-6 membered heterocyclyl). Examples of heterocyclyl groups include, e.g., azetidinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuryl,and tetrahydropyranyl. Examples of spiro heterocyclyl rings include, but are not limited to, bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6- oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinyl, 5,7- dihydrofuro[3,4-d]pyrimidinyl, and 5,7-dihydrothieno[3,4-d]pyrimidinyl, where the heterocyclyl can be bound via either ring of the fused system. The term “oxo”, as used herein, refers to a =O moiety. The terms “optional” and “optionally”, as used herein, mean that the subsequently described event or circumstance may or may not occur and that the description includes instances where the event or circumstance occurs and instances where it does not. Accordingly, the term “optionally substituted” infers that any one or more (e.g., 1, 2, 1 to 5, 1 to 3, 1 to 2, etc.) hydrogen atoms on the designated atom or moiety or group may be replaced or not replaced by an atom or moiety or group other than hydrogen. By way of illustration and not limitation, the phrase “methyl optionally substituted with one or more chloro” encompasses -CH3, -CH2Cl, - CHCl2, and -CCl3moieties. It is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments. The term “pharmaceutically acceptable salt”, as used herein, of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifyingny-280888914 Attorney Docket No.: 308642000140 a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. See, e.g., Handbook of Pharmaceutical Salts Properties, Selection, and Use, International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), which is incorporated herein by reference in its entirety. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, trifluoroacetic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. Isotopically labeled forms of the compounds depicted herein may be prepared. Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I, and125I, respectively. In some embodiments, a compound of formula (I) is provided wherein one or more hydrogen is replaced by deuterium or tritium. Some of the compounds provided herein may exist as tautomers. Tautomers are in equilibrium with one another. By way of illustration, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardlessny-280888915 Attorney Docket No.: 308642000140 of the nature of the equilibrium among tautomers, the compounds of this disclosure are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, for example, amide-containing compounds are understood to include their imidic acid tautomers. Likewise, imidic-acid containing compounds are understood to include their amide tautomers. Also provided herein are prodrugs of the compounds depicted herein, or a pharmaceutically acceptable salt thereof. Prodrugs are compounds that may be administered to an individual and release, in vivo, a compound depicted herein as the parent drug compound. It is understood that prodrugs may be prepared by modifying a functional group on a parent drug compound in such a way that the modification is cleaved in vitro or in vivo to release the parent drug compound. See, e.g., Rautio, J., Kumpulainen, H., Heimbach, T. et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov 7, 255–270 (2008), which is incorporated herein by reference in its entirety. The compounds of the present disclosure, or their pharmaceutically acceptable salts, may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- (or as (D)- or (L)- for amino acids). The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms and mixtures thereof in any ratio. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques, for example, chromatography and / or fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or the resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC), and chiral supercritical fluid chromatography (SFC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless specified otherwise, it is intended that the present disclosure includes both E and Z geometric isomers. Likewise, cis- and trans- are used in their conventional sense to describe relative spatial relationships. A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds, but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose structures are non-superimposableny-280888916 Attorney Docket No.: 308642000140 mirror images of one another. “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other. Where enantiomeric and / or diastereomeric forms exist of a given structure, flat bonds indicate that all stereoisomeric forms of the depicted structure may be present, e.g., . Where enantiomeric forms exist of a given structure, flat bonds and the presence of a “ * ” symbol, or wedged or dashed bonds in the presence of “or 1”, indicates that the composition is made up of at least 90%, by weight, of a single isomer with unknown absolute stereochemistry, Where enantiomeric and / or diastereomeric forms exist of a given structure with two or more stereocenters, flat bonds and the presence of two or more “ * ” symbols indicate the composition is made up of at least 90%, by weight, of a single enantiomer or diastereomer with unknown absolute stereochemistry, Where enantiomeric and / or diastereomeric forms exist of a given structure with two or more stereocenters, dashes or wedges and the presence of two or more “or” symbols with theny-280888917 Attorney Docket No.: 308642000140 same numerical value indicate the composition is made up of at least 90%, by weight, of a single isomer with known relative stereochemistry, e.g., . Where enantiomeric and / or diastereomeric forms exist of a given structure, the composition is made up of at least 90%, by weight, dashes or wedges indicate a single enantiomer or diastereomer with known relative or absolute stereochemistry, e.g., . COMPOUNDS In one aspect, provided herein is a compound of formula (I), (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is -C(R17)(R18)-, -C(O)-, -O-, -NR10-, or -S(O)n-; R1and R2are independently H, D, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, or C2-4 haloalkynyl, wherein the C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, and C2-4 haloalkynyl are independently optionally substituted with -OR10or -N(R10)(R10); orny-280888918 Attorney Docket No.: 308642000140 R1and R2are taken together with the carbon atom to which they are attached to form a C3-6cycloalkyl or a 4-6 membered heterocyclyl, wherein the C3-6 cycloalkyl and 4-6 membered heterocyclyl are optionally substituted with one or more R2a; R3and R4are independently H, D, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, C2-4 haloalkynyl, -OR10, -N(R10)(R10), C3-6 cycloalkyl, or 4-6 membered heterocyclyl, wherein the C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, and C2-4haloalkynyl are independently optionally substituted with -OR10, -N(R10)(R10), C3-6 cycloalkyl, or 4-6 membered heterocyclyl, and the C3-6cycloalkyl and the 4-6 membered heterocyclyl of R3and R4are optionally substituted with one or more R4a; or R3and R4are taken together with the carbon atom to which they are attached to form a C3-6 cycloalkyl or a 3-6 membered heterocyclyl, wherein the C3-6cycloalkyl or the 3-6 membered heterocyclyl are optionally substituted with one or more R4a; R5is H, C1-2 alkyl, C1-2 haloalkyl, or C3-5 cycloalkyl; R6is H, C1-2 alkyl, C1-2 haloalkyl, or C3-5 cycloalkyl; R7is 5-6 membered heteroaryl or partially unsaturated 8-14 membered heterocyclyl, wherein a carbon atom adjacent to a heteroatom on the 5-6 membered heteroaryl or 8-14 membered heterocyclyl is substituted by R8, the 5-6 membered heteroaryl is optionally further substituted with one or more R9, and the 8-14 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of oxo and R9; R8is halo or -S(O)n(R13); each R9is independently halo, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, C2-4 haloalkynyl, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), -O- C(O)-R12, -C(O)-R12, -S(O)n(R12), C3-6cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein the C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, and C2-4 haloalkynyl are independently optionally substituted with one or more R9a; the C3-6cycloalkyl and 4-6 membered heterocyclyl are independently optionally substituted with one or more R9b; and the phenyl and 5-6 membered heteroaryl are each independently optionally substituted with one or more R9c;ny-280888919 Attorney Docket No.: 308642000140 each R9ais independently D, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), - C(O)-R12, -S(O)n(R12), C3-6 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-6 membered heteroaryl, wherein, the C3-6cycloalkyl is optionally substituted by one or more R14, and the 4-10 membered heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of oxo, halo, and R14; each R9bis independently halo, -OR10, -N(R10)(R10), C1-4alkyl, C1-4haloalkyl, or oxo; or each R9cis independently halo, -CN, -OR10, -N(R10)(R10), C1-4 alkyl, or C1-4 haloalkyl; each R10is independently H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkenyl, C1-4 alkynyl, C3-4 cycloalkyl, or 3-8 membered heterocyclyl; wherein the C1-4alkyl, C1-4haloalkyl, C1-4alkenyl, or C1-4alkynyl is optionally substituted by one or more R10a, and the C3-4cycloalkyl or 3-8 membered heterocyclyl is optionally substituted by one or more R10b; and each R10ais independently D, -OR14, or C3-4 cycloalkyl; each R2a, R4a, and R10bis independently halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyl-(OR14), C1-4 haloalkyl-(OR14), -OR14, or -N(R14)(R14); X is N, or CR11; R11is H, halo, C1-4 alkyl, C1-4 haloalkyl, or -CN; each R12is independently C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, C2-4 haloalkynyl, C3-6 cycloalkyl, -OR14, -N(R14)(R14), or 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted by halo, C1-4 alkyl, or C1-4 haloalkyl; R13is C1-4alkyl or C1-4haloalkyl; each R14is independently H, C1-4 alkyl, C1-4 haloalkyl, or C3-6 cycloalkyl; n is independently at each occurrence 0, 1, or 2; indicates a single or double bond, wherein when is a single bond, p and q are each 2, and when is a double bond, p and q are each 1; each R15and R16is independently H, D, or C1-4 alkyl; R17is H, -CH3, -CF3, halo, or -OH; and R18is H, -CH3, -CF3, or halo,ny-280888920 Attorney Docket No.: 308642000140 or R17and R18are taken together with the carbon to which they are attached to form a cyclopropyl, provided that when L is -O-, each of R1-R6is H, R7is 2-chloropyrimidin-4-yl, X is CF, is a single bond, and each R15and R16is H, then R9is not ethoxymethyl. In one aspect, provided herein is a compound of formula (I): (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is -C(R17)(R18)-, -C(O)-, -O-, -NR10-, or -S(O)n-; R1and R2are independently H, D, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, or C2-4 haloalkynyl, wherein the C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, and C2-4haloalkynyl are independently optionally substituted with -OR10or -N(R10)(R10); or R1and R2are taken together with the carbon atom to which they are attached to form a C3-6 cycloalkyl or a 4-6 membered heterocyclyl, wherein the C3-6 cycloalkyl and 4-6 membered heterocyclyl are optionally substituted with one or more R2a; R3and R4are independently H, D, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, C2-4 haloalkynyl, -OR10, -N(R10)(R10), C3-6 cycloalkyl, or 4-6 membered heterocyclyl, wherein the C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, and C2-4haloalkynyl are independently optionally substituted with -OR10, -N(R10)(R10), C3- 6cycloalkyl, or 4-6 membered heterocyclyl, and the C3-6cycloalkyl and the 4-6 membered heterocyclyl of R3and R4are optionally substituted with one or more R4a; or R3and R4are taken together with the carbon atom to which they are attached to form a C3-6 cycloalkyl or a 3-6 membered heterocyclyl, wherein the C3-6cycloalkyl or the 3-6 membered heterocyclyl are optionally substituted with one or more R4a;ny-280888921 Attorney Docket No.: 308642000140 R5is H, C1-2alkyl, C1-2haloalkyl, or C3-5cycloalkyl; R6is H, C1-2 alkyl, C1-2 haloalkyl, or C3-5 cycloalkyl; R7is 5-6 membered heteroaryl or partially unsaturated 8-14 membered heterocyclyl, wherein a carbon atom adjacent to a heteroatom on the 5-6 membered heteroaryl or 8-14 membered heterocyclyl is substituted by R8, the 5-6 membered heteroaryl is optionally further substituted with one or more R9, and the 8-14 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of oxo and R9; R8is halo or -S(O)n(R13); each R9is independently halo, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, C2-4haloalkynyl, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), -O- C(O)-R12, -C(O)-R12, -S(O)n(R12), C3-6 cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein the C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, and C2-4haloalkynyl are independently optionally substituted with one or more R9a; the C3-6 cycloalkyl and 4-6 membered heterocyclyl are independently optionally substituted with one or more R9b; and the phenyl and 5-6 membered heteroaryl are each independently optionally substituted with one or more R9c; each R9ais independently D, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), - C(O)-R12, -S(O)n(R12), C3-6 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-6 membered heteroaryl, wherein, the C3-6cycloalkyl is optionally substituted by one or more R14, and the 4-10 membered heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of oxo and R14; each R9bis independently halo, -OR10, -N(R10)(R10), C1-4alkyl, C1-4haloalkyl, or oxo; or each R9cis independently halo, -CN, -OR10, -N(R10)(R10), C1-4alkyl, or C1-4haloalkyl; each R10is independently H, C1-4 alkyl, C1-4 haloalkyl, or C3-4 cycloalkyl; wherein the C1-4 alkyl or C1-4 haloalkyl is optionally substituted by one or more R10a, and the C3-4cycloalkyl is optionally substituted by one or more R10b; and each R10ais independently D, -OR14, or C3-4 cycloalkyl; each R2a, R4a, and R10bis independently halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyl-(OR14), C1-4 haloalkyl-(OR14), -OR14, or -N(R14)(R14);ny-280888922 Attorney Docket No.: 308642000140 X is N, or CR11; R11is H, halo, C1-4 alkyl, C1-4 haloalkyl, or -CN; each R12is independently C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, C2-4haloalkynyl, C3-6cycloalkyl, -OR14, or -N(R14)(R14); R13is C1-4 alkyl or C1-4 haloalkyl; each R14is independently H, C1-4 alkyl, or C1-4 haloalkyl; n is independently at each occurrence 0, 1, or 2; indicates a single or double bond, wherein when is a single bond, p and q are each 2, and when is a double bond, p and q are each 1; each R15and R16is independently H, D, or C1-4alkyl; R17is H, -CH3, -CF3, halo, or -OH; and R18is H, -CH3, -CF3, or halo, or R17and R18are taken together with the carbon to which they are attached to form a cyclopropyl, provided that when L is -O-, each of R1-R6is H, R7is 2-chloropyrimidin-4-yl, X is CF, is a single bond, and each R15and R16is H, then R9is not ethoxymethyl. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing: R5is H or C1-2 alkyl; R6is H or C1-2alkyl; each R9ais independently D, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), - C(O)-R12, -S(O)n(R12), C3-6 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-6 membered heteroaryl, wherein the 4-10 membered heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of oxo, halo, and R14; and each R4ais C1-4alkyl. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing:ny-280888923 Attorney Docket No.: 308642000140 R5is H or C1-2alkyl; R6is H or C1-2 alkyl; each R9ais independently D, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), - C(O)-R12, -S(O)n(R12), C3-6cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-6 membered heteroaryl, wherein the 4-10 membered heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of oxo, halo, and R14; and each R4ais C1-4alkyl. In some embodiments, when L is -O-, each of R1-R6is H, R7is 2-chloropyrimidin-4-yl, X is CF, is a single bond, and each R15and R16is H, then R9is not ethoxymethyl. In some embodiments, the compound is not 2-((2-chloro-5-(ethoxymethyl)pyrimidin-4- yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing: R5is H or C1-2 alkyl; R6is H or C1-2alkyl; each R9ais independently D, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), - C(O)-R12, -S(O)n(R12), C3-6 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-6 membered heteroaryl, wherein the 4-10 membered heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of oxo and R14; and each R4ais C1-4alkyl. In some embodiments, the compound of formula (I) is a compound of formula (I-a-1):ny-280888924 Attorney Docket No.: 308642000140 stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is -C(R17)(R18)- or -C(O)-. In some embodiments, the compound of formula (I) is a compound of formula (I-a-2): acceptable salt of any of the foregoing, wherein L is -C(R17)(R18)- or -C(O)-. In some embodiments, the compound of formula (I) is a compound of formula (Ib-1): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-b-2): pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-c-1):ny-280888925 Attorney Docket No.: 308642000140 stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-c-2): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-d-1): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-d-2): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-e):ny-280888926 Attorney Docket No.: 308642000140 stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-f): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-g): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-h): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-i): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-j):ny-280888927 Attorney Docket No.: 308642000140 stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-k): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-m): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-n): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) is a compound of formula (I-o): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is -C(R17)(R18)-, -C(O)-,ny-280888928 Attorney Docket No.: 308642000140 -O-, -NR10-, -S-, -S(O)-, or -S(O)2-. In some embodiments, L is -C(R17)(R18)-, -C(O)-, -NR10-, - S-, -S(O)-, or -S(O)2-. In some embodiments, L is -C(R17)(R18)-, -C(O)-, -O-, or -NR10-. In some embodiments, L is -C(R17)(R18)-, -C(O)-, or -NR10-. In some embodiments, L is -CH2-, -CHF-, - CF2-, -CH(CH3)-, -C(CH3)2-, -C(CH3)(CF3)-, -C(OH)(H)-, -C(OH)(CH3)-, -C(OH)(CF3)-, , -C(O)-, -O-, -N(H)-, or -N(C1-4 alkyl)-. In some embodiments, L is -CH2-, -CHF-, - -, -C(CH3)2-, -C(CH3)(CF3)-, -C(OH)(H)-, -C(OH)(CH3)-, -C(OH)(CF3)-, , -C(O)-, -N(H)-, or -N(C1-4 alkyl)-. In some embodiments, L is -CH2-, -CHF-, -CF2- , -O-, -N(H)-, or -N(C1-4 alkyl)-. In some embodiments, L is -CH2-, -CHF-, -CF2-, -N(H)-, or - N(C1-4alkyl)-. In some embodiments, L is -CH2-, -O-, -N(H)-, or -N(C1-4alkyl)-. In some embodiments, L is -CH2-, -O-, -N(H)-, or -N(C1-4 alkyl)-. In some embodiments, L is -N(H)- or - N(C1-4 alkyl)-. In some embodiments, L is -O-, -N(H)-, or -N(CH3)-. In some embodiments, L is -N(H)- or -N(CH3)-. In some embodiments, L is -O- or -N(H)-. In some embodiments, L is -O-. In some embodiments, L is -N(H)-. In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R1and R2are H, or R1and R2are taken together with the carbon atom to which they are attached to form a C3-6cycloalkyl or a 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more R2a. In some embodiments, R1and R2are H, or R1and R2are taken together with the carbon atom to which they are attached to form a C3-6cycloalkyl or a 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with C1-4 alkyl. In some embodiments, R1and R2are H, or R1and R2are taken together with the carbon atom to which they are attached to form a cyclopropyl or N-methylazetidinyl. In some embodiments, R1and R2are each H. In some embodiments of a compound of formula (I), or a pharmaceutically acceptable salt of any of the foregoing, R3and R4are independently H, C1-4alkyl, or C1-4haloalkyl, or R3and R4are taken together with the carbon atom to which they are attached to form a C3-6cycloalkyl or a 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl is optionally substituted with one or more R4a. In some embodiments, R3and R4are independently H, C1-4 alkyl, or C1-4haloalkyl, or R3and R4are taken together with the carbon atom to which they are attached to form a C3-6 cycloalkyl or a 3-6 membered heterocyclyl, wherein the 3-6 memberedny-280888929 Attorney Docket No.: 308642000140 heterocyclyl is optionally substituted with C1-4alkyl. In some embodiments, R3and R4are independently H, -CH3, or -CF3, or R3and R4are taken together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, or N-methylazetidinyl. In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R5is H, C1-2 alkyl, or C1-2 haloalkyl. In some embodiments, R5is H, -CH3, -CH2CH3, -CH2CF3, or -CH2CF2H. In some embodiments, R5is H, -CH3, or -CH2CH3.In some embodiments, R5is H, or -CH3.In some embodiments, R5is H. In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R6is H, C1-2alkyl, or C1-2haloalkyl. In some embodiments, R6is H, -CH3, -CH2CH3, -CH2CF3, or -CH2CF2H. In some embodiments, R6is H, -CH3, or -CH2CH3. In some embodiments, R6is H, or -CH3. In some embodiments, R6is H. In some embodiments, R5and R6are each H. In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R1, R2, R5, and R6are each H. In some embodiments, R1, R2, R3, R4, R5, and R6are each H. In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R7is a 5-6 membered heteroaryl substituted by R8at a carbon atom adjacent to a heteroatom and optionally substituted with one or more R9. In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R7is a 5-membered heteroaryl substituted by R8at a carbon atom adjacent to a heteroatom and optionally substituted with one or more R9. In some embodiments, R7is pyrazolyl, oxazolyl, or thiazolyl, wherein the pyrazolyl, oxazolyl, or thiazolyl is substituted by R8at a carbon atom adjacent to a heteroatom and optionally substituted with one or more R9. In some embodiments, R7is pyrazolyl substituted by R8at a carbon atom adjacent to a heteroatom and optionally substituted with one or more R9. In some embodiments, R7is oxazolyl substituted by R8at a carbon atom adjacent to a heteroatom and optionally substituted with one or more R9. In some embodiments, R7is thiazolyl substituted by R8at a carbon atom adjacent to a heteroatom and optionally substituted with one or more R9. In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R7is a 6-memberedny-280888930 Attorney Docket No.: 308642000140 heteroaryl substituted by R8at a carbon atom adjacent to a heteroatom and optionally substituted with one or more R9. In some embodiments, R7is pyrimidinyl, pyridinyl, or pyridazyl, wherein the pyrimidinyl, pyridinyl, or pyridazyl is substituted by R8at a carbon atom adjacent to a heteroatom and optionally substituted with one or more R9. In some embodiments, R7is pyrimidinyl substituted by R8at a carbon atom adjacent to a heteroatom and optionally substituted with one or more R9. In some embodiments, R7is pyridinyl substituted by R8at a carbon atom adjacent to a heteroatom and optionally substituted with one or more R9. In some embodiments, R7is pyridizinyl substituted by R8at a carbon atom adjacent to a heteroatom and optionally substituted with one or more R9. In some embodiments, some embodiments, wherein R10is independently H, C3-4 alkyl, C1-4 haloalkyl, or C3-4 cycloalkyl, wherein the C3-4 alkyl or C1-4 haloalkyl is optionally substituted by one or more R10a, and the C3-4cycloalkyl is optionally substituted by one or more R10b. In some embodiments, R7is Cl , wherein R10is independently H, C1-4 haloalkyl, or C3-4 cycloalkyl, wherein the C1-4 haloalkyl is optionally substituted by one or more R10a, and the C3-4cycloalkyl is optionally substituted by one or more R10b. In some embodiments,10 wherein R is independently H, methyl, or C3-4 cycloalkyl, wherein the C3-4 cycloalkyl is optionally substitutedny-280888931 Attorney Docket No.: 308642000140 by one or more R10b. In some embodiments, , wherein R10is independently H or C3-4 cycloalkyl, wherein the C3-4 cycloalkyl is optionally substituted by one or more R10b. In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R7is an 8-14 membered heterocyclyl substituted by R8and optionally substituted with one or more R9. In some embodiments, R7is 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, wherein the 5,6,7,8- tetrahydropyrido[4,3-d]pyrimidinyl is substituted by R8and optionally substituted with one or more R9. In some embodiments, optionally substituted by 1, 2, or 3 R9groups. In some embodiments, optionally substituted by 1 or 2 R9groups. In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R8is halo. In some embodiments, R8is Cl or F. In some embodiments, R8is Cl. In some embodiments, R8is - S(O)n(R13). In some embodiments, R8is -S(O)n(C1-4 alkyl). In some embodiments, R8is - S(O)n(CH3). In some embodiments, R8is -S(R13). In some embodiments, R8is -S(C1-4alkyl). In some embodiments, R8is -S(CH3). In some embodiments, R8is -S(O)(R13). In some embodiments, R8is -S(O)(C1-4 alkyl). In some embodiments, R8is -S(O)( CH3). In some embodiments, R8is -S(O)2(R13). In some embodiments, R8is -S(O)2(C1-4 alkyl). In some embodiments, R8is -S(O)2(CH3). In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R9is C1-4 alkyl optionally substituted by one or more R9a. In some embodiments, R9ais -CN, -OR10, -C(O)-R12, - S(O)2(R12), C3-6cycloalkyl, or 4-10 membered heterocyclyl optionally substituted by one of moreny-280888932 Attorney Docket No.: 308642000140 substituents selected from the group consisting of oxo and -CH3. In some embodiments, R9ais - CN, -OR10, -C(O)-R12, -S(O)2(R12), C3-6 cycloalkyl, or 4-10 membered heterocyclyl optionally substituted by one of more substituents selected from the group consisting of oxo, halo, and - CH3. In some embodiments, R9ais -CN, -OH, -O(C1-4alkyl), -O(C1-4haloalkyl), -O(C3-6cycloalkyl), -O(4-6 membered heterocyclyl), -C(O)-(C3-6 cycloalkyl), -C(O)-[N(C1-4 alkyl)(C1-4 alkyl)], -S(O)2(C1-4 alkyl), -S(O)2[N(C1-4 alkyl)(C1-4 alkyl)], C3-6 cycloalkyl, or 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl is optionally substituted by one of more substituents selected from the group consisting of oxo and -CH3. In some embodiments, R9ais - CN, -OH, -O(C1-4 alkyl), -O(C1-4 haloalkyl), -O(C3-6 cycloalkyl), -O(4-6 membered heterocyclyl), -C(O)-(C3-6cycloalkyl), -C(O)-[N(C1-4alkyl)(C1-4alkyl)], -S(O)2(C1-4alkyl), -S(O)2[N(C1-4alkyl)(C1-4alkyl)], C3-6cycloalkyl, or 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl is optionally substituted by one of more substituents selected from the group consisting of oxo, halo, and -CH3. In some embodiments, R9ais selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholino, isothiazolidinyl, and 5- azaspiro[2.4]heptanyl. In some embodiments, R9is C1-4alkyl. In some embodiments, R9is -CH3. In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R9is C1-4alkyl optionally substituted one or more R9aand further substituted by one or more deuterium. In some embodiments, R9is C1-4 alkyl substituted by -O(C1-4 alkyl), wherein the at least one of the C1-4 alkyl or -O(C1-4alkyl) is further substituted by one or more deuterium. In some embodiments, R9is -CH3O(CH2CH3). In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R9is C3-6cycloalkyl optionally substituted by one or more R9b. In some embodiments, R9is cyclopropyl. In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R9is halo, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, -CH2S(O)2(C1-4alkyl), -CN, -CH2(CN), -CH2(4-8 membered heterocyclyl), -CH2O(C1-4 alkyl), -CH2O(C1-4 haloalkyl), -CH2O(C3-6 cycloalkyl), -CH2O(4-6 membered heterocyclyl), -C(O)-(C1-4 alkyl), -C(O)-(C3-6 cycloalkyl), -C(O)-O(C1-4 alkyl), -C(O)- N(H)(C1-4alkyl), or -C(O)-N(C1-4alkyl)(C1-4alkyl), wherein the -CH2(4-8 membered heterocyclyl) is optionally substituted by one or more groups selected from C1-4alkyl and oxo. In some embodiments, R9is halo, -CH3, -CF3, -CHF2, -CH2CF3, -CH2CF2H, cyclopropyl, -ny-280888933 Attorney Docket No.: 308642000140 CH2S(O)2CH3, -CN, -CH2(CN), -CH2(5-7 membered heterocyclyl), -CH2OCH3, -CH2- OCH2CH3, -CH2O(CF3), -CH2O(CHF2), -CH2O(cyclopropyl), -CH2O(tetrahydrofuranyl), -C(O)- CH3, -C(O)-(cyclopropyl), -C(O)-OCH3, -C(O)-N(H)(CH3), or -C(O)-N(CH3)(CH3), wherein the -CH2(5-7 membered heterocyclyl) is optionally substituted by one or more groups selected from -CH3 and oxo. In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R7is selected from the group consisting of: ny-280888934 Attorney Docket No.: 308642000140 , ny-280888935 Attorney Docket No.: 308642000140 In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R7is selected from the group consisting of: ny-280888936 Attorney Docket No.: 308642000140 ny-280888937 Attorney Docket No.: 308642000140 In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R7is selected from the group consisting of:ny-280888938 Attorney Docket No.: 308642000140 , . In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, each R10is independently H, C1-4 alkyl, C1-4 haloalkyl, or C3-4 cycloalkyl; wherein the C1-4 alkyl or C1-4 haloalkyl is optionally substituted by one or more D, -OH, -O(C1-4 alkyl), or -O(C1-4 haloalkyl), and the C3-4 cycloalkyl is optionally substituted by one or more halo, C1-4alkyl, C1-4haloalkyl, -O(C1-4alkyl), -NH2, -NH(C1-4 alkyl), or -N(C1-4 alkyl)(C1-4 alkyl). In some embodiments, R10is independently H, C1-4 alkyl, C1-4 haloalkyl, or C3-4 cycloalkyl; wherein the C1-4 alkyl is optionally substituted byny-280888939 Attorney Docket No.: 308642000140 one or more D, -OH, -O(CH3), or -O(CF3), and the C3-4cycloalkyl is optionally substituted by one or more F, Cl, Br, -CH3, -O(CH3), -NH2, -NH(CH3), or -N(CH3)(CH3). In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, each R10is independently H, C1-4 alkyl, C1-4 haloalkyl, or C3-4 cycloalkyl. In some embodiments, each R10is independently H, -CH3, -CH2CH3, CF3, or cyclopropyl. In some embodiments, each R10is independently H, - CH3, or -CH2CH3. In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, X is CR11. In some embodiments, R11is H or halo. In some embodiments, R11is H or F. In some embodiments, R11is H or Cl. In some embodiments, R11is H or Br. In some embodiments, X is N. In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, each R15and R16is H, D, or C1-4alkyl. In some embodiments, each R15and R16is H, D, or -CH3. In some embodiments, each R15and R16is H or D. In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R17is H, -CH3, or halo. In some embodiments of a compound of formula (I), or a pharmaceutically acceptable salt of any of the foregoing, R17is H or -CH3. In some embodiments of a compound of formula (I), or a pharmaceutically acceptable salt of any of the foregoing, R17is H or halo. In some embodiments, R17is H. In some embodiments of a compound of formula (I), any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, R18is H, -CH3, or halo. In some embodiments of a compound of formula (I), or a pharmaceutically acceptable salt of any of the foregoing, R18is H or -CH3. In some embodiments of a compound of formula (I), or a pharmaceutically acceptable salt of any of the foregoing, R18is H. In some embodiments, R17and R18are both H. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound, or a pharmaceutically acceptable salt of any of the foregoing, is selected from Table 1. In someny-280888940 Attorney Docket No.: 308642000140 embodiments of a compound of formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound, or a pharmaceutically acceptable salt of any of the foregoing, is selected from compounds 1-141 of Table 1. In one aspect, provided herein is a compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from the compounds enumerated in Table 1. In some embodiments, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from compounds 1-32 and 34-141 of Table 1. In some embodiments, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from compounds 1-32 and 34-189 of Table 1. In some embodiments, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from compounds 1-32, 34-43, and 45-141 of Table 1. In some embodiments, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from compounds 1-32, 34-43, and 45-189 of Table 1. Table 1 ny-280888941 Attorney Docket No.: 308642000140 ny-280888942 Attorney Docket No.: 308642000140 ny-280888943 Attorney Docket No.: 308642000140 ny-280888944 Attorney Docket No.: 308642000140 ny-280888945 Attorney Docket No.: 308642000140 ny-280888946 Attorney Docket No.: 308642000140 ny-280888947 Attorney Docket No.: 308642000140 ny-280888948 Attorney Docket No.: 308642000140 ny-280888949 Attorney Docket No.: 308642000140 ny-280888950 Attorney Docket No.: 308642000140 ny-280888951 Attorney Docket No.: 308642000140 ny-280888952 Attorney Docket No.: 308642000140 ny-280888953 Attorney Docket No.: 308642000140 ny-280888954 Attorney Docket No.: 308642000140 ny-280888955 Attorney Docket No.: 308642000140 ny-280888956 Attorney Docket No.: 308642000140 ny-280888957 Attorney Docket No.: 308642000140 ny-280888958 Attorney Docket No.: 308642000140 ny-280888959 Attorney Docket No.: 308642000140 ny-280888960 Attorney Docket No.: 308642000140 ny-280888961 Attorney Docket No.: 308642000140 ny-280888962 Attorney Docket No.: 308642000140 ny-280888963 Attorney Docket No.: 308642000140 ny-280888964 Attorney Docket No.: 308642000140 ny-280888965 Attorney Docket No.: 308642000140 ny-280888966 Attorney Docket No.: 308642000140 ny-280888967 Attorney Docket No.: 308642000140 ny-280888968 Attorney Docket No.: 308642000140 ny-280888969 Attorney Docket No.: 308642000140 ny-280888970 Attorney Docket No.: 308642000140 ny-280888971 Attorney Docket No.: 308642000140 ny-280888972 Attorney Docket No.: 308642000140 ny-280888973 Attorney Docket No.: 308642000140 ny-280888974 Attorney Docket No.: 308642000140 In some embodiments, provided herein is a compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from the group consisting of: 2-((2-chloro-5-((methylsulfonyl)methyl)pyrimidin-4-yl)oxy)-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((4-chloro-5-((methylsulfonyl)methyl)pyrimidin-2-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((methylsulfonyl)methyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;ny-280888975 Attorney Docket No.: 308642000140 2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloropyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2-((2-chloropyrimidin-4-yl)oxy)-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloropyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)- 1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((4-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloropyrimidin-4-yl)amino)-1'-fluoro-6',8',9',11'-tetrahydrospiro[cyclopropane- 1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; tert-butyl 2-chloro-4-((1'-fluoro-7'-oxo-5',6',7',8',9',11'-hexahydrospiro[cyclopropane- 1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-2'-yl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carboxylate;ny-280888976 Attorney Docket No.: 308642000140 2'-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1'-fluoro- 6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]- 7'(5'H)-one; 2'-((4-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)oxy)-1'-fluoro- 6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]- 7'(5'H)-one; 2'-((2-chloropyrimidin-4-yl)oxy)-1'-fluoro-6',8',9',11'-tetrahydrospiro[cyclopropane- 1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2'-((4-chloropyrimidin-2-yl)oxy)-1'-fluoro-6',8',9',11'-tetrahydrospiro[cyclopropane- 1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2'-((2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1'-fluoro-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2'-((2-chloropyrimidin-4-yl)amino)-1'-fluoro-1-methyl-6',8',9',11'- tetrahydrospiro[azetidine-3,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2-((6-chloropyrazin-2-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(morpholinomethyl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloropyrimidin-4-yl)amino)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((2-oxopyrrolidin-1-yl)methyl)pyrimidin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((4-chloro-5-((2-oxopyrrolidin-1-yl)methyl)pyrimidin-2-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2,5-dichloropyridin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro- 10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;ny-280888977 Attorney Docket No.: 308642000140 2-((2-chloro-6-(methoxymethyl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((6-chloropyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((methylsulfonyl)methyl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-6-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)- 1'-fluoro-6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin]-7'(5'H)-one; 2-((2-chloro-6-isopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)- 1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-(2-hydroxy-2-methylpropyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7- one; 2-((2-chloro-6-(1-methylcyclopropyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7- one; 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-10- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-methyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1- fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2,5-dichloropyridin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;ny-280888978 Attorney Docket No.: 308642000140 2-(2-((2,5-dichloropyridin-4-yl)amino)-3-fluoropyridin-4-yl)-1,5,6,7-tetrahydro-4H- pyrrolo[3,2-c]pyridin-4-one; 2-((2-chloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-cyclopropylpyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R)-2-((2-chloro-5-((3-methyl-2-oxopyrrolidin-1-yl)methyl)pyrimidin-4-yl)oxy)-1- fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((5-acetyl-2-chloropyridin-4-yl)amino)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((6-chloropyridazin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((4-chloro-5-(ethoxymethyl)pyrimidin-2-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; methyl [(R) or (S)]-6-chloro-4-((1-fluoro-10-methyl-7-oxo-6,7,8,9,10,11-hexahydro-5H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-2-yl)amino)nicotinate; 2-((2-chloro-6-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((6-chloro-3-cyclopropylpyridazin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-2-((2-chloropyrimidin-4-yl)amino)-1-fluoro-10-methyl-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-isopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;ny-280888979 Attorney Docket No.: 308642000140 (S) or (R)-2-((2-chloropyrimidin-4-yl)amino)-1-fluoro-10-methyl-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-2-((2-chloro-5-(cyclopropoxymethyl)pyrimidin-4-yl)amino)-1-fluoro-10- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S) or (R)-2-((2-chloro-5-(cyclopropoxymethyl)pyrimidin-4-yl)amino)-1-fluoro-10- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S)-2-((2-chloro-5-(((tetrahydrofuran-3-yl)oxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S)-2-((4-chloro-5-(((tetrahydrofuran-3-yl)oxy)methyl)pyrimidin-2-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((6-chloropyridazin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((6-chloro-3-(trifluoromethyl)pyridazin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((5-acetyl-2-chloropyridin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((5-acetyl-2-chloropyridin-4-yl)amino)-1'-fluoro-1-methyl-6',8',9',11'- tetrahydrospiro[azetidine-3,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2-((2-chloro-6-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;ny-280888980 Attorney Docket No.: 308642000140 2-((2-chloro-5-(hydroxymethyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1'-fluoro- 8',9'-dihydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(11'H)-one; 2-((4-chloropyrimidin-2-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1- fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S) or (R)-2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1- fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(hydroxymethyl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(2-hydroxypropan-2-yl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S) or (R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)amino)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)amino)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(((3S,4R)-3,4-difluoropyrrolidin-1-yl)methyl)pyrimidin-4-yl)oxy)-1- fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((4-chloro-5-(((3S,4R)-3,4-difluoropyrrolidin-1-yl)methyl)pyrimidin-2-yl)oxy)-1- fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-2-((2-chloro-5-(1-hydroxyethyl)pyrimidin-4-yl)oxy)-1-fluoro-8,9,10,11- tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)-one; 2'-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)amino)-1'-fluoro-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one;ny-280888981 Attorney Docket No.: 308642000140 (S) or (R)-2-((4-chloro-5-(ethoxymethyl)pyrimidin-2-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-2-((4-chloro-5-(ethoxymethyl)pyrimidin-2-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S) or (R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(difluoromethyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-1'-fluoro-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2-((2-chloro-6-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-(2,2-difluoroethyl)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-cyclopropyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1- fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-6-methyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1'- fluoro-8',9'-dihydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]- 7'(11'H)-one 2-((2-chloro-6-cyclopropyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-1- fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-(2,2-difluoroethyl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)- 1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-(methyl-d3)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro- 10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-10- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;ny-280888982 Attorney Docket No.: 308642000140 2-((2-chloro-6-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1- fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6,7-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro- 10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro- 10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-9- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-9- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-cyclopropyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)- 1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-(methyl-d3)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)- 1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-ethyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1- fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-methyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1- fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-methyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1- fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-6-methyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1'- fluoro-6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]- 7'(5'H)-one; 2-((2-chloro-6,7-dimethyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)- 1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-8,9,10,11- tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)-one; 2-((2-chloro-5-((trifluoromethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;ny-280888983 Attorney Docket No.: 308642000140 2-((2-chloro-5-((trifluoromethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((6-chloro-3-(ethoxymethyl)pyridazin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((trifluoromethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(cyclopropoxymethyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(1-hydroxyethyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrimidin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(cyclopropoxymethyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-9-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)oxy)-1'-fluoro-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 6-chloro-N,N-dicyclopropyl-4-((1-fluoro-7-oxo-6,7,8,9,10,11-hexahydro-5H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-2-yl)amino)pyridazine-3-carboxamide; 2-((2-chloro-5-(3,4-difluoropyrrolidine-1-carbonyl)pyridin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((3-acetyl-6-chloropyridazin-4-yl)amino)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; chloropyridin-4-yl)amino)-1-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;ny-280888984 Attorney Docket No.: 308642000140 2'-((5-acetyl-2-chloropyridin-4-yl)amino)-1'-fluoro-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2-((6-chloro-3-(ethoxymethyl)pyridazin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;; 2-((2-chloro-5-((trifluoromethoxy)methyl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)amino)-1'-fluoro-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)amino)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)amino)-1'-fluoro-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2'-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1'-fluoro- 8',9'-dihydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(11'H)-one; 2-((2-chloro-5-(3,4-difluoropyrrolidine-1-carbonyl)pyridin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloropyrimidin-4-yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 6-chloro-N,N-dicyclopropyl-4-((1-fluoro-7-oxo-6,7,8,9,10,11-hexahydro-5H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-2-yl)oxy)pyridazine-3-carboxamide; 2-((2-chloro-5-(trifluoromethyl)pyridin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloropyrimidin-4-yl)amino)-1'-fluoro-6',8',9',11'-tetrahydrospiro[oxetane-2,10'- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro- 11-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;ny-280888985 Attorney Docket No.: 308642000140 2-(4-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1-fluoro-11- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':3,4]cyclopenta[1,2-f]isoquinolin-7-one; 2-((6-chloropyrimidin-4-yl)methyl)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-6-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)amino)-1'-fluoro-5',6',8',9'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin]-7'(11'H)-one; 2'-((4-chloro-6-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)amino)-1'-fluoro-5',6',8',9'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin]-7'(11'H)-one; 2-(2-chloro-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl)-1-fluoro-8,9,10,11-tetrahydro- 5H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)-one; 2-((6-chloro-3-(trifluoromethyl)pyridazin-4-yl)amino)-1-fluoro-8,9,10,11-tetrahydro-5H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)-one; (S) or (R)-2-((2-chloro-5-(1-hydroxyethyl)pyrimidin-4-yl)oxy)-1-fluoro-8,9,10,11- tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)-one; (R) or (S)-2-((2-chloropyrimidin-4-yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S) or (R)-2-((2-chloropyrimidin-4-yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S) or (R)-4-[2-chloro-5-(difluoromethoxymethyl)-4-pyrimidinyloxy]-3-fluoro-14- methyl-5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2(7),3,5,11(16)-pentaen-12-one; 2'-((4-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)oxy)-1'-fluoro- 8',9'-dihydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5] pyrrolo[2,3-f]isoquinolin]-7'(11'H)-one; (R) or (S)-2-((2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-10- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S) or (R)-2-((2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-10- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;ny-280888986 Attorney Docket No.: 308642000140 (R) or (S)-2-((5-((difluoromethoxy)methyl)-4-iodopyrimidin-2-yl)oxy)-1-fluoro-9- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((trans-3,4-difluoropyrrolidin-1-yl)methyl)pyrimidin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((prop-2-yn-1-yloxy)methyl) pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f] isoquinolin-7-one; (S) or (R)-2-((5-acetyl-2-chloropyridin-4-yl)amino)-1-fluoro-10-methyl-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-4-[2-chloro-5-(cyclopropoxymethyl)-4-pyrimidinyloxy]-3-fluoro-15-methyl- 5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2(7),3,5,11(16)-pentaen-12-one; (R) or (S)-2-((5-acetyl-2-chloropyridin-4-yl)amino)-1-fluoro-10-methyl-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S) or (R)-4-[2-chloro-5-(cyclopropoxymethyl)-4-pyrimidinyloxy]-3-fluoro-15-methyl- 5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2(7),3,5,11(16)-pentaen-12-one; (S) or (R)-2-((2-chloro-6-cyclobutyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)- 1-fluoro-10-methyl-8,9,10,11-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)- one; (R) or (S)-2-((2-chloro-6-cyclobutyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)- 1-fluoro-10-methyl-8,9,10,11-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)- one; (R) or (S)-2-((2-chloro-6-(methyl-d3)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one; (S) or (R)-2-((2-chloro-6-(methyl-d3)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one; (R) or (S)-2-((2-chloro-6-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1- fluoro-10-methyl-8,9,10,11-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)-one;ny-280888987 Attorney Docket No.: 308642000140 (S) or (R)-2-((2-chloro-6-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1- fluoro-10-methyl-8,9,10,11-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)-one; 4-(2-chloro-6-ethyl-5,6,7,8-tetrahydro-1,3,6-triaza-4-naphthyloxy)-3-fluoro-15,15- dimethyl-5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2,4,6,11(16)-pentaen-12-one; (R) or (S)-4-(2-chloro-6-ethyl-5,6,7,8-tetrahydro-1,3,6-triaza-4-naphthyloxy)-3-fluoro- 14-methyl-5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2,4,6,11(16)-pentaen-12- one; (S) or (R)-4-(2-chloro-6-ethyl-5,6,7,8-tetrahydro-1,3,6-triaza-4-naphthyloxy)-3-fluoro- 14-methyl-5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2,4,6,11(16)-pentaen-12- one; 4-(2-chloro-6-ethyl-5,6,7,8-tetrahydro-1,3,6-triaza-4-naphthyloxy)-3-fluoro-14,14- dimethyl-5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2,4,6,11(16)-pentaen-12-one; (S) or (R)-2-((2-chloro-6-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one; (R) or (S)-2-((2-chloro-6-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one; (S) or (R)-2-((2-chloro-6-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one; (R) or (S)-2-((2-chloro-6-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one; (S) or (R)-2-((2-chloro-6-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one; (R) or (S)-2-((2-chloro-5-((2,2,2-trifluoroethoxy) methyl)pyrimidin-4-yl)oxy)-1-fluoro- 10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo [2,3-f]isoquinolin-7-one;ny-280888988 Attorney Docket No.: 308642000140 (S) or (R)-2-((5-acetyl-2-chloropyridin-4-yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-2-((5-acetyl-2-chloropyridin-4-yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-6-(methyl-d3)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)amino)-1'-fluoro-6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin]-7'(5'H)-one; (S) or (R)-2-((2-chloro-6-(methyl-d3)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)amino)-1-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one; (R) or (S)-2-((2-chloro-6-(methyl-d3)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)amino)-1-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one; (S) or (R)-2-((2-chloro-6-(methyl-d3)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)amino)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one; (R) or (S)-2-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-10- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S) or (R)-2-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-10- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-2-((4-chloro-5-((difluoromethoxy)methyl)pyrimidin-2-yl)oxy)-1-fluoro-10- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S) or (R)-2-((4-chloro-5-((difluoromethoxy)methyl)pyrimidin-2-yl)oxy)-1-fluoro-10- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; and (R) or (S)-2-((2-chloro-6-(methyl-d3)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)amino)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one.ny-280888989 Attorney Docket No.: 308642000140 In some embodiments, provided herein is a compound or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from the group consisting of: 2-((2-chloro-5-((methylsulfonyl)methyl)pyrimidin-4-yl)oxy)-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((4-chloro-5-((methylsulfonyl)methyl)pyrimidin-2-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((methylsulfonyl)methyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloropyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2-((2-chloropyrimidin-4-yl)oxy)-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloropyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)- 1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;ny-280888990 Attorney Docket No.: 308642000140 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((4-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloropyrimidin-4-yl)amino)-1'-fluoro-6',8',9',11'-tetrahydrospiro[cyclopropane- 1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; tert-butyl 2-chloro-4-((1'-fluoro-7'-oxo-5',6',7',8',9',11'-hexahydrospiro[cyclopropane- 1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-2'-yl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carboxylate; 2'-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1'-fluoro- 6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]- 7'(5'H)-one; 2'-((4-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)oxy)-1'-fluoro- 6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]- 7'(5'H)-one; 2'-((2-chloropyrimidin-4-yl)oxy)-1'-fluoro-6',8',9',11'-tetrahydrospiro[cyclopropane- 1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2'-((4-chloropyrimidin-2-yl)oxy)-1'-fluoro-6',8',9',11'-tetrahydrospiro[cyclopropane- 1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2'-((2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1'-fluoro-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2'-((2-chloropyrimidin-4-yl)amino)-1'-fluoro-1-methyl-6',8',9',11'- tetrahydrospiro[azetidine-3,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2-((6-chloropyrazin-2-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(morpholinomethyl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloropyrimidin-4-yl)amino)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;ny-280888991 Attorney Docket No.: 308642000140 2-((2-chloro-5-((2-oxopyrrolidin-1-yl)methyl)pyrimidin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((4-chloro-5-((2-oxopyrrolidin-1-yl)methyl)pyrimidin-2-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2,5-dichloropyridin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro- 10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-(methoxymethyl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((6-chloropyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((methylsulfonyl)methyl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-6-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)- 1'-fluoro-6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin]-7'(5'H)-one; 2-((2-chloro-6-isopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)- 1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-(2-hydroxy-2-methylpropyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7- one;ny-280888992 Attorney Docket No.: 308642000140 2-((2-chloro-6-(1-methylcyclopropyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7- one; 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-10- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-methyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1- fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2,5-dichloropyridin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-(2-((2,5-dichloropyridin-4-yl)amino)-3-fluoropyridin-4-yl)-1,5,6,7-tetrahydro-4H- pyrrolo[3,2-c]pyridin-4-one; 2-((2-chloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-cyclopropylpyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R)-2-((2-chloro-5-((3-methyl-2-oxopyrrolidin-1-yl)methyl)pyrimidin-4-yl)oxy)-1- fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((5-acetyl-2-chloropyridin-4-yl)amino)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((6-chloropyridazin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((4-chloro-5-(ethoxymethyl)pyrimidin-2-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; methyl [(R) or (S)]-6-chloro-4-((1-fluoro-10-methyl-7-oxo-6,7,8,9,10,11-hexahydro-5H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-2-yl)amino)nicotinate;ny-280888993 Attorney Docket No.: 308642000140 2-((2-chloro-6-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((6-chloro-3-cyclopropylpyridazin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-2-((2-chloropyrimidin-4-yl)amino)-1-fluoro-10-methyl-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-isopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S) or (R)-2-((2-chloropyrimidin-4-yl)amino)-1-fluoro-10-methyl-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-2-((2-chloro-5-(cyclopropoxymethyl)pyrimidin-4-yl)amino)-1-fluoro-10- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S) or (R)-2-((2-chloro-5-(cyclopropoxymethyl)pyrimidin-4-yl)amino)-1-fluoro-10- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S)-2-((2-chloro-5-(((tetrahydrofuran-3-yl)oxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S)-2-((4-chloro-5-(((tetrahydrofuran-3-yl)oxy)methyl)pyrimidin-2-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((6-chloropyridazin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((6-chloro-3-(trifluoromethyl)pyridazin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;ny-280888994 Attorney Docket No.: 308642000140 2-((5-acetyl-2-chloropyridin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((5-acetyl-2-chloropyridin-4-yl)amino)-1'-fluoro-1-methyl-6',8',9',11'- tetrahydrospiro[azetidine-3,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2-((2-chloro-6-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(hydroxymethyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1'-fluoro- 8',9'-dihydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(11'H)-one; 2-((4-chloropyrimidin-2-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1- fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S) or (R)-2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1- fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(hydroxymethyl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(2-hydroxypropan-2-yl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S) or (R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)amino)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)amino)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;ny-280888995 Attorney Docket No.: 308642000140 2-((2-chloro-5-(((3S,4R)-3,4-difluoropyrrolidin-1-yl)methyl)pyrimidin-4-yl)oxy)-1- fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((4-chloro-5-(((3S,4R)-3,4-difluoropyrrolidin-1-yl)methyl)pyrimidin-2-yl)oxy)-1- fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-2-((2-chloro-5-(1-hydroxyethyl)pyrimidin-4-yl)oxy)-1-fluoro-8,9,10,11- tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)-one; 2'-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)amino)-1'-fluoro-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; (S) or (R)-2-((4-chloro-5-(ethoxymethyl)pyrimidin-2-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-2-((4-chloro-5-(ethoxymethyl)pyrimidin-2-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (S) or (R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; (R) or (S)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(difluoromethyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-1'-fluoro-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2-((2-chloro-6-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-(2,2-difluoroethyl)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-cyclopropyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1- fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-6-methyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1'- fluoro-8',9'-dihydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]- 7'(11'H)-oneny-280888996 Attorney Docket No.: 308642000140 2-((2-chloro-6-cyclopropyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-1- fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-(2,2-difluoroethyl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)- 1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-(methyl-d3)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro- 10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-10- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1- fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6,7-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro- 10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro- 10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-9- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-9- methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-cyclopropyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)- 1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-(methyl-d3)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)- 1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-ethyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1- fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-methyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1- fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-6-methyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1- fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;ny-280888997 Attorney Docket No.: 308642000140 2'-((2-chloro-6-methyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1'- fluoro-6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]- 7'(5'H)-one; 2-((2-chloro-6,7-dimethyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)- 1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-8,9,10,11- tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)-one; 2-((2-chloro-5-((trifluoromethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((trifluoromethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((6-chloro-3-(ethoxymethyl)pyridazin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((trifluoromethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(cyclopropoxymethyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(1-hydroxyethyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrimidin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-(cyclopropoxymethyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-9-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)oxy)-1'-fluoro-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one;ny-280888998 Attorney Docket No.: 308642000140 6-chloro-N,N-dicyclopropyl-4-((1-fluoro-7-oxo-6,7,8,9,10,11-hexahydro-5H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-2-yl)amino)pyridazine-3-carboxamide; 2-((2-chloro-5-(3,4-difluoropyrrolidine-1-carbonyl)pyridin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((3-acetyl-6-chloropyridazin-4-yl)amino)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; chloropyridin-4-yl)amino)-1-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((5-acetyl-2-chloropyridin-4-yl)amino)-1'-fluoro-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2-((6-chloro-3-(ethoxymethyl)pyridazin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;; 2-((2-chloro-5-((trifluoromethoxy)methyl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)amino)-1'-fluoro-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)amino)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)amino)-1'-fluoro-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; 2'-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1'-fluoro- 8',9'-dihydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(11'H)-one; 2-((2-chloro-5-(3,4-difluoropyrrolidine-1-carbonyl)pyridin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2-((2-chloropyrimidin-4-yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one;ny-280888999 Attorney Docket No.: 308642000140 6-chloro-N,N-dicyclopropyl-4-((1-fluoro-7-oxo-6,7,8,9,10,11-hexahydro-5H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-2-yl)oxy)pyridazine-3-carboxamide; 2-((2-chloro-5-(trifluoromethyl)pyridin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one; 2'-((2-chloropyrimidin-4-yl)amino)-1'-fluoro-6',8',9',11'-tetrahydrospiro[oxetane-2,10'- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one; and 2-((2-chloro-5-(oxetan-2-yl)pyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one. PHARMACEUTICAL COMPOSITIONS Provided herein are pharmaceutical compositions comprising one or more compounds of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, provided herein is a pharmaceutical composition comprising (i) a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises a therapeutically effective amount of the compound. Suitable pharmaceutically acceptable excipients may include, for example, fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending / gelling agent, or wet granulation agent. Examples of suitable excipients are well-known to those skilled in the art. See, e.g., Handbook of Pharmaceutical Excipients, Pharmaceutical Press (2017), which is incorporated herein by reference in its entirety. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Academic Press, 23rded. (2020), which is incorporated herein by reference in its entirety. METHODS OF TREATMENTny-2808889100 Attorney Docket No.: 308642000140 The MAP kinase pathway is associated with many diseases, including, but not limited to autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, respiratory diseases, Alzheimer’s disease, and hormone-related diseases. MAP kinase inhibitors are sought as therapeutic agents. See, e.g., United States Patent No.10,138,256 B2 and United States Patent No.11,098,061, each of which is incorporated herein by reference in its entirety. Compounds having inhibitory activity towards mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2 or MK2) have also been reported in literature for use in treating certain inflammatory disorders See, e.g., U.S. Patent Application Publication No.2016 / 0075720, U.S. Patent Application Publication No.2022 / 0251105, U.S. Patent Application Publication No. 2023 / 0255979, and international patent applications WO 2020 / 236636 and WO 2022 / 020562, each of which is incorporated herein by reference in its entirety. Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2 or MK2) has been reported in the literature to mediate multiple p38 MAPK-dependent cellular responses. See, e.g., U.S. Patent Application Publication No.2016 / 0075720, hereby incorporated herein by reference in its entirety. MK2 has also been reported to be an important intracellular regulator of the production of cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and interferon gamma (IFNγ), each of which are involved in several acute and chronic inflammatory diseases. MK2 has also been implicated in heart failure, brain ischemic injury, regulation of stress resistance, and the production of TNF-α. See, e.g., Deak et al., EMBO.17:4426-4441 (1998); Shi et al., Biol. Chem.383:1519-1536 (2002); Staklatvala., Curr. Opin. Pharmacol.4:372-377 (2004); Shiroto et al., J. Mol. Cardiol.38:93-97 (2005); Vittal et al., Am. J. Respir. Cell Mol. Biol.49: 47-57 (2013); Murgo, et al., Front. Pharmacol.14: 1303646 (2023); and Ward, et al., J. Pept. Sci.15: 668-674 (2009), each of which is incorporated here by reference in its entirety. In one aspect, provided is a method for treating a disease or condition mediated by MK2, comprising administering to a sufbject in need thereof a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e-1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-ny-2808889101 Attorney Docket No.: 308642000140 2), (I-d-1), (I-d-2), (I-e-1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, a therapeutically effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I- c-1), (I-c-2), (I-d-1), (I-d-2), (I-e-1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e-1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I- j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients is administered. In some embodiments, the subject is a human. In some embodiments, the disease or condition mediated by MK2 is an inflammatory arthropathy, a systemic condition or connective tissue disease, a neurodegenerative or neuroinflammatory disease, an inflammatory bowel disease, a skin autoimmune disorder, an autoimmune disease of the eye, a respiratory disease, or diabetes. In some embodiments, the disease or condition mediated by MK2 is a fibrotic disease. In some embodiments, the disease or condition is pulmonary fibrosis, idiopathic pulmonary fibrosis, nonalcoholic steatohepatitis (NASH), or liver fibrosis. In some embodiments, the disease or condition is pulmonary fibrosis or liver fibrosis. In some embodiments, the disease or condition is idiopathic pulmonary fibrosis. In some embodiments, the disease or condition is nonalcoholic steatohepatitis (NASH). In some embodiments, the inflammatory arthropathy is rheumatoid arthritis, juvenile arthritis, Still's disease, juvenile rheumatoid arthritis, systemic onset rheumatoid arthritis, Pauciarticular rheumatoid arthritis, Pauciarticular juvenile rheumatoid arthritis, Polyarticular rheumatoid arthritis, enteropathic arthritis, juvenile Reiter's Syndrome, ankylosing spondylitis, juvenile ankylosing spondylitis, SEA Syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, psoriatic arthritis, juvenile enteropathic arthritis, polymyalgia rheumatica,ny-2808889102 Attorney Docket No.: 308642000140 enteropathic spondylitis, Juvenile Idiopathic Arthritis (JIA), juvenile psoriatic arthritis, systemic onset juvenile rheumatoid arthritis, giant cell arteritis, or secondary osteoarthritis from inflammatory diseases. In some embodiments, the systemic condition or connective tissue disease is lupus, systemic lupus erythematosus, juvenile systemic lupus erythematosus, nephritis, Sjögren's syndrome, scleroderma (systemic sclerosis), Raynaud's phenomenon, juvenile scleroderma, polymyositis, dermatomyositis, polymyositis-dermatomyositis, polymyalgia rheumatica, mixed connective tissue disease, sarcoidosis, fibromyalgia, Vasculitis Microscopic Polyangiitis, vasculitis, eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss Syndrome), granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), polyarteritis nodosa, Henoch-Schönlein purpura, idiopathic thrombocytopenic thrombotic purpura, juvenile vasculitis, polyarteritis nodossa (also known as panarteritis nodosa, periarteritis nodosa Kussmaul disease, Kussmaul-Maier disease or PAN), serum sickness, myasthenia gravis, Takayasu's arteritis, Behçet's syndrome, Kawasaki's disease (mucocutaneous lymph node syndrome), Buerger's disease (thromboangiitis obliterans), Vogt–Koyanagi–Harada syndrome, Addison's disease, Hashimoto's thyroiditis, primary biliary sclerosis, autoimmune hepatitis, chronic aggressive hepatitis, nonalcoholic hepatic steatosis, sclerosing cholangitis, membranous glomerulopathy, polymyositis, myositis, atherosclerosis, autoimmune hemolytic anemia, autoimmune orchitis, Goodpasture's disease, chronic graft-versus-host disease, acute graft- versus-host disease, or Sjogren’s syndrome. In some embodiments, the neurodegenerative and neuroinflammatory disease is Multiple Sclerosis, Amyotropic Lateral Sclerosis, Guillain-Barre disease, Autoimmune encephalomyelitis, Alzheimer's disease, major depressive disorder, traumatic brain injury, epilepsy, Parkinson’s disease, or bipolar disorder. In some embodiments, the inflammatory bowel disease is Crohn's disease, ulcerative colitis, Celiac Sprue, Celiac diseases, proctitis, eosinophilic gastroenteritis, autoimmune atrophic gastritis of pernicious anemia, or mastocytosis. In some embodiments, the skin autoimmune disorder is psoriasis, atopic dermatitis, eczema dermatitis, dermatitis, pruritus, epidermal hyperplasia, juvenile dermatomyositis, dermatomyositis, or hidradenitis suppurativa. In some embodiments, the psoriasis is plaque psoriasis, guttate psoriasis, psoriatic epidermal hyperplasia, inverse psoriasis, pustular psoriasis, or erythrodermic psoriasis.ny-2808889103 Attorney Docket No.: 308642000140 In some embodiments, autoimmune disease of the eye is Graves' disease, noninfectious uveitis, dry eye syndrome, sympathetic ophthalmia, Cogan's syndrome, keratoconjunctivitis, vernal conjunctivitis, uveitis (including uveitis associated with Behcet's disease and lens-induced uveitis), keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, ocular neovascularization, or an ocular manifestation of another autoimmune disease. In some embodiments, the respiratory disease is asthma, chronic obstructive pulmonary disease, or acute respiratory disease. In some embodiments, the disease or condition mediated by MK2 is type I diabetes mellitus, type II diabetes mellitus, or juvenile onset diabetes. In some embodiments, the disease or condition mediated by MK2 is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis, ulcerative colitis, Crohn's disease, hidradenitis suppurativa, cryopyrin-associated periodic syndromes (CAPS), Juvenile Idiopathic Arthritis (JIA), and pancreatic cancer. In some embodiments, the disease or condition mediated by MK2 is a cancer selected from the group consisting of pancreatic cancer, colorectal cancer, multiple myeloma, lung cancer, gastric cancer, breast cancer, nasopharyngeal cancer, skin cancer, bladder cancer, prostate cancer, head and neck cancer, and glioblastoma. In some embodiments, the disease or condition mediated by MK2 is pancreatic cancer. In one aspect, provided herein is a method of inhibiting the activity of a MK2, comprising contacting a MK2 with an effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e-1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c- 2), (I-d-1), (I-d-2), (I-e-1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or any-2808889104 Attorney Docket No.: 308642000140 pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In one aspect, provided herein is a method of covalently modifying a MK2, comprising contacting a MK2 with an effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e- 1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45- 189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d- 1), (I-d-2), (I-e-1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1- 32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In one aspect, provided herein is a covalently modified MK2 formed by contacting a MK2 with an effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e-1), (I-e-2), (I- f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e-1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In one aspect, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e- 1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45- 189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt ofny-2808889105 Attorney Docket No.: 308642000140 any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d- 1), (I-d-2), (I-e-1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1- 32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in the treatment of a disease or condition mediated by MK2. In one aspect, provided herein is the use of a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e- 1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45- 189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d- 1), (I-d-2), (I-e-1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1- 32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, in the manufacture a medicament for the treatment of a disease or condition mediated by MK2. KITS The present disclosure further provides kits for carrying out the methods disclosed herein. The kits may comprise a compound or pharmaceutically acceptable salt thereof as described herein and suitable packaging. The kits may comprise one or more containers comprising any compound described herein. In one aspect, a kit includes a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a label and / or instructions for use of the compound in the treatment of a disease or disorder described herein. The kits may comprise a unit dosage form of the compound. Provided herein are kits, comprising (i) an effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e-1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1- 32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceuticallyny-2808889106 Attorney Docket No.: 308642000140 acceptable salt of any of the foregoing, and (ii) instructions for use in treating an MK2-mediated disease, disorder, or condition in an individual in need thereof. Also provided herein are kits, comprising (i) a pharmaceutical composition comprising an effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c- 1), (I-c-2), (I-d-1), (I-d-2), (I-e-1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (ii) instructions for use in treating an MK2-mediated disease, disorder, or condition in an individual in need thereof. In some embodiments, the individual is a human. Provided herein are kits, comprising (i) a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e- 1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45- 189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an MK2-mediated disease, disorder, or condition in an individual in need thereof. Also provided herein are kits, comprising (i) a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e- 1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45- 189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (ii) instructions for use in treating an MK2- mediated disease, disorder, or condition in an individual in need thereof. In some embodiments, the individual is a human. Articles of manufacture are also provided, wherein the article of manufacture comprises a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e-1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I- n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. Also provided herein are articles of manufacture,ny-2808889107 Attorney Docket No.: 308642000140 comprising a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (I-a-1), (I-a-2), (I-b-1), (I-b-2), (I-c-1), (I-c-2), (I-d-1), (I-d-2), (I-e-1), (I-e-2), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-m), (I-n), (I-o), a compound selected from the compounds enumerated in Table 1, a compound selected from compounds 1-32, 34-43, and 45-189 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag. METHODS OF PREPARING Provided herein are processes of preparing a compound of formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing. The following synthetic methods, along with those that are detailed in the Schemes and Examples, are merely illustrative of some of the methods by which the compounds of the present disclosure, or an embodiment or aspect thereof, can be synthesized. Various modifications to these synthetic reaction schemes can be made, as will be apparent to those of ordinary skill in the art. Although certain exemplary embodiments are depicted and described herein, the compounds of the present disclosure, or any variation or embodiment thereof, may be prepared using appropriate starting materials according to the methods described generally herein and / or by methods available to one of ordinary skill in the art. When a specific stereoisomer, or an unspecified stereoisomer, or a mixture of stereoisomers is shown in the following general procedures, it is understood that similar chemical transformations can be performed on other specific stereoisomers, or an unspecified stereoisomer, or mixtures thereof. Where specific reagents or solvents are specified for reactions in the general procedures, the skilled artisan will recognize that other reagents or solvents can be substituted as desired. General Procedure 1ny-2808889108 Attorney Docket No.: 308642000140 To a solution of core (1.0 eq) and warhead (1.5 eq) in DMSO (20 volumes) was added Ag2CO3or Cs2CO3(3.0 eq) at 25°C. The reaction mixture was stirred 80 °C for multiple hours and monitored by LCMS. After the core was completely consumed and a major peak with desired m / z was detected, the reaction solution was cooled to 20oC and then poured into MeOH (100 volumes). The quenched reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove most of the solvents. The solution was slowly added into ice water (50 volumes) and the solid that precipitated out was collected by filtration. The solid cake was purified by column (SiO2, DCM / MeOH=1:0 to 10:1) and prep-TLC (EtOAc / MeOH = 10 :1). The products were obtained as a tan to off-white solids. General Procedure 2 To a solution of core (1.0 eq) in DMSO (20 volumes) were added warhead (1.5 eq) and Cs2CO3(3.0 eq) at 20 °C. Then the resulting mixture was stirred at 50 °C until the LCMS showed complete consumption of starting materials and a new peak with desired m / z was detected. The reaction mixture was treated with water (20 volumes) and extracted with ethyl acetate (3 X 10 volumes). The combined organic phase was washed with brine (10 volumes), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-TLC (petroleum ether: ethyl acetate: NH3H2O = 10:1:0.1) to afford the product as tan to off-white solids.ny-2808889109 Attorney Docket No.: 308642000140 General procedure 3: To a solution of core (1.0 eq) in 1,4-dioxane (10 volumes) were added warhead (1.2 eq), Xantphos (0.2 eq), Pd2(dba)3 (0.1 eq) and Cs2CO3 (3 eq) at 25°C. The reaction mixture was stirred 100°C until LCMS showed complete consumption of the core and peaks with desired m / z were detected. The suspension was filtered through a pad of silica gel and the filter cake was washed with ethyl acetate (3 X 20 volumes). The combined organics were washed with H2O (10 volumes) and saturated aqueous NaCl (10 volumes), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 0 / 1) to afford the final products (sometimes regioisomeric products based on the chloro groups displaced) as tan to off-white solids. Enumerated Embodiments Enumerated Embodiment 1. A compound of formula (I): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: L is -C(R17)(R18)-, -C(O)-, -O-, -NR10-, or -S(O)n-; R1and R2are independently H, D, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, or C2-4 haloalkynyl, wherein the C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, and C2-4 haloalkynyl are independently optionally substituted with -OR10or -N(R10)(R10); orny-2808889110 Attorney Docket No.: 308642000140 R1and R2are taken together with the carbon atom to which they are attached to form a C3-6 cycloalkyl or a 4-6 membered heterocyclyl, wherein the C3-6 cycloalkyl and 4-6 membered heterocyclyl are optionally substituted with one or more R2a; R3and R4are independently H, D, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, C2-4 haloalkynyl, -OR10, -N(R10)(R10), C3-6 cycloalkyl, or 4-6 membered heterocyclyl, wherein the C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, and C2-4haloalkynyl are independently optionally substituted with -OR10, -N(R10)(R10), C3- 6cycloalkyl, or 4-6 membered heterocyclyl, and the C3-6cycloalkyl and the 4-6 membered heterocyclyl of R3and R4are optionally substituted with one or more R4a; or R3and R4are taken together with the carbon atom to which they are attached to form a C3-6cycloalkyl or a 3-6 membered heterocyclyl, wherein the C3-6cycloalkyl or the 3-6 membered heterocyclyl are optionally substituted with one or more R4a; R5is H, C1-2 alkyl, C1-2 haloalkyl, or C3-5 cycloalkyl; R6is H, C1-2 alkyl, C1-2 haloalkyl, or C3-5 cycloalkyl; R7is 5-6 membered heteroaryl or partially unsaturated 8-14 membered heterocyclyl, wherein a carbon atom adjacent to a heteroatom on the 5-6 membered heteroaryl or 8-14 membered heterocyclyl is substituted by R8, the 5-6 membered heteroaryl is optionally further substituted with one or more R9, and the 8-14 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of oxo and R9; R8is halo or -S(O)n(R13); each R9is independently halo, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, C2-4 haloalkynyl, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), -O- C(O)-R12, -C(O)-R12, -S(O)n(R12), C3-6cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein the C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, and C2-4 haloalkynyl are independently optionally substituted with one or more R9a;ny-2808889111 Attorney Docket No.: 308642000140 the C3-6cycloalkyl and 4-6 membered heterocyclyl are independently optionally substituted with one or more R9b; and the phenyl and 5-6 membered heteroaryl are each independently optionally substituted with one or more R9c; each R9ais independently D, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), - C(O)-R12, -S(O)n(R12), C3-6 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-6 membered heteroaryl, wherein, the C3-6cycloalkyl is optionally substituted by one or more R14, and the 4-10 membered heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of oxo and R14; each R9bis independently halo, -OR10, -N(R10)(R10), C1-4alkyl, C1-4haloalkyl, or oxo; or each R9cis independently halo, -CN, -OR10, -N(R10)(R10), C1-4 alkyl, or C1-4 haloalkyl; each R10is independently H, C1-4alkyl, C1-4haloalkyl, or C3-4cycloalkyl; wherein the C1-4alkyl or C1-4haloalkyl is optionally substituted by one or more R10a, and the C3-4 cycloalkyl is optionally substituted by one or more R10b; and each R10ais independently D, -OR14, or C3-4 cycloalkyl; each R2a, R4a, and R10bis independently halo, C1-4alkyl, C1-4haloalkyl, C1-4alkyl-(OR14), C1-4haloalkyl-(OR14), -OR14, or -N(R14)(R14); X is N, or CR11; R11is H, halo, C1-4alkyl, C1-4haloalkyl, or -CN; each R12is independently C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, C2-4 haloalkynyl, C3-6 cycloalkyl, -OR14, or -N(R14)(R14); R13is C1-4alkyl or C1-4haloalkyl; each R14is independently H, C1-4alkyl, or C1-4haloalkyl; n is independently at each occurrence 0, 1, or 2; indicates a single or double bond, wherein when is a single bond, p and q are each 2, andny-2808889112 Attorney Docket No.: 308642000140 when is a double bond, p and q are each 1; each R15and R16are independently H, D, or C1-4 alkyl; R17is H, -CH3, -CF3, halo, or -OH; and R18is H, -CH3, -CF3, or halo, or R17and R18are taken together with the carbon to which they are attached to form a cyclopropyl. Enumerated Embodiment 2. The compound of Enumerated Embodiment 1, wherein: R5is H or C1-2 alkyl; R6is H or C1-2alkyl; each R9ais independently D, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), - C(O)-R12, -S(O)n(R12), C3-6 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-6 membered heteroaryl, wherein the 4-10 membered heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of oxo and R14; and each R4ais C1-4 alkyl. Enumerated Embodiment 3. The compound of Enumerated Embodiment 1 or 2, wherein the compound is a compound of formula (I-a-1): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is -C(R17)(R18)- or -C(O)-. Enumerated Embodiment 4. The compound of Enumerated Embodiment 1 or 2, wherein the compound is a compound of formula (I-a-2):ny-2808889113 Attorney Docket No.: 308642000140 stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is -C(R17)(R18)- or -C(O)-. Enumerated Embodiment 5. The compound of Enumerated Embodiment 1 or 2, wherein the compound is a compound of formula (Ib-1): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Enumerated Embodiment 6. The compound of Enumerated Embodiment 1 or 2, wherein the compound is a compound of formula (I-b-2): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Enumerated Embodiment 7. The compound of Enumerated Embodiment 1 or 2, wherein the compound is a compound of formula (I-c-1):ny-2808889114 Attorney Docket No.: 308642000140 stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Enumerated Embodiment 8. The compound of Enumerated Embodiment 1 or 2, wherein the compound is a compound of formula (I-c-2): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Enumerated Embodiment 9. The compound of Enumerated Embodiment 1 or 2, wherein the compound is a compound of formula (I-d-1): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Enumerated Embodiment 10. The compound of Enumerated Embodiment 1 or 2, wherein the compound is a compound of formula (I-d-2):ny-2808889115 Attorney Docket No.: 308642000140 stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Enumerated Embodiment 11. The compound of any of Enumerated Embodiments 1-4, or a pharmaceutically acceptable salt thereof, wherein L is -C(R17)(R18)-, -O-, or -NR10-. Enumerated Embodiment 12. The compound of any of Enumerated Embodiments 1-4 or 11, or a pharmaceutically acceptable salt thereof, wherein L is -CH2-, -CHF-, -CF2-, -O-, -N(H)-, or -N(C1-4alkyl)-.. Enumerated Embodiment 13. The compound of any of Enumerated Embodiments 1-4, 11, or 12, or a pharmaceutically acceptable salt thereof, wherein In some embodiments, L is -O-, -N(H)-, or -N(C1-4alkyl)-. Enumerated Embodiment 14. The compound of any of Enumerated Embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein R1and R2are H, or R1and R2are taken together with the carbon atom to which they are attached to form a C3-6 cycloalkyl or a 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more R2a. Enumerated Embodiment 15. The compound of any of Enumerated Embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein R1and R2are H, or R1and R2are taken together with the carbon atom to which they are attached to form a C3-6cycloalkyl or a 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with C1-4alkyl. Enumerated Embodiment 16. The compound of any of Enumerated Embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein R1and R2are H, or R1and R2are taken together with the carbon atom to which they are attached to form a cyclopropyl or N-methylazetidinyl.ny-2808889116 Attorney Docket No.: 308642000140 Enumerated Embodiment 17. The compound of any of Enumerated Embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein R1and R2are each H. Enumerated Embodiment 18. The compound of any of Enumerated Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein: R3and R4are independently H, C1-4 alkyl, or C1-4 haloalkyl, or R3and R4are taken together with the carbon atom to which they are attached to form a C3-6cycloalkyl or a 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl is optionally substituted with one or more R4a. Enumerated Embodiment 19. The compound of any of Enumerated Embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein: R3and R4are independently H, C1-4alkyl, or C1-4haloalkyl, or R3and R4are taken together with the carbon atom to which they are attached to form a C3-6cycloalkyl or a 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl is optionally substituted with C1-4alkyl. Enumerated Embodiment 20. The compound of any of Enumerated Embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein: R3and R4are independently H, -CH3, or -CF3, or R3and R4are taken together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, or N-methylazetidinyl. Enumerated Embodiment 21. The compound of any of Enumerated Embodiments 1 or 3- 20, or a pharmaceutically acceptable salt thereof, wherein R5is H, C1-2 alkyl, or C1-2 haloalkyl. Enumerated Embodiment 22. The compound of any of Enumerated Embodiments 1 or 3- 21, or a pharmaceutically acceptable salt thereof, wherein R5is H, -CH3, -CH2CH3, -CH2CF3, or -CH2CF2H. Enumerated Embodiment 23. The compound of any of Enumerated Embodiments 1 or 3- 22, or a pharmaceutically acceptable salt thereof, wherein R6is H, C1-2alkyl, or C1-2haloalkyl.ny-2808889117 Attorney Docket No.: 308642000140 Enumerated Embodiment 24. The compound of any of Enumerated Embodiments 1 or 3- 23, or a pharmaceutically acceptable salt thereof, wherein R6is H, -CH3, -CH2CH3, -CH2CF3, or -CH2CF2H. Enumerated Embodiment 25. The compound of any of Enumerated Embodiments 1-24, or a pharmaceutically acceptable salt thereof, wherein R5and R6are each H. Enumerated Embodiment 26. The compound of any of Enumerated Embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R5, and R6are each H. Enumerated Embodiment 27. The compound of any of Enumerated Embodiments 1-26, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, and R6are each H. Enumerated Embodiment 28. The compound of any of Enumerated Embodiments 1-27, or a pharmaceutically acceptable salt thereof, wherein R7is a 5-6 membered heteroaryl substituted by R8and optionally substituted with one or more R9. Enumerated Embodiment 29. The compound of any of Enumerated Embodiments 1-28, or a pharmaceutically acceptable salt thereof, wherein R7is a 5-membered heteroaryl substituted by R8and optionally substituted with one or more R9. Enumerated Embodiment 30. The compound of any of Enumerated Embodiments 1-29, wherein R7is pyrazolyl, oxazolyl, or thiazolyl, wherein the pyrazolyl, oxazolyl, or thiazolyl is substituted by R8and optionally substituted with one or more R9. Enumerated Embodiment 31. The compound of any of Enumerated Embodiments 1-28, or a pharmaceutically acceptable salt thereof, wherein R7is a 6-membered heteroaryl substituted by R8and optionally substituted with one or more R9. Enumerated Embodiment 32. The compound of any of Enumerated Embodiments 1-28 or 31, or a pharmaceutically acceptable salt thereof, wherein R7is pyrimidinyl substituted by R8and optionally substituted with one or more R9. Enumerated Embodiment 33. The compound of any of Enumerated Embodiments 1-28, or 31, or a pharmaceutically acceptable salt thereof, wherein R7is pyridinyl, wherein the pyridinyl is substituted by R8and optionally substituted with one or more R9.ny-2808889118 Attorney Docket No.: 308642000140 Enumerated Embodiment 34. The compound of any of Enumerated Embodiments 1-27, or a pharmaceutically acceptable salt thereof, wherein R7is a 8-14 membered heterocyclyl substituted by R8and optionally substituted with one or more R9. Enumerated Embodiment 35. The compound of any of Enumerated Embodiments 1-27 or 34, or a pharmaceutically acceptable salt thereof, wherein R7is 5,6,7,8-tetrahydropyrido[4,3- d]pyrimidinyl, wherein the 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine is substituted by R8and optionally substituted with one or more R9. Enumerated Embodiment 36. The compound of any of Enumerated Embodiments 1-35, or a pharmaceutically acceptable salt thereof, wherein R8is halo. Enumerated Embodiment 37. The compound of any of Enumerated Embodiments 1-36, or a pharmaceutically acceptable salt thereof, wherein R8is Cl or F. Enumerated Embodiment 38. The compound of any of Enumerated Embodiments 1-37, or a pharmaceutically acceptable salt thereof, wherein R8is Cl. Enumerated Embodiment 39. The compound of any of Enumerated Embodiments 1-38, or a pharmaceutically acceptable salt thereof, wherein R9is C1-4 alkyl optionally substituted by one or more R9a. Enumerated Embodiment 40. The compound of any of Enumerated Embodiments 1-39, wherein R9ais -CN, -OR10, -C(O)-R12, -S(O)2-(R12), C3-6 cycloalkyl, or 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl is optionally substituted by one of more substituents selected from the group consisting of oxo and -CH3. Enumerated Embodiment 41. The compound of any of Enumerated Embodiments 1-40, wherein R9ais -CN, -OH, -O(C1-4 alkyl), -O(C1-4 haloalkyl), -O(C3-6 cycloalkyl), -O(4-6 membered heterocyclyl), -C(O)-(C3-6cycloalkyl), -C(O)-[N(C1-4alkyl)(C1-4alkyl)], -S(O)2-(C1-4alkyl), -S(O)2-N(C1-4alkyl)(C1-4alkyl), C3-6cycloalkyl, or 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl is optionally substituted by one of more substituents selected from the group consisting of oxo and -CH3.ny-2808889119 Attorney Docket No.: 308642000140 Enumerated Embodiment 42. The compound of any of Enumerated Embodiments 1-41, wherein R9ais selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholino, isothiazolidinyl, and 5-azaspiro[2.4]heptanyl. Enumerated Embodiment 43. The compound of any of Enumerated Embodiments 1-39, wherein R9is C1-4 alkyl. Enumerated Embodiment 44. The compound of any of Enumerated Embodiments 1-39 or 43, wherein R9is -CH3. Enumerated Embodiment 45. The compound of any of Enumerated Embodiments 1-38, or a pharmaceutically acceptable salt thereof, wherein R9is C3-6 cycloalkyl optionally substituted by one or more R9b. Enumerated Embodiment 46. The compound of any of Enumerated Embodiments 1-38 or 45, or a pharmaceutically acceptable salt thereof, wherein R9is cyclopropyl. Enumerated Embodiment 47. The compound of any of Enumerated Embodiments 1-29, 32 or 33, wherein Enumerated Embodiment 48. The compound of any of Enumerated Embodiments 1-27 or 34-38, wherein optionally substituted by 1, 2, or 3 R9groups. Enumerated Embodiment 49. The compound of any of Enumerated Embodiments 1-27 or 34-38, wherein optionally substituted by 1 or 2 R9groups.ny-2808889120 Attorney Docket No.: 308642000140 Enumerated Embodiment 50. The compound of any of Enumerated Embodiments 1-27, or a pharmaceutically acceptable salt thereof, wherein R7is selected from the group consisting of: ny-2808889121 Attorney Docket No.: 308642000140 Enumerated Embodiment 51. The compound of any of Enumerated Embodiments 1, 2, 4, 6, 8, or 10-50, or a pharmaceutically acceptable salt thereof, wherein X is CR11. Enumerated Embodiment 52. The compound of Enumerated Embodiment 51, or a pharmaceutically acceptable salt thereof, wherein R11is H or halo.ny-2808889122 Attorney Docket No.: 308642000140 Enumerated Embodiment 53. The compound of Enumerated Embodiment 51 or 52, or a pharmaceutically acceptable salt thereof, wherein R11is H or F. Enumerated Embodiment 54. The compound of any of Enumerated Embodiments 1-3, 5, 7, 9, 11 or 11-50, or a pharmaceutically acceptable salt thereof, wherein X is N. Enumerated Embodiment 55. A compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from Table 1. Enumerated Embodiment 56. A pharmaceutical composition comprising a compound of any of Enumerated Embodiments 1-55, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. Enumerated Embodiment 57. A method for treating a disease or condition mediated by MK2, comprising administering to a subject in need thereof a compound of any of Enumerated Embodiments 1-55, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of Enumerated Embodiment 56. Enumerated Embodiment 58. The method of Enumerated Embodiment 57, wherein a therapeutically effective amount of the compound is administered. Enumerated Embodiment 59. The method of Enumerated Embodiment 57 or 58, wherein said disease or condition mediated by MK2 is an inflammatory disorder. Enumerated Embodiment 60. The method of Enumerated Embodiment 57 or 58, wherein said disease or condition mediated by MK2 is ankylosing spondylitis, rheumatoid arthritis, psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn’s disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren’s syndrome, scleroderma, ulcerative colitis, asthma, uveitis, psoriatic arthritis, hidradenitis suppurativa, cryopyrin-associated periodic syndromes, or juvenile idiopathic arthritis.ny-2808889123 Attorney Docket No.: 308642000140 Enumerated Embodiment 61. The method of Enumerated Embodiment 57 or 58, wherein said disease or condition mediated by MK2 is ankylosing spondylitis, rheumatoid arthritis, psoriasis, Crohn’s disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren’s syndrome, scleroderma, ulcerative colitis, or asthma. Enumerated Embodiment 62. The method of Enumerated Embodiment 57 or 58, wherein said disease or condition mediated by MK2 is rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis, ulcerative colitis, Crohn’s disease, hidradenitis suppurativa, cryopyrin-associated periodic syndromes, or juvenile idiopathic arthritis. Enumerated Embodiment 63. The method of Enumerated Embodiment 57 or 58, wherein said disease or condition mediated by MK2 is a cancer selected from pancreatic cancer, colorectal cancer, multiple myeloma, lung cancer, gastric cancer, breast cancer, nasopharyngeal cancer, skin cancer, bladder cancer, prostate cancer, head and neck cancer, or glioblastoma. Enumerated Embodiment 64. The method of Enumerated Embodiment 57 or 58, wherein said disease or condition mediated by MK2 is pancreatic cancer. Enumerated Embodiment 65. The method of any of Enumerated Embodiments 57-64, wherein the subject is a human. Enumerated Embodiment 66. A method of inhibiting the activity of a MK2, comprising contacting a MK2 with an effective amount of a compound of any of Enumerated Embodiments 1-55, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Enumerated Embodiment 67. A method of covalently modifying a MK2, comprising contacting a MK2 with an effective amount of a compound of any of Enumerated Embodiments 1-55, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Enumerated Embodiment 68. A covalently modified MK2 formed by the method of Enumerated Embodiment 67.ny-2808889124 Attorney Docket No.: 308642000140 Enumerated Embodiment 69. The compound of any of Enumerated Embodiments 1-55, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Enumerated Embodiment 56 for use in the treatment of a MK2- mediated disease or disorder. Enumerated Embodiment 70. Use of a compound of any of Enumerated Embodiments 1- 55, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Enumerated Embodiment 56 in the manufacture of a medicament for the treatment of a disease or disorder mediated by MK2. Enumerated Embodiment 71. A kit, comprising (i) a compound of any one of Enumerated Embodiments 1-55, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Enumerated Embodiment 56, and (ii) instructions for use in treating an MK2-mediated disease or condition in an individual in need thereof. EXAMPLES The following synthetic reaction schemes, which are detailed in the Schemes and Examples, are merely illustrative of some of the methods by which the compounds of the present disclosure, or an embodiment or aspect thereof, can be synthesized. Various modifications to these synthetic reaction schemes can be made, as will be apparent to those of ordinary skill in the art. The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data. Although certain exemplary embodiments are depicted and described herein, the compounds of the present disclosure, or any variation or embodiment thereof, may be prepared using appropriate starting materials according to the methods described generally herein and / or by methods available to one of ordinary skill in the art. Synthetic Examplesny-2808889125 Attorney Docket No.: 308642000140 As depicted in the Schemes and Examples below, in certain exemplary embodiments, compounds of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are prepared according to the general procedures. The general methods below, and other methods known to synthetic chemists of ordinary skill in the art, can be applied to all formulae, embodiments, and species described herein. Example 1 – Synthesis of 2-((2-chloro-5-((methylsulfonyl)methyl)pyrimidin-4-yl)oxy)- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (Compound 1) Step 1. Preparation of 4-hydroxy-5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca- 1(10),2, 4,6,11(16)-pentaen-12-one. A solution of tert-butyl 4-chloro-12-oxo-5,13,17- triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2,4,6,11(16)-pentaene-13-carboxylate (0.1 g, 1 eq, 267 µmol) in water (1 mL) and acetic acid (3 mL) was heated to 145 ℃ and stirred at 145 ℃ for 6 hours under microwave condition. LCMS showed starting material peak was consumed, and the desired peak was detected. Four additional vials were set up as described above. After cooling to 25 ℃, five reaction mixtures were combined and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (ethyl acetate / methyl alcohol = 1 / 1, Rf = 0.3) to afford 0.2 g (58.58%) of 4-hydroxy-5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca- 1(10),2, 4,6,11(16)-pentaen-12-one as a brown solid. LCMS (ESI+): Rt = 0.427 min, m / z 256.2 (M+H)+. Step 2. Preparation of 2-((2-chloro-5-((methylsulfonyl)methyl)pyrimidin-4-yl)oxy)- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one. To a solution of 4-hydroxy-5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2,4,6,11(16)-pentaen-12- one (50 mg, 1 eq, 196 µmol) in dimethyl sulfoxide (1 mL) was added 2,4-dichloro-5-(mesyl- methyl)pyrimidine (47.2 mg, 1 eq, 196 µmol) and cesium carbonate (128 mg, 2 eq, 392 µmol) atny-2808889126 Attorney Docket No.: 308642000140 25 ℃. The resulting mixture was stirred at 25 ℃ for 1 hour. LCMS showed starting material peak was consumed and the desired peak was detected. Two additional vials were set up as described above. All three reaction mixtures were combined and filtered, and the filtrate was purified by prep-HPLC to afford 35 mg (12.95%) of Compound 1 as a white solid. LCMS (ESI+): Rt = 1.304 min, m / z = 460.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) 11.92 (s, 1H), 8.72 (s, 1H), 8.09 (s, 1H), 7.13 (s, 1H), 7.06 (br s, 1H), 4.71 (s, 2H), 3.39 (br d, J = 2.0 Hz, 2H), 3.15 (s, 3H), 2.90 (br dd, J = 6.3, 14.6 Hz, 4H), 2.81 (br t, J = 6.8 Hz, 2H). Example 2 – Synthesis of 2-((4-chloro-5-((methylsulfonyl)methyl)pyrimidin-2-yl)oxy)-1- fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (Compound 2) and 2-((2-chloro-5-((methylsulfonyl)methyl)pyrimidin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (Compound 3) Step 1. Preparation of 3-fluoro-4-hydroxy-5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶] heptadeca-1(10),2,4,6,11(16)-pentaen-12-one. A solution of tert-butyl 4-chloro-3-fluoro-12- oxo-5,13,17-triazatetracyclo [8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2,4,6,11(16)-pentaene-13- carboxylate (0.1 g, 1 eq, 255 µmol) in water (1 mL) and acetic acid (3 mL) was heated to 130 ℃ and stirred at 130 ℃ for 6 hours under microwave conditions. LCMS showed the starting material was consumed and the desired peak was detected. Two additional vials were set up as described above. After cooling to 20 ℃, all three reaction mixtures were combined and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLCny-2808889127 Attorney Docket No.: 308642000140 to give 45 mg (11.61%) of 3-fluoro-4-hydroxy-5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶] heptadeca-1(10),2,4,6,11(16)-pentaen-12-one as a white solid. LCMS (ESI+): Rt = 0.805 min, m / z 274.0 (M+H)+. Step 2. Preparation of 2-((4-chloro-5-((methylsulfonyl)methyl)pyrimidin-2-yl)oxy)- 1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one and 2- ((2-chloro-5-((methylsulfonyl)methyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one. To a solution of 3-fluoro-4-hydroxy- 5,13,17-triazatetracyclo [8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2,4,6,11(16)-pentaen-12-one (15 mg, 1 eq, 54.9 µmol) and 2,4-dichloro-5-(mesylmethyl)pyrimidine (13.2 mg, 1 eq, 54.9 µmol) in dimethyl sulfoxide (1.5 mL) was added cesium carbonate (35.8 mg, 2 eq, 110 µmol) at 25 ℃. The resulting mixture was stirred at 25 ℃ for 1 hour. LCMS showed starting material was consumed and two peaks with desired mass were detected. Two additional vials were set up as described above. All three reaction mixtures were combined and filtered. The filtrate was purified by prep-HPLC to afford 2 mg (2.38%) of Compound 2 as a light yellow solid and 7 mg (7.95%) of Compound 3. Compound 2: LCMS: Rt = 2.107 min, 89.33% purity, m / z = 477.9 (M+H)+.1H NMR (400 MHz, DMSO-d6) 11.66 (s, 1H), 8.79 - 8.75 (m, 1H), 8.00 (s, 1H), 7.12 (br s, 1H), 4.76 (s, 2H), 3.40 - 3.36 (m, 2H), 3.15 (s, 3H), 2.98 - 2.93 (m, 4H), 2.83 (t, J = 6.8 Hz, 2H). Compound 3: LCMS (ESI+): Rt = 1.159 min, 1.213 min, m / z 478.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) 11.66 (s, 1H), 9.03 (s, 1H), 7.49 (s, 1H), 7.16 (br s, 1H), 4.86 - 4.43 (m, 2H), 3.44 - 3.35 (m, 2H), 3.00 (s, 3H), 2.97 - 2.83 (m, 4H), 2.79 - 2.63 (m, 2H).ny-2808889128 Attorney Docket No.: 308642000140 Example 3 – Synthesis of 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7- one (Compound 6) Step 1. Preparation of 3-fluoro-4-hydroxy-5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶] heptadeca-1(10),2,4,6,11(16)-pentaen-12-one. To a solution of tert-butyl 4-chloro-3-fluoro-12- oxo-5,13,17-triazatetracyclo [8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2,4,6,11(16)-pentaene-13- carboxylate (0.2 g, 1 eq, 510 µmol) in dioxane (2 mL) and water (2 mL) was added bis(tert- butyl)[2',4',6'-tris(isopropyl)-2-biphenylyl]phosphine (65 mg, 0.3 eq, 153 µmol), palladium— (1E,4E)-1,5-diphenyl-1,4-pentadien-3-one (2 / 3) (140 mg, 0.3 eq, 153 µmol), and potassium hydroxide (286 mg, 10 eq, 5.1 mmol) at 25 ℃. The reaction mixture was heated to 90 ℃ and stirred at 90 ℃ for 0.5 hour. LCMS showed starting material was consumed and the desired mass was detected. Three additional vials were set up as described above. After cooling to 20 ℃, all four reaction mixtures were combined, diluted with water (20 mL), and extracted with ethyl acetate (10 mL). The solid was formed in the aqueous phase, and the aqueous phase was filtered. The filter cake was dried under reduced pressure to give a residue. The residue was triturated with ethyl acetate (30 mL) and filtered. The filter cake was dried under reduced pressure to afford 220 mg (39.43%) of 3-fluoro-4-hydroxy-5,13,17-triazatetracyclo [8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2,4,6,11(16)-pentaen-12-one as a grey solid. LCMS (ESI+): Rt = 0.220 min, m / z 274.0 (M+H)+.ny-2808889129 Attorney Docket No.: 308642000140 Step 2. Preparation of tert-butyl 2-chloro-4-((1-fluoro-7-oxo-6,7,8,9,10,11- hexahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-2-yl)oxy)-7,8-dihydropyrido[4,3-d] pyrimidine-6(5H)-carboxylate. To a solution of 3-fluoro-4-hydroxy-5,13,17-triazatetracyclo [8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2(7),3,5,11(16)-pentaen-12-one (90 mg, 1 eq, 329 µmol) in dimethyl sulfoxide (1 mL) was added tert-butyl 2,4-dichloro-5,6,7,8-tetrahydro-1,3,6-triaza-6- naphthoate (130 mg, 1.3 eq, 428 µmol) and potassium carbonate (137 mg, 3 eq, 988 µmol) at 25 ℃. The reaction mixture was heated to 30 ℃ and stirred at 30 ℃ for 4 hours. LCMS showed starting material was consumed and two peaks with desired mass were detected. After cooling to 25 ℃, all three reaction mixtures were combined and diluted with water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The organic phase was combined, washed with brine (30 mL), and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (eluting with petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to afford 250 mg of crude product, which was further purified by prep-HPLC to afford 30 mg of tert-butyl 2-chloro-4-((1- fluoro-7-oxo-6,7,8,9,10,11-hexahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-2-yl)oxy)- 7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate as a white solid. LCMS (ESI+): Rt = 0.651 min, 0.710 min, m / z 541.0 (M+H)+. Step 3. Preparation of 2-((2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7- one. To tert-butyl 2-chloro-4-((1-fluoro-7-oxo-6,7,8,9,10,11-hexahydro-5H-pyrido[3',4':4,5] pyrrolo[2,3-f]isoquinolin-2-yl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.2 g, 1 eq, 370µmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL)at 25 ℃. The reaction mixture was stirred at 25 ℃ for 1 hour. LCMS showed starting material was consumed and the desired peak was detected. The reaction mixture was concentrated under reduced pressure to afford 200 mg (crude) of 2-((2-chloro-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one as a yellow oil. LCMS (ESI+): Rt = 0.293 min, m / z 441.0 (M+H)+. Step 4. Preparation of 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one. To 2-((2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1- fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (0.2 g, crude) in methanol (2 mL, 49.4 mmol) was added formaldehyde 37% (w / w) (44.2 mg, 1.2 eq,ny-2808889130 Attorney Docket No.: 308642000140 544 µmol) and sodium boranuidcarbonitrile (57 mg, 2 eq, 907 µmol) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 1 hour. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC to afford 55 mg of Compound 6 as a white solid. LCMS (ESI+): Rt = 0.373 min, 0.412 min, m / z 455.0 (M+H)+.1H NMR (400 MHz, CDCl3) 9.03 (br dd, J = 1.9, 8.3 Hz, 1H), 7.89 (s, 1H), 5.37 (br s, 1H), 3.72 (s, 2H), 3.66 - 3.59 (m, 2H), 3.21 - 3.14 (m, 2H), 3.07 - 3.01 (m, 2H), 3.01 - 2.90 (m, 4H), 2.85 (t, J = 5.8 Hz, 2H), 2.57 (s, 3H). Example 4 – Synthesis of 2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (Compound 4) Step 1. Preparation of tert-butyl 4-(2-chloro-5-fluoro-4-pyrimidinylamino)-3-fluoro- 12-oxo-17-{[2-(trimethylsilyl)ethoxy]methyl}-5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶] heptadeca-1(10),2(7),3,5,11(16)-pentaene-13-carboxylate. To a solution of tert-butyl 4- chloro-3-fluoro-12-oxo-17-{[2-(trimethylsilyl)ethoxy]methyl}-5,13,17-triazatetracyclo [8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2,4,6,11(16)-pentaene-13-carboxylate (0.2 g, 383 µmol) in 1,4- dioxane (4 mL, 46.9 mmol) was added 2-chloro-5-fluoro-4-pyrimidinylamine (56.5 mg, 383 µmol), dicaesium carbonate (374 mg, 3 eq, 1.15 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethyl-9H-xanthene (44.3 mg, 0.2 eq, 76.6 µmol), and palladium—(1E,4E)-1,5-diphenyl-1,4- pentadien-3-one (2 / 3) (70.2 mg, 0.2 eq, 76.6 µmol) at 20 ℃ under nitrogen. The mixture was heated to 100 ℃ and stirred at 100 ℃ for 12 hours. LCMS showed the starting material was consumed completely and the desired mass was detected. Four vials were set up as described above. After cooling to 20 ℃, all five reaction mixtures were combined, diluted with water (50 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gelny-2808889131 Attorney Docket No.: 308642000140 (eluting with petroleum ether / ethyl acetate = 100 / 0 to 0 / 1) to obtain tert-butyl 4-(2-chloro-5- fluoro-4-pyrimidinylamino)-3-fluoro-12-oxo-17-{[2-(trimethylsilyl)ethoxy]methyl}-5,13,17- triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2(7),3,5,11(16)-pentaene-13-carboxylate (110 mg, 139 µmol) as a yellow solid. LCMS (ESI+): Rt= 0.472 min, m / z 503.1 / 505.1 (M+H)+. Step 2. Preparation of 2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one. A solution of tert-butyl 4-(2-chloro-5-fluoro-4-pyrimidinylamino)-3-fluoro-12-oxo-5,13,17-triazatetracyclo [8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10),2(7),3,5,11(16)-pentaene-13-carboxylate (110 mg, 0.57 eq, 219 µmol) in dichloromethane (5 mL, 78.1 mmol) and trifluoroacetic acid (0.5 mL) was stirred at 20 ℃ for 1 hour. LCMS showed the starting material was consumed completely and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (neutral condition: column: Waters Xbridge BEH C18100 × 30 mm × 10 µm; mobile phase: [A: water (10 mM ammonium bicarbonate); B: acetonitrile]; B%: 15.00% - 45.00%, 8.00 min) to give Compound 4 (25.7 mg, 60.7 µmol) as a yellow solid. LCMS (ESI+): Rt = 1.168 min, m / z 403.1 / 405.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 10.50 (br d, J = 5.8 Hz, 1H), 8.41 (d, J = 3.1 Hz, 1H), 8.07 (s, 1H), 7.10 (br s, 1H), 3.40 - 3.37 (m, 2H), 2.98 - 2.88 (m, 4H), 2.84 (t, J = 6.8 Hz, 2H). Example 5 – Synthesis of 2-((2-chloropyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (Compound 5) Step 1. Preparation of tert-butyl 4-(2-chloro-4-pyrimidinylamino)-3-fluoro-12-oxo- 17-{[2-(trimethylsilyl)ethoxy]methyl}-5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca- 1(10),2(7),3,5,11(16)-pentaene-13-carboxylate. To a solution of tert-butyl 4-chloro-3-fluoro-ny-2808889132 Attorney Docket No.: 308642000140 12-oxo-17-{[2-(trimethylsilyl)ethoxy]methyl}-5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶] heptadeca-1(10),2,4,6,11(16)-pentaene-13-carboxylate (0.2 g, 383 µmol) in 1,4-dioxane (4 mL, 46.9 mmol) was added 2-chloro-4-pyrimidinylamine (49.6 mg, 383 µmol), dicaesium carbonate (374 mg, 3 eq, 1.15 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (44.3 mg, 0.2 eq, 76.6 µmol), and palladium—(1E,4E)-1,5-diphenyl-1,4-pentadien-3-one (2 / 3) (70.2 mg, 0.2 eq, 76.6 µmol) at 20 ℃ under nitrogen. The mixture was heated to 100 ℃ and stirred at 100 ℃ for 12 hours. LCMS showed the starting material was consumed completely and the desired mass was detected. Four vials were set up as described above. After cooling to 20 ℃, all five reaction mixtures were combined, diluted with water (50 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluting with petroleum ether / ethyl acetate = 100 / 0 to 0 / 1) to obtain tert-butyl 4-(2-chloro-4-pyrimidinylamino)-3-fluoro-12-oxo-17- {[2-(trimethylsilyl)ethoxy]methyl}-5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca- 1(10),2(7),3,5,11(16)-pentaene-13-carboxylate (130 mg, 194 µmol) as a yellow solid. LCMS (ESI+): Rt = 0.512 min, m / z 485.1 / 487.1 (M+H)+. Step 2. Preparation of 2-((2-chloropyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one. A solution of tert-butyl 4-(2-chloro-4- pyrimidinylamino)-3-fluoro-12-oxo-5,13,17-triazatetracyclo [8.7.0.0²,⁷.0¹¹,¹⁶] heptadeca- 1(10),2(7),3,5,11(16)-pentaene-13-carboxylate (130 mg, 268 µmol) in trifluoroacetic acid (0.5 mL) and dichloromethane (5 mL) was stirred at 20 ℃ for 1.5 hours. LCMS showed starting material was consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to give Compound 5 (10.3 mg, 25.4 µmol) as a white solid. LCMS (ESI+): Rt= 1.284 min, m / z 385.1 / 387.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 10.46 - 10.30 (m, 1H), 8.31 (d, J = 5.9 Hz, 1H), 8.00 (s, 1H), 7.53 (d, J = 5.9 Hz, 1H), 7.09 (s, 1H), 3.40 - 3.36 (m, 2H), 2.96 - 2.90 (m, 2H), 2.90 - 2.82 (m, 4H).Example 6 – Synthesis of tert-butyl 2-chloro-1-fluoro- 7-oxo-5,6,7,9,10,11-hexahydro-8H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline-8-carboxylate (Intermediate 1)ny-2808889133 Attorney Docket No.: 308642000140 Step 1. Preparation of 5-allyl-2-chloro-3-fluoroisonicotinaldehyde. To a solution of 2-chloro-3-fluoropyridine (10 g, 76.05 mmol) in tetrahydrofuran (250 Ml) was added tert- butyllithium (5.1 g, 1.3 M, 79.85 mmol) dropwise over 15 min at -78 ℃. After stirring for 1 hour, N-[2-(dimethylamino)ethyl]-N-methyl-formamide (10.4 g, 79.85 mmol) was added slowly, and the reaction mixture was warmed to -40 ℃ and stirred for an additional10 minutes. Next, n- butyllithium (7.3 g, 1.6 M, 114.05 mmol) was added to the reaction mixture. The red-brown solution was stirred at -30 ℃ for 3 hours, and then copper(I) bromide (14.2 g, 98.85 mmol) was added. The reaction mixture was allowed to reach 0 ℃ and stirred at this temperature for 1 hour. After cooling back to -30 ℃, a solution of allyl bromide (14.7 g, 121.65 mmol) in tetrahydrofuran (150 mL) was added. The reaction mixture was stirred at -10 ℃ for 1 hour. TLC (petroleum ether:ethyl acetate = 5:1, Rf = 0.72) showed the starting material was consumed and one new spot formed. The mixture was quenched with saturated ammonium chloride (300 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~10% ethyl acetate / petroleum ether gradient @ 200 mL / min) to give 5-allyl-2-chloro-3-fluoroisonicotinaldehyde (4.8 g, yield 32%) as a yellow oil.ny-2808889134 Attorney Docket No.: 3086420001401H NMR (400 MHz, DMSO-d6) δ =3.73 (br d, J = 6.13 Hz, 2 H) 5.02 - 5.11 (m, 2 H) 5.92 - 6.05 (m, 1 H) 8.33 (s, 1 H) 10.32 (s, 1 H). Step 2. Preparation of 1-(5-allyl-2-chloro-3-fluoropyridin-4-yl)prop-2-en-1-ol. To a solution of 5-allyl-2-chloro-3-fluoroisonicotinaldehyde (28 g, 140 mmol) in tetrahydrofuran (400 mL) was added vinylmagnesium bromide (28.2 g, 1 M, 215 mmol) over 10 minutes at 0 ℃. The mixture was stirred at 0 ℃ for 2 hours. LCMS showed the starting material was consumed and a new peak with the desired mass was detected. The mixture was quenched with saturated ammonium chloride (1000 mL) and extracted with ethyl acetate (3 × 500 mL). The organic phase was washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~15% ethyl acetate / petroleum ether gradient @ 200 mL / min) to give 1-(5-allyl-2-chloro-3-fluoropyridin-4-yl)prop-2-en-1-ol (16.8 g, yield 39.45%) as a colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 2.62 (br s, 1 H) 3.33 - 3.70 (m, 2 H) 5.02 (br d, J =17.01 Hz, 1 H) 5.16 (br d, J =10.01 Hz, 1 H) 5.22 - 5.44 (m, 2 H) 5.56 (br d, J =4.63 Hz, 1 H) 5.95 (ddt, J =16.76, 10.51, 6.00, 6.00 Hz, 1 H) 6.03 - 6.21 (m, 1 H) 8.02 (s, 1 H). Step 3. Preparation of 3-chloro-4-fluoro-5,8-dihydroisoquinolin-5-ol. To a solution of 1-(5-allyl-2-chloro-3-fluoropyridin-4-yl)prop-2-en-1-ol (3.1 g, 13.62 mmol) in dichloromethane (140 mL) was added benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin- 2-ylidene]-dichloro-ruthenium;tricyclohexylphosphane (578.01 mg, 680.83 μmol). The mixture was stirred at 15 ℃ for 3 hours. LCMS showed the starting material was consumed and one major peak with the desired mass was detected. The mixture was filtered and concentrated under vacuum to give a residue, which was purified by flash silica gel chromatography (ISCO®; 200 g SepaFlash® Silica Flash Column, Eluent of 0~15%, petroleum ether gradient / ethyl acetate @ 200 mL / min) to give 3-chloro-4-fluoro-5,8-dihydroisoquinolin-5-ol (2.3 g, yield 84.62%) as a green solid.1H NMR (400 MHz, CDCl3) δ ppm 2.57 (br d, J =5.75 Hz, 1 H) 3.31 - 3.60 (m, 2 H) 5.47 (br s, 1 H) 6.06 - 6.16 (m, 1 H) 6.17 - 6.26 (m, 1 H) 8.12 (s, 1 H). Step 4. Preparation of 3-chloro-4-fluoro-5,6,7,8-tetrahydroisoquinolin-5-ol. To a solution of 3-chloro-4-fluoro-5,8-dihydroisoquinolin-5-ol (13.2 g, 66.1 mmol) in methanol (400 mL) was added platinum dioxide (1.32g, 5.81 mmol). The mixture was stirred at 15 ℃ for 2 hours under a hydrogen atmosphere (balloon) (15 Psi). LCMS showed the starting material was consumed and one major peak with the desired mass was detected. The mixture was filtered andny-2808889135 Attorney Docket No.: 308642000140 washed with methanol (50 mL). The filtrate was concentrated under vacuum to give a residue, which was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0 to 5:1, TLC showed Rf= 0.55, PE:EA = 2: 1) to afford 3-chloro-4-fluoro-5,6,7,8-tetrahydroisoquinolin- 5-ol (9.5 g, yield 64.13%) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 1.69 - 1.97 (m, 4 H) 1.98 - 2.05 (m, 1 H) 2.27 (br s, 1 H) 2.53 - 2.65 (m, 1 H) 2.75 - 2.86 (m, 1 H) 5.03 (br d, J =3.63 Hz, 1 H) 7.96 (s, 1 H). Step 5. Preparation of 3-chloro-4-fluoro-7,8-dihydroisoquinolin-5(6H)-one. To a solution of dimethyl sulfoxide (1.09 g, 13.90 mmol) in dichloromethane (20 mL) was added oxalyl chloride (969.45 mg, 7.64 mmol) in dichloromethane (50 mL) at -60 ℃. After stirring at - 60 ℃ for 5 minutes, a solution of 3-chloro-4-fluoro-5,6,7,8-tetrahydroisoquinolin-5-ol (1.4 g, 6.94 mmol) in dichloromethane (20 mL) was added dropwise into the mixture over 3 minutes, and the mixture was stirred for an additional 15 minutes. Triethylamine (3.51 g, 34.72 mmol) was added, and the mixture was stirred at -60 ℃ for 5 minutes. The resulting mixture was warmed to 20 ℃ and stirred 2.5 hours. LCMS showed the starting material was consumed and one major peak with the desired mass was detected. The mixture was poured into ice water (30 mL) and extracted with dichloromethane (3 × 20 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give a residue, which was triturated with n-heptane (30 mL) at 0 ℃ and filtered. The filter cake was dried under vacuum to give 3-chloro-4-fluoro-7,8- dihydroisoquinolin-5(6H)-one (1.2 g, yield 87%) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 2.19 (quin, J =6.38 Hz, 2 H) 2.68 - 2.77 (m, 2 H) 2.99 (t, J =6.13 Hz, 2 H) 8.26 (s, 1 H). Step 6. Preparation of 6-bromo-3-chloro-4-fluoro-7,8-dihydroisoquinolin-5(6H)-one. To a solution of bromine (8.6 g, 43.1 mmol) in acetic acid (100 mL) was added 3-chloro-4- fluoro-7,8-dihydroisoquinolin-5(6H)-one (3.4 g, 43.1 mmol) in hydrogen bromide (40 mL, 37% acetic acid solution) dropwise at 15 ℃. Then, the mixture was stirred at 35 ℃ for 15 minutes. LCMS showed the starting material was consumed and one major peak with the desired mass was detected. The reaction mixture was basified with saturated sodium carbonate to pH = 8 and extracted with ethyl acetate (3 × 200 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 6-bromo-3-chloro-4-fluoro-7,8-dihydroisoquinolin-5(6H)-one (8 g, yield 66.67%) as a white solid, which was used in the next step without purification.1H NMRny-2808889136 Attorney Docket No.: 308642000140 (400 MHz, CDCl3) δ ppm 2.51 - 2.58 (m, 2 H) 2.97 - 3.05 (m, 1 H) 3.31 (br d, J =10.26 Hz, 1 H) 4.69 (t, J =3.75 Hz, 1 H) 8.29 (s, 1 H). Step 7. Preparation of tert-butyl 2-chloro-1-fluoro-7-oxo-5,6,7,9,10,11-hexahydro- 8H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline-8-carboxylate. To a solution of 6-bromo-3- chloro-4-fluoro-7,8-dihydroisoquinolin-5(6H)-one (8 g, 28.7 mmol) in methanol (35 mL) were added tert-butyl-2, 4-dioxopiperidine-1-carboxylate (8.58 g, 40.2 mmol) and ammonium acetate (6.64 g, 86.2 mmol). The mixture was stirred at 15 ℃ for 2 hours and warmed to 70 ℃ for an additional 2 hours. LCMS showed the starting material was consumed and one major peak with the desired mass was detected. The reaction mixture was concentrated under vacuum to give the crude product, which was triturated with dichloromethane (50 mL) to afford tert-butyl 2-chloro- 1-fluoro-7-oxo-5,6,7,9,10,11-hexahydro-8H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline-8- carboxylate (Intermediate 1) (4.3 g, yield 38.2%) as a white solid. LCMS: RT=2.534 min,98.2% purity, m / z = 392.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 9 H) 2.91(br d, J =6.75 Hz, 2 H) 2.93 - 3.06 (m, 4 H) 3.95 (t, J =6.32 Hz, 2 H) 5.76 (s, 1 H) 8.07 (s, 1 H) 11.54 - 12.33 (m, 1 H). Example 7 – Synthesis of tert-butyl 2-chloro-7-oxo-5,6,7,9,10,11-hexahydro-8H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline-8-carboxylate (Intermediate 2) Intermediate 2ny-2808889137 Attorney Docket No.: 308642000140 Step 1. Preparation of 3-chloro-5,6,7,8-tetrahydroisoquinoline. To a solution of 3- chloroisoquinoline (25 g, 30.56 mmol) in trifluoroacetic acid (250 mL) and trifluoro- methanesulfonic acid (75 mL) was added platinum dioxide (3 g, 60.05 mmol). The mixture was stirred at 30 ℃ for 15 hours under a hydrogen atmosphere (15 psi). TLC (petroleum ether:ethyl acetate = 5:1, Rf = 0.6) showed the starting material was consumed completely and one major spot formed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 5:1) to afford 3-chloro-5,6,7,8-tetrahydroisoquinoline (10.5 g, yield 41%) as a yellow oil.1H NMR (400 MHz, CDCl3) 1.65 - 1.80 (m, 4 H) 2.59 - 2.73 (m, 4 H) 8.00 (s, 1 H). Step 2. Preparation of (E)-3-chloro-7,8-dihydroisoquinolin-5(6H)-one oxime. To a solution of 3-chloro-5,6,7,8-tetrahydroisoquinoline (10.3 g, 61.73 mmol) in tetrahydrofuran (100 mL) was added potassium tert-butoxide (20.78 g, 185.20 mmol) in tetrahydrofuran (200 mL). After stirring at 15 ℃ for 4 hours, tert-butyl nitrite (12.73 g, 123.47 mmol) was added to the reaction mixture at 0 ℃. The resulting mixture was stirred at 15 ℃ for 2 hours. LCMS showed the starting material was consumed and two new peaks with the desired mass were detected. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was crystallized from dichloromethane (100 mL) at 20 ℃ to afford (E)-3-chloro-7,8- dihydroisoquinolin-5(6H)-one oxime (11 g, yield 91%) as a brown solid.1H NMR (400 MHz, DMSO-d6) 1.83 (m, 2 H) 1.95 (m, 1 H) 2.58 - 2.62 (m, 1 H) 2.72 (t, J=6.63 Hz, 2 H) 2.78 (t, J=6.00 Hz, 2 H) 2.89 (t, J=6.19 Hz, 1 H) 7.74 (s, 1 H) 8.35 (s, 1 H) 8.44 (s, 1 H) 8.69 (s, 1 H). Step 3. Preparation of 3-chloro-7,8-dihydroisoquinolin-5(6H)-one. To a solution of (E)-3-chloro-7,8-dihydroisoquinolin-5(6H)-one oxime (11 g, 61.73 mmol) in acetone (120 mL) was added hydrochloric acid (100 mL, 2.84 mol). The mixture was stirred at 60℃ for 3 hours. LCMS showed the starting material was consumed and one major peak with the desired mass was detected. The reaction mixture was quenched with a sodium carbonate aqueous solution (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by reverse-phase HPLC (0.1% HCl condition) to afford 3-chloro-7,8-dihydroisoquinolin-5(6H)-one (8.1 g, yield 79.72%) as a brown solid.1H NMR (400 MHz, DMSO-d6) 2.21 (m, 2 H) 2.68 - 2.78 (m, 2 H) 2.98 (t, J=6.13 Hz, 2 H) 7.82 (s, 1 H) 8.47 (s, 1 H).ny-2808889138 Attorney Docket No.: 308642000140 Step 4. Preparation of 6-bromo-3-chloro-7,8-dihydroisoquinolin-5(6H)-one. To a solution of 3-chloro-7,8-dihydroisoquinolin-5(6H)-one (8 g, 44.05 mmol) in hydrobromic acid (80 mL) was added bromine (7.04 g, 44.05 mol) at 0 ℃. The mixture was stirred at 20℃ for 2 hours. LCMS showed ~7% starting material remained and one major peak with the desired mass was detected. The mixture was quenched with sodium carbonate aqueous solution (200 mL) and extracted with ethyl acetate (3 × 100mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 6-bromo-3-chloro-7,8-dihydroisoquinolin-5(6H)-one (7.36 g, crude) as a brown solid.1H NMR (400 MHz, DMSO-d6) 2.46 (m, 2 H) 2.89 (m, 1 H) 3.15 - 3.27 (m, 1 H) 4.68 (t, J=3.88 Hz, 1 H) 7.82 (s, 1 H) 8.43 (s, 1 H). Step 5. Preparation of tert-butyl 2-chloro-7-oxo-5,6,7,9,10,11-hexahydro-8H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline-8-carboxylate. To a solution of 6-bromo-3-chloro- 7,8-dihydroisoquinolin-5(6H)-one (7.2 g, 23.49 mmol) in methanol (80 mL) were added tert- butyl 2,4-dioxopiperidine-1-carboxylate (6.01 g, 28.19 mmol) and ammonium acetate (5.43 g, 70.438 mmol). After stirring at 20 ℃ for 2 hours, the mixture was warmed to 80 ℃ for 14 hours. LCMS showed the starting material was consumed and one major peak with the desired mass was detected. The mixture was treated with water (150 mL) and extracted with ethyl acetate (3 × 80 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Phenomenex Gemini-NX80 × 40 mm × 3 µm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 25%-50% B over 10.0 min) to afford tert-butyl 2-chloro-7-oxo-5,6,7,9,10,11-hexahydro-8H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline-8-carboxylate (Intermediate 2) (2.8 g, yield 31.88%) as a gray solid.1H NMR (400 MHz, DMSO-d6) 1.47 (s, 9 H) 2.86 (br d, J=7.25 Hz, 2 H) 2.88 - 2.99 (m, 4 H) 3.96 (t, J=6.25 Hz, 2 H) 7.42 (s, 1 H) 8.15 (s, 1 H) 12.18 (br s, 1 H). Example 8 – General Procedure A: Synthesis of (S)-2-((2-chloro-6-methyl-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one and (R)-2-((2-chloro-6-methyl-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (Compounds 75 and 76).ny-2808889139 Attorney Docket No.: 308642000140 Example 1_1: To a solution of 6-bromo-3-chloro-4-fluoro-7,8-dihydro-5(6H)- isoquinolinone (175 g, 628 mmol) in methanol (1.75 L, 43.2 mol) were added tert-butyl 5- methyl-2,4-dioxo-1-piperidinecarboxylate (171 g, 1.2 eq., 754 mmol) and ammonium acetate (145 g, 3 eq., 1.89 mol) at 25°C. The reaction mixture was stirred 80°C for 3 h. LCMS showed the starting material was consumed and one peak with desired mass was detected. The reaction mixture was concentrated to remove 2 / 3 of methanol, then poured into ice water (3 L). The solid was obtained by filtration, washed with petroleum ether, and dried to give crude product. The crude product was triturated with petroleum ether: methyl tertbutyl ether = 10:1 for 10 h. Filtration and concentrated to dryness to afford tert-butyl 2-chloro-1-fluoro-10-methyl-7-oxo- 5,6,7,9,10,11-hexahydro-8H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline-8-carboxylate (251 g, 519 mmol, 82.68% yield) as a brown solid. Example 1_2: The compound tert-butyl 2-chloro-1-fluoro-10-methyl-7-oxo- 5,6,7,9,10,11-hexahydro-8H-pyrido [3',4':4,5]pyrrolo[2,3-f]isoquinoline-8-carboxylate (249 g, 614 mmol) was dissolved in hydrogen chloride in ethyl acetate (2.49 L, 4M). The resulting mixture was stirred at 25℃ for 1 h. LCMS showed the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to give a residue, which was triturated with 1,4-dioxane (5 volumes) at 25℃ for 2 h. After filtration, the solid was concentrated under reduced pressure to afford 2-chloro-1-fluoro-10-methyl-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5] pyrrolo[2,3-f]isoquinolin-7-one (190 g, 532 mmol, 86.79% yield) as a yellow solid.ny-2808889140 Attorney Docket No.: 308642000140 Example 1_3: To a solution of 2-chloro-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5] pyrrolo[2,3-f]isoquinolin-7-one (60 g, 196 mmol) in 1,4-dioxane (0.6 L, 7.03 mol) were added potassium hydroxide (55.1 g, 5 eq., 981 mmol) in water (0.3 L, 16.7 mol) , di-tert-butyl (2',4',6'-triisopropyl-2-biphenylyl) phosphine (25 g, 0.3 eq., 58.9 mmol) and (1E,4E)-1,5-diphenyl-1,4-pentadien-3-one-1 ,5-diphenyl-1,4-pentadien-3-one-palladium (1 / 2 / 2) (18 g, 0.1 eq., 19.6 mmol) at 25 °C. Then the resulting mixture was stirred at 90 °C for 2 h. LCMS showed the starting material was consumed and one main peak with desired mass was detected. Two additional vials were set up as described above. All the three reactions were combined and filtered. The pad was washed with ethyl acetate (800 mL). The aqueous phase was washed with ethyl acetate (800 mL ×3) and adjusted to pH 3~4 with solid citric acid at 0 °C. The mixture was filtered and the filter cake was washed with water (300 mL × 3), dried under vacuum to afford 1-fluoro-2-hydroxy- 10-methyl-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (145 g, 505 mmol , 91.13% yield) as a yellow solid. Example 1_4: To a solution of 1-fluoro-2-hydroxy-10-methyl-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo [2,3-f]isoquinolin-7-one (31 g, 108 mmol) in dimethyl sulfoxide (620 mL, 8.66 mol) were added Ag2CO3(149 g, 5 eq., 540 mmol) and tert-butyl 2,4-dichloro- 7,8-dihydropyrido[4,3-d]pyrimidine -6(5H)-carboxylate (49.2 g, 1.5 eq., 162 mmol) at 25 °C. Then the resulting mixture was stirred at 80 °C for 16 h. LCMS showed the starting material was consumed and one main peak with desired mass was detected. Two additional vials were set up as described above. All the three reactions were combined, diluted with methanol (4 L), and then stirred at 25 °C for 0.5 h. Then the resulting mixture was filtered through a celite pad and the celite pad was washed with methanol (300 mL × 3). The filtrate was concentrated, was poured into ice water (8 L) and extracted with dichloromethane (2 L ×4). The organic layer was combined and dried over sodium sulfate, filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel (petroleum ether / dichloromethane =1:0 to 0:1 then dichloromethane / ethyl acetate=1:0 to 4:1) to give tert-butyl 2-chloro-4-((1-fluoro-10- methyl-7-oxo-6,7,8,9,10,11-hexahydro-5H-pyrido [3',4':4,5]pyrrolo[2,3-f]isoquinolin-2-yl)oxy)- 7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (53 g , 79.3 mmol, 24.48%) as a yellow solid. Example 1_5: To a solution of tert-butyl 2-chloro-4-((1-fluoro-10-methyl-7-oxo- 6,7,8,9,10,11-hexahydro-5H-pyrido [3',4':4,5]pyrrolo[2,3-f]isoquinolin-2-yl)oxy)-7,8-ny-2808889141 Attorney Docket No.: 308642000140 dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (40 g, 1 eq., 72.1 mmol) in dichloromethane (0.8 L, 12.5 mol) were added trimethyl(trifluoromesyloxy)silane (80.1 g, 5 eq., 360 mmol) and 2,6-dimethylpyridine (42 mL, 5 eq., 360 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. LCMS showed the starting material was consumed and one main peak with desired mass was detected. The reaction mixture was concentrated under reduce pressure to afford 2-((2-chloro- 5,6,7,8-tetrahydropyrido [4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (32.8 g, 72.1 mmol, crude) as yellow oil. Example 1_6: To a solution of 2-((2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one (32.8 g, 1 eq., 72.1 mmol) in methanol (0.2 L, 4.94 mol) were added formaldehyde (29.3 g, 5 eq., 361 mmol) and sodium cyanoborohydride (9.06 g, 2 eq., 144 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS showed the starting material was consumed completely and the desired mass was detected. The reaction mixture was poured into ice-saturated NaHCO3 aqueous (1 L) and extracted with dichloromethane (500 ml × 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel chromatography eluted with Petroleum ether : Ethyl acetate = 1:0 to 0:1 to Dichloromethane : methanol = 1:0 to 9:1 to 1:1 to afford 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-1-fluoro- 10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (28 g, 53.7 mmol) as a yellow solid. Compounds 75 and 76: 2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-4-yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (20 g, 42.7 mmol) was purified by prep-SFC (column: ChiralPak IH, 250*50mm, 10um; mobile phase: [A: CO2;B: IPA(0.1%NH3H2O)];B%: 60.00%-60.00%,18.00min;flow rate:180.00g / min) to afford (R) or (S)-2-((2-chloro-6-methyl- 5,6,7,8-tetrahydropyrido [4,3-d]pyrimidin-4-yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (8.604 g, 18 mmol, 97.9% purity) as pale yellow solid, and (S) or (R)-2-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-4-yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (8.23 g, 17.1 mmol) as a white solid.ny-2808889142 Attorney Docket No.: 308642000140 The compounds in Table S-1 were synthesized using General Procedure A. In some . In some instances, compounds were prepared using intermediates and procedures similar to those in, e.g., U.S. Patent No.10,138,256 and U.S. Patent Application Publication No.2016 / 0075720, each of which is incorporated herein by reference in its entirety. Table S-1. ny-2808889143 Attorney Docket No.: 308642000140 ny-2808889144 Attorney Docket No.: 308642000140 ny-2808889145 Attorney Docket No.: 308642000140 ny-2808889146 Attorney Docket No.: 308642000140 ny-2808889147 Attorney Docket No.: 308642000140 ny-2808889148 Attorney Docket No.: 308642000140 ny-2808889149 Attorney Docket No.: 308642000140 ny-2808889150 Attorney Docket No.: 308642000140 ny-2808889151 Attorney Docket No.: 308642000140 ny-2808889152 Attorney Docket No.: 308642000140 ny-2808889153 Attorney Docket No.: 308642000140 ny-2808889154 Attorney Docket No.: 308642000140 ny-2808889155 Attorney Docket No.: 308642000140 Example 9 – General Procedure B: Synthesis of 2'-((2-chloro-6-(2,2-difluoroethyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1'-fluoro-5',6',8',9'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo [2,3-f]isoquinolin]-7'(11'H)- one (Compound 145).ny-2808889156 Attorney Docket No.: 308642000140 Example 2_1: To a solution of 2'-chloro-1'-fluoro-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one (4.8 g, 1 eq., 15.1 mmol) in dimethylformamide (50 mL) were added cesium carbonate (24.6 g, 5 eq., 75.5 mmol) and (2-chloromethoxyethyl)tris(methyl)silane (8.02 mL, 3 eq., 45.3 mmol) at 25 °C. The mixture was stirred at 80 °C for 3 h and monitored by LCMS. The mixture was quenched by water (50 mL) and extracted with ethyl acetate (100 mL x 3). Then the organic phase was combined and concentrated under reduced pressure to give a residue, which was purified by silica gel column (eluted with petroleum ether / ethyl acetate= 100:1 to 4 / 6) to give 2'-chloro-1'- fluoro-11'-((2-(trimethylsilyl)ethoxy)methyl)-6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one (5 g, 11.2 mmol, 73.8% yield) as a white solid. Example 2_2: To a solution of 2'-chloro-1'-fluoro-11'-((2-(trimethylsilyl)ethoxy)methyl)- 6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)- one (2.5 g, 1 eq., 5.58 mmol) in tetrahydrofuran (25 mL) was added n-butyl lithium (2.5 M, 3.35 mL, 1.5 eq., 8.37 mmol) at -78 °C and stirred at -78 °C for 10 min. To the above mixture was added tert-butoxycarbonyl -tert-butyl carbonate (1.92 mL, 1.5 eq., 8.37 mmol) and stirred at 0 °C for 1 h. The mixture was quenched by water (15 mL) and extracted with ethyl acetate (15 mL x 3), the organic phase was combined and concentrated under reduced pressure to give a residue, which was purified by silica gel column (eluted petroleum ether / ethyl acetate = 100 / 0 to 9 / 1) to give tert-butyl 2'-chloro-1'-fluoro-7'-oxo-11'-((2-(trimethylsilyl)ethoxy)methyl)-5',6',7',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline]-8'(9'H)-ny-2808889157 Attorney Docket No.: 308642000140 carboxylate (2.5 g, 4.55 mmol, 81.73% yield) as a white solid. LCMS: Rt: 0.715 min; [M+H]+= 548.3.1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 5.19 (s, 2H), 3.80 (s, 2H), 3.29 - 3.20 (m, 2H), 3.08 - 3.00 (m, 2H), 2.76 (t, J = 7.2 Hz, 2H), 1.58 (s, 9H), 1.56 - 1.52 (m, 2H), 1.14 - 1.08 (m, 2H), 0.83 - 0.76 (m, 2H), -0.07 (s, 9H). Example 2_3: To a solution of tert-butyl 2'-chloro-1'-fluoro-7'-oxo-11'-((2- (trimethylsilyl)ethoxy)methyl)-5',6',7',11'-tetrahydrospiro[cyclopropane-1,10'- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline]-8'(9'H)-carboxylate (2.5 g, 1 eq., 4.56 mmol) in 1,4- dioxane (50 mL) were added diphenylmethanimine (992 mg, 1.2 eq., 5.47 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (1.32 g, 0.5 eq., 2.28 mmol), (1E,4E)-1,5- diphenyl-1,4-pentadien-3-one—1,5-diphenyl-1,4-pentadien-3-one—palladium (1 / 2 / 2) (2.09 g, 0.5 eq, 2.28 mmol) and caesium carbonate (2.97 g, 2 eq., 9.12 mmol) at 25 °C. After heated to 100 °C, the mixture was stirred at 100 °C for 4 h under nitrogen atmosphere then monitored by LCMS. The mixture was quenched by water (50 mL) and extracted with ethyl acetate (50 mL x 3), the organic phase was combined and concentrated under reduced pressure to give a residue, which was purified by silica gel column (petroleum ether / ethyl acetate = 100 / 1 to 1 / 3) to give tert-butyl 2'-((diphenylmethylene)amino)-1'-fluoro-7'-oxo-11'-((2- (trimethylsilyl)ethoxy)methyl)-5',6',7',11'-tetrahydrospiro[cyclopropane-1,10'- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline]-8'(9'H)-carboxylate (1.5 g, 2.16 mmol, 47.46% yield) as a yellow solid. Example 2_4: To a solution of tert-butyl tert-butyl 2'-((diphenylmethylene)amino)-1'- fluoro-7'-oxo-11'-((2-(trimethylsilyl)ethoxy)methyl)-5',6',7',11'-tetrahydrospiro[cyclopropane- 1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline]-8'(9'H)-carboxylate (1.5 g, 1 eq., 2.16 mmol) in tetrahydrofuran (15 mL) was added hydrogen chloride (5 M, 4.33 mL, 10 eq., 21.6 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h and monitored by LCMS. The mixture was quenched by saturated sodium bicarbonate and adjusted pH = 8. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was combined and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (petroleum ether / ethyl acetate = 1 / 1, Rf = 0.5) to give tert-butyl 2'-amino-1'-fluoro-7'-oxo-11'-((2-(trimethylsilyl)ethoxy)methyl)- 5',6',7',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline]- 8'(9'H)-carboxylate as a yellow solid.ny-2808889158 Attorney Docket No.: 308642000140 Example 2_5: To a solution of tert-butyl 2'-amino-1'-fluoro-7'-oxo-11'-((2- (trimethylsilyl)ethoxy)methyl)-5',6',7',11'-tetrahydrospiro[cyclopropane-1,10'- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline]-8'(9'H)-carboxylate (0.5 g, 1 eq., 946 µmol) in 1,4- dioxane (5 mL) was added tert-butyl 2,4-dichloro-5,6,7,8-tetrahydro-1,3,6-triaza-6-naphthoate (575 mg, 2 eq., 1.89 mmol), dicaesium carbonate (924 mg, 3 eq., 2.84 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (109 mg, 0.2 eq., 189 µmol) and (1E,4E)-1,5- diphenyl-1,4-pentadien-3-one—1,5-diphenyl-1,4-pentadien-3-one—palladium (1 / 2 / 2) (86.6 mg, 0.1 eq., 94.6 µmol) at 25 °C. After purged and degassed nitrogen for 3 times, the mixture was stirred at 100 °C for 12 h under nitrogen atmosphere and monitored by LCMS. After cooling to 25 °C, the mixture was quenched by water (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was combined and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Waters Xbridge BEH C18250 x 50 mm x 10 um; mobile phase: [A: water (10 mM NH4HCO3); B: acetonitrile]; B%: 65.00%-90.00%, 10.00min; flow rate:60.00mL / min) to give tert-butyl 2'-((6-(tert-butoxycarbonyl)-2-chloro-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1'-fluoro-7'-oxo-11'-((2- (trimethylsilyl)ethoxy)methyl)-5',6',7',11'-tetrahydrospiro[cyclopropane-1,10'- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline]-8'(9'H)-carboxylate (130 mg, 0.16 mmol, yield 17.26%). Example 2_6: To a solution of tert-butyl 2'-((6-(tert-butoxycarbonyl)-2-chloro-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1'-fluoro-7'-oxo-11'-((2- (trimethylsilyl)ethoxy)methyl)-5',6',7',11'-tetrahydrospiro[cyclopropane-1,10'- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline]-8'(9'H)-carboxylate (110 mg, 1 eq., 138 µmol) in dichloromethane (2.2 mL) was added tetrachlorostannane (162 µL, 10 eq., 1.38 mmol) at 0 °C. The reaction mixture was allowed to warm to 25 °C and stirred at 25 °C for 3 h then monitored by LCMS. The mixture was quenched by sodium bicarbonate solution and adjusted pH = 9, then extracted with ethyl acetate (2 mL x 3). The organic phase was combined and concentrated under reduced pressure to give 2'-((2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1'- fluoro-6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]- 7'(5'H)-one (50 mg, 107.3 µmol, yield 77.7%) as a yellow solid, which was used for next step directly. Compound 145: To a solution of 2'-((2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 4-yl)amino)-1'-fluoro-6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-ny-2808889159 Attorney Docket No.: 308642000140 f]isoquinolin]-7'(5'H)-one (50 mg, 1 eq., 107 µmol) in dimethyl sulfoxide (1 mL) was added 1,1- difluoro-2-(trifluoromesyloxy)ethane (34.5 mg, 1.5 eq., 161 µmol), N-ethylbis(isopropyl)amine (53.2 µL, 3 eq., 322 µmol) and caesium fluoride (48.9 mg, 3 eq., 322 µmol) at 25 °C. After heating to 60 °C, the mixture was stirred at 60 °C for 3 h and monitored by LCMS. The mixture was quenched by water (2 mL) and extracted with ethyl acetate (2 mL x 3). The organic phase was combined and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Phenomenex Luna C18100 x 30 mm x 3 um; mobile phase: [A: water (0.2% formic acid); B: acetonitrile]; B%: 10.00%- 45.00%, 8.00 min; flow rate: 25.00 mL / min) to give 2'-((2-chloro-6-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)- 1'-fluoro-6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin]-7'(5'H)-one (5.0 mg, 9.19 µmol, yield 8.56%) as a yellow solid. The compounds in Table S-2 were synthesized using General Procedure B. In some In some instances, compounds were prepared using intermediates and procedures similar to those in, e.g., U.S. Patent No.10,138,256 and U.S. Patent Application Publication No.2016 / 0075720, each of which is incorporated herein by reference in its entirety. Table S-2.ny-2808889160 Attorney Docket No.: 308642000140 ny-2808889161 Attorney Docket No.: 308642000140 ny-2808889162 Attorney Docket No.: 308642000140 ny-2808889163 Attorney Docket No.: 308642000140 ny-2808889164 Attorney Docket No.: 308642000140 ny-2808889165 Attorney Docket No.: 308642000140 ny-2808889166 Attorney Docket No.: 308642000140 ny-2808889167 Attorney Docket No.: 308642000140 Example 10 – General Procedure C: Synthesis of (S)-2-((2-chloro-5-((2,2,2- trifluoroethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one and (R)-2-((2-chloro-5-((2,2,2- trifluoroethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (Compounds 177 and 178). Example 3_1: To a solution of 1-fluoro-2-hydroxy-10-methyl-5,6,8,9,10,11-hexahydro- 7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (0.1 g, 1 eq., 348 µmol) in dimethylsulfoxide (1 mL) at 25 °C were added 2-chloro-4-iodo-5-((2,2,2-trifluoroethoxy)methyl)pyrimidine (123 mg, 348 µmol) and caesium carbonate (227 mg, 2 eq., 696 µmol). The reaction mixture was stirred at 25 °C for 1 h and monitored by LCMS. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge BEH C18100 * 30 mm * 10 um; mobile phase: [A: H2O (10 mM NH4HCO3); B: ACN]; B%: 40.00%-70.00%, 8.00 min; flow rate: 25.00 ml / min) to give 2-((2-chloro-5-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (25 mg, 48.8 µmol, 14% yield) as a white solid. Compounds 177 and 178: 2-((2-chloro-5-((2,2,2-trifluoroethoxy) methyl) pyrimidin-4- yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one was separated by SFC separation (column: DAICEL CHIRALPAK IC (250 mm * 30 mm, 10 um); mobile phase: [A: CO2; B: EtOH (0.1% NH3H2O)]; B%: 40.00% - 40.00%, 16.00 min; flow rate: 70.00 g / min) to give (S)-2-((2-chloro-5-((2,2,2-trifluoroethoxy) methyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl-5,6,8,9,10,11-hexahydro-7H-ny-2808889168 Attorney Docket No.: 308642000140 pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (13.9 mg, 27 µmol, 34% yield) as a white solid. (R)-2-((2-chloro-5-((2,2,2-trifluoroethoxy) methyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (15.5 mg, 30.2 µmol, 30% yield) as a white solid. The compounds in Table S-3 were synthesized using General Procedure C. In some was replaced with other diketone linkers like . In some instances, compounds were prepared using intermediates and procedures similar to those in, e.g., U.S. Patent No.10,138,256 and U.S. Patent Application Publication No.2016 / 0075720, each of which is incorporated herein by reference in its entirety. Table S-3. ny-2808889169 Attorney Docket No.: 308642000140 ny-2808889170 Attorney Docket No.: 308642000140 ny-2808889171 Attorney Docket No.: 308642000140 ny-2808889172 Attorney Docket No.: 308642000140 ny-2808889173 Attorney Docket No.: 308642000140 Example 11: General Procedure D: Alternative procedure for the synthesis of 2-((2- chloropyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (Compound 5). ny-2808889174 Attorney Docket No.: 308642000140 Example 4_1: To a solution of tert-butyl 2-chloro-1-fluoro-7-oxo-5,6,7,9,10,11- hexahydro-8H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline-8-carboxylate (10 g, 25.5 mmol) and 2-chloropyrimidin-4-amine (3.97 g, 30.6 mmol) in 1,4-dioxane (200 mL) was added dicaesium carbonate (24.9 g, 76.6 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (2.95 g, 5.1 mmol) and (1E,4E)-1,5-diphenyl-1,4-pentadien-3-one—1,5-diphenyl-1,4-pentadien-3-one— palladium (1 / 2 / 2) (2.34 g, 2.55 mmol) at 25 °C under nitrogen atmosphere. The mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. Then monitored by LCMS. The mixture was quenched by addition of water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a tert-butyl 2-((2- chloropyrimidin-4-yl)amino)-1-fluoro-7-oxo-5,6,7,9,10,11-hexahydro-8H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline-8-carboxylate (20 g, 41.2 mmol, 56% yield). The crude product was used into next step without further purification. Compound 5: To a solution of tert-butyl 2-((2-chloropyrimidin-4-yl)amino)-1-fluoro-7- oxo-5,6,7,9,10,11-hexahydro-8H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinoline-8-carboxylate (20 g, 41.2 mmol) in dichloromethane (210 mL) was added trifluoroacetic acid (70 mL) at 25 °C. The reaction was stirred at 25 °C for 1 h. Then monitored by LCMS. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (TFA) to give 2-((2- chloropyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one as yellow solid.1H NMR showed TFA was residual inside. The product was purified by prep-HPLC (FA) after neutralization with sat. NaHCO3 (aq.) to give 2-((2- chloropyrimidin-4-yl)amino)-1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one (590 mg, yield 3.61%) as yellow solid. The compounds in Table S-4 were synthesized using General Procedure D. In some O replaced with other linkers likeny-2808889175 Attorney Docket No.: 308642000140 . In some instances, compounds were prepared using intermediates and procedures similar to those in, e.g., U.S. Patent No.10,138,256 and U.S. Patent Application Publication No.2016 / 0075720, each of which is incorporated herein by reference in its entirety. Table S-4. ny-2808889176 Attorney Docket No.: 308642000140 ny-2808889177 Attorney Docket No.: 308642000140 ny-2808889178 Attorney Docket No.: 308642000140 Example 12: General Procedure E: Synthesis of 2'-((2-chloro-6-(methyl-d3)-5-oxo-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1'-fluoro-6',8',9',11'- tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo [2,3-f]isoquinolin]-7'(5'H)-one (Compound 181).ny-2808889179 Attorney Docket No.: 308642000140 Example 5_1: To a solution of 2'-amino-1'-fluoro-11'-((2-(trimethylsilyl)ethoxy)methyl)- 6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)- one (150 mg, 350 µmol) and 1055_3 (165 mg, 0.7 mmol) in 1,4-dioxane (3 mL) was added N- ethylbis(isopropyl)amine (136 mg, 1.05 mmol) at 25 °C, the reaction was stirred at 100 °C for 12 h under N2 atmosphere. TLC (ethyl acetate, f: material=0.5, Rf : P1 =0.12) showed the starting material spots were consumed and one new spot formed. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under pressure to give a residue. The residue was purified by column on silica gel (eluted with petroleum ether: ethyl acetate =100: 0 to 10: 1) to give 2'-((2-chloro-6-(methyl-d3)-5-oxo-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1'-fluoro-11'-((2-(trimethylsilyl)ethoxy)methyl)- 6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)- one (0.1 g, yield 22.78%) as yellow solid. Compound 181: To a solution of 2'-((2-chloro-6-(methyl-d3)-5-oxo-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1'-fluoro-11'-((2-(trimethylsilyl)ethoxy)methyl)- 6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)- one (50 mg, 94.9 µmol) in dichloromethane (2.5 mL) was added sodium hydrogen carbonate (159 mg, 1.9 mmol) at 25 °C, the reaction was stirred at 25 °C for 0.5 h. Then monitored by LCMS. The mixture was filtered to remove water and purified by prep-HPLC to give 2'-((2- chloro-6-(methyl-d3)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1'-fluoro- 6',8',9',11'-tetrahydrospiro[cyclopropane-1,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)- one (8.5 mg, yield 3.7%) as yellow solid. The compounds in Table S-5 were synthesized using General Procedure E. In some instances, was replaced with other diketone linkers likeny-2808889180 Attorney Docket No.: 308642000140 . intermediates and procedures similar to those in, e.g., U.S. Patent No.10,138,256 and U.S. Patent Application Publication No.2016 / 0075720, each of which is incorporated herein by reference in its entirety. Table S-5. ny-2808889181 Attorney Docket No.: 308642000140 ny-2808889182 Attorney Docket No.: 308642000140 Example 13 – General Procedure F: Synthesis of 2-((2,5-dichloropyridin-4-yl)oxy)-1-fluoro- 5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (Compound Compound 43: To a solution of 3-fluoro-4-hydroxy-5,13,17- triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(10), 2(7),3,5,11(16)-pentaen-12-one (0.2 g, 1 eq, 732 µmol) and 4-bromo-2,5-dichloropyridine (166 mg, 1 eq., 732 µmol) in dimethylacetamide (3 mL) was added (Bu4NCuI)2(164 mg, 0.2 eq, 146 µmol), Me4-phenanthroline (17.3 mg, 0.1 eq, 73.2 µmol) and cesium carbonate (477 mg, 2 eq, 1.46 mmol) under N2. The reaction mixture wasny-2808889183 Attorney Docket No.: 308642000140 stirred at 120 °C for 12 h and detected by LCMS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep- HPLC (column: Waters xbridge 150*25 mm 10 um; mobile phase: [A: H2O (10 mM NH4HCO3); B: ACN]; B%: 40.00%-70.00%, 9.00 min; flow rate: 25.00 ml / min) to afford 4-(2,5-dichloro-4- pyridyloxy)-3-fluoro-5,13,17-triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶] heptadeca-1(10),2(7),3,5,11(16)- pentaen-12-one (34 mg, 81.1 µmol, 11% yield) as a yellow solid. Table S-6. Example 14: General Procedure G: Synthesis of 2-((2-chloro-5-((prop-2-yn-1- yloxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11-hexahydro-7H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (Compound 158). Compound 158: To a solution of 2-chloro-4-iodo-5-((prop-2-yn-1- yloxy)methyl)pyrimidine (0.5 g, 1 eq., 1.62 mmol) in dimethyl sulfoxide (5 mL) at 25°C was added 1-fluoro-2-hydroxy-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7-one (443 mg, 1 eq., 1.62 mmol) and dicaesium carbonate (1.06 g, 2 eq., 3.24 mmol). The reaction mixture was stirred at 25 °C for 2 h and monitored by LCMS. The solution was purified directly by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40 mm*10 um; mobile phase: [A: H2O (10 mM NH4HCO3); B: ACN]; B%: 20.00%-55.00%, 8.00 min) tony-2808889184 Attorney Docket No.: 308642000140 obtain 2-((2-chloro-5-((prop-2-yn-1-yloxy)methyl)pyrimidin-4-yl)oxy)-1-fluoro-5,6,8,9,10,11- hexahydro-7H-pyrido [3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (35.9 mg, 77.3 µmol, 4% yield) as a white solid. The compounds in Table S-7 were synthesized using General Procedure G. In some O N Boc O instances, was replaced with other diketone linkers like . In some instances, was replaced with other linkers some instances, compounds were prepared using intermediates and procedures similar to those in, e.g., U.S. Patent No.10,138,256 and U.S. Patent Application Publication No.2016 / 0075720, each of which is incorporated herein by reference in its entirety. Table S-7. ny-2808889185 Attorney Docket No.: 308642000140 ny-2808889186 Attorney Docket No.: 308642000140 Example 15: Separate Synthetic Procedure H1: Synthesis of 2'-((2-chloropyrimidin-4- yl)amino)-1'-fluoro-1-methyl-6',8',9',11'-tetrahydrospiro[azetidine-3,10'- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one (Compound 23).ny-2808889187 Attorney Docket No.: 308642000140 Example 8_1: A mixture of tert-butyl 4'-amino-3'-fluoro-12'-oxospiro[azetidine-3,15'- [5,13,17]triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca[1(10),2(7),3,5,11(16)]pentaene]-1- carboxylate (0.1 g, 1 eq., 242 µmol), 2,4-dichloropyrimidine (43.2 mg, 1.2 eq., 290 µmol), sodium 2-methyl-2-propanolate (46.5 mg, 2 eq., 484 µmol) and XantPhos Pd G4 (23.3 mg, 0.1 eq., 24.2 µmol) in 1,4-dioxane (6 mL) was degassed and purged with nitrogen for 3 times. The mixture was heated to 90 °C and stirred at 90 °C for 12 hr under nitrogen atmosphere, then monitored by TLC. Nine additional vails were set up as described above. All ten reaction mixtures were combined and diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3). The organic phase was combined, washed with brine (50 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by TLC (ethyl acetate = 1, Rf = 0.3) to afford tert-butyl 4'-(2-chloro-4- pyrimidinylamino)-3'-fluoro-12'-oxospiro[azetidine-3,15'- [5,13,17]triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶] heptadeca[1(10),2(7),3,5,11 (16)]pentaene]-1- carboxylate (270 mg, 513 µmol, 21.2% yield) as a yellow solid. Example 8_2: To a solution of tert-butyl 4'-(2-chloro-4-pyrimidinylamino)-3'-fluoro-12'- oxospiro[azetidine-3,15'- [5,13,17]triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca[1(10),2(7),3,5,11(16)]pentaene]-1- carboxylate (270 mg, 1 eq., 513 µmol) in trifluoroacetic acid (3 mL). The mixture was stirred at 25 °C for 10 min and monitored by LCMS. The reaction mixture was concentrated under reduced pressure to afford 4'-(2-chloro-4-pyrimidinylamino)-3'-fluorospiro[azetidine-3,15'- [5,13,17]triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca [1(10),2(7),3,5,11(16)]pentaen]-12'-one(200ny-2808889188 Attorney Docket No.: 308642000140 mg 376 µmol, 73.19% yield) as yellow oil, which was used for next step without further purification. LCMS: Rt: 0.298 min; [M+H]+= 426.1. Compound 23: To a solution of 4'-(2-chloro-4-pyrimidinylamino)-3'- fluorospiro[azetidine-3,15'- [5,13,17]triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca[1(10),2(7),3,5,11(16)]pentaen]-12'-one (0.2 g, 1 eq., 470 µmol), formaldehyde (28.2 mg, 2 eq., 939 µmol) and triethylamine (143 mg, 3 eq., 1.41 mmol) in methanol (10 mL) at 25 °C. After stirring at 25 °C for 30 min, to above mixture was added sodium boranuidcarbonitrile (88.5 mg, 3 eq., 1.41 mmol) at 0 °C. The mixture was allowed to warm to 25 °C and stirred at 25 °C for 30 min then monitored by LCMS. The reaction was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: XP t C18100 * 25 mm * 7 um; mobile phase: [A: water (10 mM ammonium bicarbonate); B: acetonitrile]; B%: 10.00%-40.00%, 8.00 min; flow rate: 25.00 ml / min) to afford 4'-(2-chloro-4-pyrimidinylamino)-3'-fluoro-1-methylspiro[azetidine-3,15'- [5,13,17]triazatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca [1(10),2(7),3,5,11(16)]pentaen]-12'-one (53.3 mg 121 µmol, 25.8% yield) as a white solid. Example 16 – Separate Synthetic Procedure H2: Synthesis of 2-((6-chloropyrimidin-4- yl)methyl)-1-fluoro-5,6,8,9,10,11-hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin- 7-one (Compound 144).ny-2808889189 Attorney Docket No.: 308642000140 Example 9_1: To a solution of starting material (50 g, 346 mmol) in dimethylformamide (500 mL) was added ethynyltris(methyl)silane (97.8 mL, 692 mmol) and triethylamine (144 mL, 1.04 mol), bis(triphenylphosphonium)—dichloro-palladamethane (1 / 1) (12.2 g, 17.3 mmol), copper iodide (6.59 g, 34.6 mmol), the mixture was stirred at 50 °C for 1 h under nitrogen atmosphere. TLC (petroleum ether: ethyl acetate = 10:1, Rf = 0.5) showed the material was consumed completely and one new spot formed. The reaction was diluted with water (500 mL) and extracted with ethyl acetate (400 mL × 3). The combined organic layers were washed with brine(500 mL × 3), dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~5 % Ethylacetate / Petroleum ethergradient @ 200 mL / min). Give Example 9_1 (36 g, yield 50.45 %) as yellow solid.ny-2808889190 Attorney Docket No.: 308642000140 Example 9_2: To a solution of Example 9_1 (36 g, 157 mmol) in methanol (324 mL) was added potassium fluoride (18.2 g, 314 mmol), the mixture was stirred at 25 °C for 1 h. TLC (petroleum ether: ethyl acetate = 10: 1, Rf= 0.3) showed the material was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to remove solvent and give residue. The residue was extracted with water (300 mL) and ethyl acetate (300 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~8 % Ethylacetate / Petroleum ethergradient @ 200 mL / min). Give Example 9_2 (19.7 g, yield 93.52 %) as yellow solid. Example 9_3: To a solution of Example 9_2 (19.7 g, 147 mmol) in tetrahydrofuran (296 mL) was added dichloro-palladamethane—triphenylphosphine (1 / 2) (10.3 g, 14.7 mmol) and tributylstannane (43.5 mL., 162 mmol) under nitrogen atmosphere, the mixture was stirred at 25 °C for 2 h. TLC (petroleum ether: ethyl acetate = 5:1, Rf= 0.8) showed the material was consumed completely and one new spot formed. The reaction mixture was extracted with water (200 mL) and ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~8 % Ethylacetate / Petroleum ethergradient @ 200 mL / min). Give Example 9_3 (26.5 g, yield 36.07 %) as yellow oil. Example 9_4: To a solution of Example 9_3 (6.5 g, 15.3 mmol) in dimethylformamide (65 mL) was added tert-butyl 4- chloro -3- fluoro- 12- oxo- 17- {[2- (trimethylsilyl)ethoxy]methyl}- 5,13,17- triazatetracyclo [8.7.0.0²,⁷.0¹¹,¹⁶] heptadeca- 1(10),2(7),3,5,11(16)-pentaene-13-carboxylate (4 g, 7.66 mmol) and bis(tri-tert- butylphosphonium)—palladium (1 / 1) (1.97 g, 3.83 mmol), the mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. LCMS showed the material was consumed and one new peak with desired mass was detected. The mixture was extracted with ethyl acetate((500 mL × 3)and water (500 mL). The combined organic layer were washed with brine (500 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The crude product was purification by Prep-HPLC (FA condition). Give Example 9_4 (2.6 g, yield 54.58 %) as yellow solid.ny-2808889191 Attorney Docket No.: 308642000140 Example 9_5: To a solution of Example 9_4 (4 g, 6.43 mmol) in tetrahydrofuran (40 mL) and water (40 mL) was added dipotassium tetraoxidoosmate (2-) dihydrate (474 mg, 1.29 mmol) at 0 °C and stirred for 10 min, then the mixture was added sodium tetraoxidoiodate (1-) (6.88 g, 32.2 mmol) at 0 °C and stirred at 25 °C for 6 h. LCMS showed the material was consumed and one new peak with desired mass was detected. The reaction mixture was added saturated sodium sulfite solution (20 mL) and extracted with ethyl acetate (100 mL × 3). The organic was dried over anhydrous sodium sulfate, filtered, and filtrate concentrated in vacuum to give crude. The crude was purified by prep-HPLC (FA condition) to give Example 9_5 (1.5 g, yield 37.38 %) as brown solid. Example 9_6: To a solution of Example 9_5 (1.5 g, 2.4 mmol) in methanol (30 mL) was added sodium borohydride (773 mg, 20.4 mmol) under 0 °C, then the mixture was stirred at 0 °C for 1 h. LCMS showed the material was consumed completely and one new peak with desired mass was detected. The reaction mixture was quenched with the addition of saturated aqueous ammonium chloride (200 mL) and extracted with ethyl acetate (100 mL × 3), the organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure afforded Example 9_6 (1.5 g, yield 83.73 %) as brown solid. The crude product was used for next step directly without purification. Example 9_7: To a solution of Example 9_6 (3 g, 4.79 mmol) in dichloromethane (30 mL) was added triethylamine (1.21 g, 12 mmol). The mixture was cooed to 0 °C and added (chlorosulfonyl)methane (730 mg, 6.37 mmol), the mixture was stirred at 0 °C for 1 h. LCMS showed the material was consumed completely and one new peak with desired mass was detected. The mixture was added water (200 mL) and extracted with dichloromethane (100 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give residue as brown solid. The crude product Example 9_7 (1.7 g, yield 40.3 %) was used for next step directly without purification. Example 9_8: To a solution of Example 9_7 (1.7 g, 1.93 mmol) in methanol (28.9 mL) was added palladium (617 mg, 5.8 mmol) and the mixture was stirred at 25 °C for 3 h under hydrogen (15 psi). LCMS showed the materail was consumed completely and one new peak with desird mass was detected. The reaction mixture was filtered and the filter cake was rinsed with methanol. Then the combined filtrates were concentrated under reduced pressure to give crude. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash®ny-2808889192 Attorney Docket No.: 308642000140 Silica Flash Column, Eluent of 0~60 % Ethyl acetate / Petroleum ethergradient @ 200 mL / min). Give Example 9_8 (750 mg, yield 63.66 %) as yellow solid. Example 9_9: To a solution of Example 9_8 (750 mg, 1.23 mmol) in dimethylformamide (7.5 mL) was added lithium chloride (521 mg, 12.3 mmol) and p-toluenesulfonic acid—water (1 / 1) (2.34 g, 12.3 mmol), then the mixture was stirred at 110 °C for 2 h. LCMS showed the material was consumed and one new peak with desired mass was detected. The reaction mixture was added water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic was dried over anhydrous sodium sulfate, filtered, and filtrate concentrated in vacuum to give crude. The residue was purified by flash silica gel chromatography (ISCO®; 6 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 5 % Methanol / Ethylacetate @ 200 mL / min). Give Example 9_9 (200 mg, yield 26.25 %) as yellow solid. Compound 144: To a solution of Example 9_9 (0.2 g, 404 µmol) in 1,2-dichloroethane (1 mL) was added N-ethylbis(isopropyl)amine (62.6 mg, 484 µmol) and phosphoryl trichloride (136 mg, 888 µmol), then the mixture was stirred at 85 °C for 2 h. LCMS showed the Example 9_9 was consumed and one new peak with Example 9_10 mass was detected. The reaction mixture was used next without purification. The reaction mixture was added trifluoroacetic acid (1 mL) and stirred 30 min at 25 °C, and added saturated sodium bicarbonate aqueous solution at 25 °C for 1 h. LCMS showed one new peak with desired mass. The crude was purified by prep- HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [A: H2O (10mM NH4HCO3); B: ACN]; B%: 20.00%-50.00%, 8.00min) to give Compound 144 (3 mg, yield 1.94 %) as light-yellow solid. Example 17 – Separate Synthetic Procedure H3: Synthesis of 2-((2-chloro-6-methyl-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro-11-methyl-5,6,8,9,10,11- hexahydro-7H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7-one (Compounds 142 and 143). ny-2808889193 Attorney Docket No.: 308642000140 Example 10_1: To a solution of starting material (1 g, 2.55 mmol) in DMA (10 mL, 108 mmol) was stirred at 0 °C. NaH 60% (153 mg, 1.5 eq., 3.83 mmol) was added and stirred at 0 °C for 0.5 h, MeI (1.81 g, 5 eq., 12.8 mmol) was added dropwise at 0 °C, The reaction mixture was stirred 0 °C for 1 h. LCMS(Rt(Product) = 0.517 min, M+H = 350.1) showed the starting material was consumed completely. The reaction mixture was quenched by NH4Cl (50 mL) for extraction and extracted with EtOAc (3×15 mL). The combined organic phase was washed with brine (15 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford the residue. The residue was purified by column chromatography (PE: EtOAc = 1:1 to 0:1) to give the Compound 10_1 (820 mg, 2.02 mmol) was obtained as yellow solid. Example 10_2: To a solution of 10_1 (820 mg, 2.02 mmol) in 1,4-dioxane (10 mL, 117 mmol) was added 737_1A (1 g, 1.82 mmol) Cs2CO3(1.97 g, 3 eq., 6.06 mmol), XantPhos (234 mg, 0.2 eq., 404 µmol) and Pd2(dba)3 (185 mg, 0.1 eq., 202 µmol) at 25°C, The reaction mixture was stirred 100 °C for 4 hrs. LCMS (Rt(Product) = 0.922 min, M+H = 551.2) showed the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to afford the residue. The residue was purified by column chromatography (PE: EtOAc = 1:1 to 0:1) to give the Compound 10_2 (1 g, 1.82 mmol) was obtained as yellow oil. Example 10_3: To a solution of 10_2 (1 g, 1.7 eq., 1.82 mmol) in tetrahydrofuran (10 mL, 123 mmol) was added 5N hydrogen chloride (688 mg, 18 eq., 18.9 mmol) at 25°C, The reaction mixture was stirred 25°C for 16h. LCMS (Rt(Product) = 0.239 min, M+H = 287.1) showed the starting material was consumed completely. The reaction mixture was quenched by NaHCO3 (15 mL) for extraction and extracted with EtOAc (3×15 mL). The combined organic phase was washed with brine (15 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford the residue. The residue was purified by column chromatography (EtOAc: MeOH = 1:0 to 0:1) to give the Compound 10_3 (0.4 g, 1.4 mmol) as yellow solid. Compounds 142 and 143: To a solution of 737_3 (0.2 g, 699 µmol) in 1,4-dioxane (2 mL, 23.4 mmol) was added Cs2CO3(50.8 mg, 3 eq., 156 µmol) MTX-01-207-1 (305 mg, 2 eq., 1.4 mmol) XantPhos (80.8 mg, 0.2 eq., 140 µmol), Pd2(dba)3 (64 mg, 0.1 eq., 69.9 µmol) at 25°C, The reaction mixture was stirred 100 °C for 3 hrs. LCMS (Rt(Product) = 0.299, 0.325 min, M+H = 468.2) showed the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to afford the residue. The residue was purifiedny-2808889194 Attorney Docket No.: 308642000140 by column chromatography ( EtOAc: MeOH = 1:0 to 1:1) to give the residue. And double purification by Prep-HPLC (neutral condition) column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [A: H2O(10mM NH4HCO3);B: ACN];B%: 15.00 %-55.00 %,8.00 min. Compound 142 (8 mg, 17.1 µmol, 2.39 % yield) and Compound 143 (1 mg, 2.14 µmol, 0.27 % yield) were obtained as brown solid. Example 18 – Separate Synthetic Procedure H4: Synthesis of 2-((2-chloro-6-(2-hydroxy-2- methylpropyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro-8,9,10,11- tetrahydro-5H-pyrido[3',4':4,5]pyrrolo [2,3-f]isoquinolin-7(6H)-one. (Compound 39) Compound 39 Compound 39: 2-((2-chloro-6-(2-hydroxy-2-methylpropyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro-8,9,10,11-tetrahydro-5H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)-one: (4 batches) To a solution of 2-((2-chloro- 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro-8,9,10,11-tetrahydro-5H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)-one (20 mg, 1 eq, 43.2 µmol) in dimethylformamide (0.5 mL, 6.46 mmol) was added potassium carbonate (17.9 mg, 3 eq, 130 µmol), 1-chloro-2-methyl-2-propanol (23.4 mg, 5 eq, 216 µmol), sodium iodide (8.26 mg, 1.3 eq, 55.1 µmol) at 25 °C. The reaction mixture was stirred at 100 °C for 12 h and monitored by LCMS. The reaction mixture was filtered and the filtrate purified by prep-HPLC (Column: Waters Xbridge Prep OBD C18150*40mm*10um; Mobile phase: A: H2O (10mM NH4HCO3); B: ACN, Gradient: B from 10.00% to 40.00% in 8.0 min) to give 2-((2-chloro-6-(2-hydroxy-2- methylpropyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro-8,9,10,11- tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)-one (12 mg, 22.5 µmol, 13% yield) as yellow solid. Example 19: Separate Synthetic Procedure H5: Synthesis of 2-((2-chloro-6-isopropyl- 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro-8,9,10,11-tetrahydro-5H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)-one. (Compound 37)ny-2808889195 Attorney Docket No.: 308642000140 Compound 37 Compound 37: 2-((2-chloro-6-isopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yl)amino)-1-fluoro-8,9,10,11-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)- one: To a solution of 2-((2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1- fluoro-8,9,10,11-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo [2,3-f]isoquinolin-7(6H)-one (50 mg, 1 eq, 105 µmol) in 1.2-dichloroethane (1 mL) was added acetone (60.7 mg, 10 eq, 1.05 mmol), acetic acid (12.6 mg, 2 eq, 209 µmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. Then sodium triacetoxyborohydride (44.3 mg, 2 eq, 209 µmol) was added to above reaction solution at 25 °C. The reaction mixture stirred at 25 °C for 12 h and monitored by LCMS. The reaction mixture was diluted with water (3 mL) and extracted with dichloromethane (3 × 1 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep- HPLC (Column: Waters Xbridge Prep OBD C18150*40mm*10um; Mobile phase: A: H2O (10mM NH4HCO3); B: ACN, Gradient: B from 10.00% to 45.00% in 8.00 min) to give 2-((2- chloro-6-isopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-1-fluoro-8,9,10,11- tetrahydro-5H-pyrido[3',4':4,5]pyrrolo [2,3-f]isoquinolin-7(6H)-one (17 mg, 33.6 µmol, 32% yield) as a yellow solid. Example 20: Separate Synthetic Procedure H6: Synthesis of 2-(2-((2,5-dichloropyridin-4- yl)amino)-3-fluoropyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Compound 44) Compound 44ny-2808889196 Attorney Docket No.: 308642000140 Example 13_1: To a solution of tert-butyl 2,4-dioxopiperidine-1-carboxylate (6.25 g, 1 eq., 29.3 mmol) and 4A sieve (0.2 g) in toluene (62.5 mL) at 20 °C was added 2,2- dimethoxyethan-1-amine (3.08 g, 1 eq., 29.3 mmol). Then the reaction mixture was stirred at 70 °C for 1 h under nitrogen atmosphere and monitored by TLC. Three additional vial was set up as described above. All the four suspensions were combined and diluted with ethyl acetate (500 mL), washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the crude of tert-butyl (Z)-4-((2,2- dimethoxyethyl)imino)-2-oxopiperidine-1-carboxylate (30 g, 0.1 mol, 85% yield) as a yellow solid, which was used directly for the next step, without further purification. Example 13_2: To a solution of tert-butyl (Z)-4-((2,2-dimethoxyethyl)imino)-2- oxopiperidine-1-carboxylate (30 g, 1 eq., 99.9 mmol) in dichloromethane (71 mL) at 0 °C was added trifluoroacetic acid (100 mL). Then the reaction mixture was stirred at 25°C for 3 h and monitored by TLC. The suspension was concentrated under reduced pressure to give a residue, which was purified via silica gel chromatography eluting with 5% methanol in ethyl acetate. Pure fractions were combined and concentrated to afford 1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one (12 g, 88.1 mmol, 88% yield) as a white solid. Example 13_3: To a solution of 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (5 g, 1 eq., 36.2 mmol) in toluene (50 mL) and tetrahydrofuran (50 mL) at 25 °C was added 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (18.4 g, 2 eq., 72.4 mmol), [Ir(OCH3)(C8H12)]2(1.31 g, 0.05 eq., 1.81 mmol) and pentacyclo[10.6.2.0²,⁷.0⁹,¹⁹.0¹⁶,²⁰]icosa-1(19),2(7),3,8,10,12 (20),13,15,17-nonaene-5,6-diol (1.04 g, 0.1 eq., 3.62 mmol) under nitrogen atmosphere. Then the reaction mixture was stirred at 100°C for 16 h under nitrogen atmosphere and monitored by TLC. One additional vial was set up as described above. Both reaction mixtures were combined and concentrated under reduced pressure to a residue, which was purified by column on silica gel (eluted with ethyl acetate) to obtain 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one (9.2 g, 34.9 mmol, 41% yield) as an off-white solid. Example 13_4: To a solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5,6,7- tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (1 g, 1.1 eq., 3.82 mmol) in 1,4-dioxane (20 mL) and water (5 mL) at 25 °C were added 4-bromo-3-fluoro-2-pyridylamine (802 mg, 1.1 eq., 4.2 mmol), dipotassium carbonate (1.58 g, 3 eq., 11.4 mmol) and 1,1'-ny-2808889197 Attorney Docket No.: 308642000140 bis(diphenylphosphino)ferrocene)palladium(II) dichloride (312 mg, 0.1 eq., 382 µmol) under nitrogen atmosphere. Then the reaction mixture was stirred at 80 °C for 3 h under nitrogen atmosphere and monitored by LCMS. One additional vial was set up as described above. Both reaction mixtures were combined and quenched with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phase was washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Column: Phenomenex Luna C1880*30 mm*3 um, Mobile phase: A: H2O (0.2% FA); B: acetonitrile, Gradient: B: 1.00% to 25.00%, in 8.00 min) to obtain 2-(2-amino-3-fluoropyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one (0.2 g, 809 µmol, 10% yield) as a yellow solid. Compound 44: To a solution of 2-(2-amino-3-fluoropyridin-4-yl)-1,5,6,7-tetrahydro-4H- pyrrolo[3,2-c]pyridin-4-one (150 mg, 1 eq., 609 µmol) in toluene (15 mL) at 25 °C was added 4- bromo-2,5-dichloropyridine (111 mg, 0.8 eq., 487 µmol), dicaesium carbonate (298 mg, 1.5 eq., 914 µmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (17.6 mg, 0.05 eq., 30.5 µmol) and (1E,4E)-1,5-diphenyl-1,4-pentadien-3-one-1,5-diphenyl-1,4-pentadien-3-one- palladium(1 / 2 / 2) (27.9 mg, 0.05 eq., 30.5 µmol) under nitrogen atmosphere. Then the reaction mixture was stirred at 140°C for 16 h under nitrogen atmosphere and monitored by LCMS. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Column: Waters Xbridge Prep OBD C18150*40 mm*10 um, Mobile phase: A: H2O (10 mM NH4HCO3); B: acetonitrile, Gradient: B: 40.00% to 75.00%, in 8.00 min) to obtain 2-(2-((2,5-dichloropyridin-4-yl)amino)-3-fluoropyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one (82.3 mg, 20.9 µmol, 33% yield) as a white solid. Example 21: Separate Synthetic Procedure H7: Synthesis of 2-((6-chloropyridazin-4- yl)oxy)-1-fluoro-8,9,10,11-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)- one (Compound 65). ny-2808889198 Attorney Docket No.: 308642000140 Compound 65: To a solution of 1-fluoro-2-hydroxy-8,9,10,11-tetrahydro-5H- pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin-7(6H)-one (0.5 g, 1 eq, 1.83 mmol) in dimethylformamide (10 mL) was added sodium hydride (293 mg, 4 eq, 7.32 mmol, 60 % purity) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 0.5 h. Then 3,5-dichloropyridazine (545 mg, 2 eq, 3.66 mmol) was added to above reaction solution at 0 °C. The reaction mixture was stirred at 110 °C for 12 h and monitored by LCMS. The reaction mixture was quenched by addition of sat.NH4Cl (10 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate =1: 1 to 0: 1) to give 2-((6- chloropyridazin-4-yl)oxy)-1-fluoro-8,9,10,11-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3- f]isoquinolin-7(6H)-one (2.3 mg, 6.12 umol, 0.3% yield) as light yellow solid. Table S-8. ny-2808889199 Attorney Docket No.: 308642000140 ny-2808889200 Attorney Docket No.: 308642000140 ny-2808889201 Attorney Docket No.: 308642000140 Biological Examples Exemplary assays for evaluating the biological activity of compounds described herein are described below. Example B-1 - MK2 Biochemical Assay An ADP-Glo™ Kinase Assay was used to monitor MK2 kinase activity by measuring effects on MK2 phosphorylation of a peptide substrate, HSP27tide (RRLNRQLSVA-amide). The kinase reaction was conducted in a 384-well, low-flange, white, flat-bottomed polystyrene nonbinding surface plate. MK2 was diluted to 0.625 nM in the BSA-containing assay buffer (40 mM Tris pH 7.5, 20 mM MgCl2, 0.125 mg / ml BSA, 0.5 mM TCEP) and 6 µL was added to each well. Subsequently, test compounds dissolved in the DMSO or the DMSO alone (as control) were diluted to 5% DMSO in BSA-free assay buffer (40 mM Tris pH 7.5, 20 mM MgCl2, 0.5 mM TCEP) and a 3 µL aliquot was added to each well. The plate was incubated at room temperature for 1 hour. The reaction was initiated by adding 3 µL of 50 µM ATP and 3 µL of 1 mg / mL substrate. The plate was incubated on the shaker at room temperature for 1 hour at 300 rpm. The reaction was terminated, and the remaining ATP depleted by adding 15 µL of ADP- Glo™ Reagent to each well. The plate was incubated for 40 minutes at room temperature. Lastly, 30 µL of the Kinase Detection Reagent was added to each well, and the plate was incubated for another 30 minutes at room temperature. The luminescence of each well was measured by EnVision® (PerkinElmer). The above procedure was performed for the compounds in Table B-1, for which the results are provided. The symbol “++++” indicates a IC50 less than or equal to 10 nM. The symbol “+++” indicates an IC50 greater than 10 nM and less than or equal to 100 nM. The symbol “++” indicates an IC50greater than 100 nM and less than or equal to 1000 nM. The symbol “+” indicates a IC50 greater than 1000 nM. TABLE B-1. ny-2808889202 Attorney Docket No.: 308642000140 Example B-2 - HeLa Cell HSP27 S78 Phosphorylation Assay Phospho HSP27 ELISA and total HSP27 ELISA was performed with PathScan® Phospho-HSP27 (Ser78) Sandwich ELISA Kit (Cell Signaling: 7290) and PathScan® Total HSP27 Sandwich ELISA Kit (Cell Signaling: 7295), respectively. HeLa cells (ATCC: CCL-2)ny-2808889203 Attorney Docket No.: 308642000140 were cultured in DMEM with 10% heat-inactivated fetal calf serum and 100 U / mL Penicillin- Streptomycin at 37 ℃ and 5% CO2. A day before the assay, HeLa cells were plated at 0.25x105 / well in a 96-well plate. On the following day, the cells were incubated with test compounds in the culture media at 37 ℃ (100 µL / well). After 1 hour incubation, the cells were treated with IL-1b (10 ng / mL) for 20 minutes at 37 ℃ (200 µl / well). After incubation, cells were washed with PBS 1x and lysed with 200 µL of lysis buffer (from ELISA kit) containing phosphatase inhibitor cocktail to each well, and incubated on ice for 5 minutes. Subsequently, cell lysates were centrifuged for 10 min (x3,000 g) at 4 ℃. The supernatant samples were assayed by ELISA for the presence of phospho-HSP27 (S78) and total HSP27. Example B-3 - PBMCs (Peripheral Blood Mononuclear Cells) TNF-α Release Assay TNF-α ELISA was performed with Human TNF alpha ELISA Kit (Abcam: ab181421). PBMCs were cultured in RPMI 1640 Medium with 10% heat-inactivated fetal calf serum and 100 U / mL Penicillin-Streptomycin at 37 ℃ and 5% CO2. PBMCs were plated at 1x105 / well in a 96-well plate and incubated with test compounds in the culture media at 37 ℃ (100 µl / well). After 3 hour incubation, the cells were treated with lipopolysaccharide (LPS, 100 ng / ml) for 4 hours at 37 ℃ (200 µL / well). After incubation, the supernatant samples were assayed by the ELISA for the presence of TNF-α. The above procedure was performed for the compounds in Table B-2, for which the results are provided. The symbol “++++” indicates a IC50 less than or equal to 10 nM. The symbol “+++” indicates an IC50greater than 10 nM and less than or equal to 100 nM. The symbol “++” indicates an IC50greater than 100 nM and less than or equal to 1000 nM. The symbol “+” indicates a IC50 greater than 1000 nM. TABLE B-2. ny-2808889204 Attorney Docket No.: 308642000140 All publication, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entireties, to the same extent as if each were incorporated by reference individually.ny-2808889205

Claims

Attorney Docket No.: 308642000140 CLAIMS What is claimed is:

1. A compound of formula (I),(I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is -C(R17)(R18)-, -C(O)-, -O-, -NR10-, or -S(O)n-; R1and R2are independently H, D, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, or C2-4 haloalkynyl, wherein the C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, and C2-4haloalkynyl are independently optionally substituted with -OR10or -N(R10)(R10); or R1and R2are taken together with the carbon atom to which they are attached to form a C3-6 cycloalkyl or a 4-6 membered heterocyclyl, wherein the C3-6cycloalkyl and 4-6 membered heterocyclyl are optionally substituted with one or more R2a; R3and R4are independently H, D, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, C2-4 haloalkynyl, -OR10, -N(R10)(R10), C3-6 cycloalkyl, or 4-6 membered heterocyclyl, wherein the C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, and C2-4 haloalkynyl are independently optionally substituted with -OR10, -N(R10)(R10), C3-6 cycloalkyl, or 4-6 membered heterocyclyl, and the C3-6 cycloalkyl and the 4-6 membered heterocyclyl of R3and R4are optionally substituted with one or more R4a; orny-2808889206Attorney Docket No.: 308642000140 R3and R4are taken together with the carbon atom to which they are attached to form a C3-6cycloalkyl or a 3-6 membered heterocyclyl, wherein the C3-6 cycloalkyl or the 3-6 membered heterocyclyl are optionally substituted with one or more R4a; R5is H, C1-2alkyl, C1-2haloalkyl, or C3-5cycloalkyl; R6is H, C1-2 alkyl, C1-2 haloalkyl, or C3-5 cycloalkyl; R7is 5-6 membered heteroaryl or partially unsaturated 8-14 membered heterocyclyl, wherein a carbon atom adjacent to a heteroatom on the 5-6 membered heteroaryl or 8-14 membered heterocyclyl is substituted by R8, the 5-6 membered heteroaryl is optionally further substituted with one or more R9, and the 8-14 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of oxo and R9; R8is halo or -S(O)n(R13); each R9is independently halo, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, C2-4haloalkynyl, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), -O- C(O)-R12, -C(O)-R12, -S(O)n(R12), C3-6 cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein the C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, and C2-4haloalkynyl are independently optionally substituted with one or more R9a; the C3-6 cycloalkyl and 4-6 membered heterocyclyl are independently optionally substituted with one or more R9b; and the phenyl and 5-6 membered heteroaryl are each independently optionally substituted with one or more R9c; each R9ais independently D, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), - C(O)-R12, -S(O)n(R12), C3-6cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, or 5-6 membered heteroaryl, wherein, the C3-6cycloalkyl is optionally substituted by one or more R14, and the 4-10 membered heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of oxo, halo, and R14; each R9bis independently halo, -OR10, -N(R10)(R10), C1-4 alkyl, C1-4 haloalkyl, or oxo; orny-2808889207Attorney Docket No.: 308642000140 each R9cis independently halo, -CN, -OR10, -N(R10)(R10), C1-4alkyl, or C1-4haloalkyl; each R10is independently H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkenyl, C1-4 alkynyl, C3-4 cycloalkyl, or 3-8 membered heterocyclyl; wherein the C1-4alkyl, C1-4haloalkyl, C1-4alkenyl, or C1-4alkynyl is optionally substituted by one or more R10a, and the C3-4 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted by one or more R10b; and each R10ais independently D, -OR14, or C3-4 cycloalkyl; each R2a, R4a, and R10bis independently halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyl-(OR14), C1-4 haloalkyl-(OR14), -OR14, or -N(R14)(R14); X is N, or CR11; R11is H, halo, C1-4 alkyl, C1-4 haloalkyl, or -CN; each R12is independently C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4haloalkenyl, C2-4alkynyl, C2-4haloalkynyl, C3-6cycloalkyl, -OR14, -N(R14)(R14), or 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted by halo, C1-4 alkyl, or C1-4 haloalkyl; R13is C1-4alkyl or C1-4haloalkyl; each R14is independently H, C1-4 alkyl, C1-4 haloalkyl, or C3-6 cycloalkyl; n is independently at each occurrence 0, 1, or 2; indicates a single or double bond, wherein when is a single bond, p and q are each 2, and when is a double bond, p and q are each 1; each R15and R16is independently H, D, or C1-4 alkyl; R17is H, -CH3, -CF3, halo, or -OH; and R18is H, -CH3, -CF3, or halo, or R17and R18are taken together with the carbon to which they are attached to form a cyclopropyl,ny-2808889208Attorney Docket No.: 308642000140 provided that when L is -O-, each of R1-R6is H, R7is 2-chloropyrimidin-4-yl, X is CF,is a single bond, and each R15and R16is H, then R9is not ethoxymethyl.

2. The compound of claim 1, wherein R5is H or C1-2 alkyl; R6is H or C1-2alkyl; each R9ais independently D, -CN, -OR10, -N(R10)(R10), -N(R10)-C(O)-R12, -N(R10)-S(O)n-(R12), - C(O)-R12, -S(O)n(R12), C3-6 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-6 membered heteroaryl, wherein the 4-10 membered heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of oxo, halo, and R14; and each R4ais C1-4 alkyl.

3. The compound of claim 1 or 2, wherein the compound is a compound of formula (I-a-1),stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is -C(R17)(R18)- or -C(O)-.

4. The compound of claim 1 or 2, wherein the compound is a compound of formula (I-a-2),stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is -C(R17)(R18)- or -C(O)-.ny-2808889209Attorney Docket No.: 308642000140 5. The compound of claim 1 or 2, wherein the compound is a compound of formula (Ib-1),stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

6. The compound of claim 1 or 2, wherein the compound is a compound of formula (I-b-2),stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

7. The compound of claim 1 or 2, wherein the compound is a compound of formula (I-c-1),stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

8. The compound of claim 1 or 2, wherein the compound is a compound of formula (I-c-2),ny-2808889210Attorney Docket No.: 308642000140stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

9. The compound of claim 1 or 2, wherein the compound is a compound of formula (I-d-1),stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

10. The compound of claim 1 or 2, wherein the compound is a compound of formula (I-d-2),stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

11. The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein L is -C(R17)(R18)-, -O-, or -NR10-.

12. The compound of any of claims 1-4 or 11, or a pharmaceutically acceptable salt thereof, wherein L is -CH2-, -CHF-, -CF2-, -O-, -N(H)-, or -N(C1-4 alkyl)-.ny-2808889211Attorney Docket No.: 308642000140 13. The compound of any of claims 1-4, 11, or 12, or a pharmaceutically acceptable salt thereof, wherein In some embodiments, L is -O-, -N(H)-, or -N(C1-4 alkyl)-.

14. The compound of any of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R1and R2are H, or R1and R2are taken together with the carbon atom to which they are attached to form a C3-6cycloalkyl or a 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more R2a.

15. The compound of any of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R1and R2are H, or R1and R2are taken together with the carbon atom to which they are attached to form a C3-6cycloalkyl or a 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with C1-4alkyl.

16. The compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R1and R2are H, or R1and R2are taken together with the carbon atom to which they are attached to form a cyclopropyl or N-methylazetidinyl.

17. The compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R1and R2are each H.

18. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R3and R4are independently H, C1-4 alkyl, or C1-4 haloalkyl, or R3and R4are taken together with the carbon atom to which they are attached to form a C3-6cycloalkyl or a 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl is optionally substituted with one or more R4a.ny-2808889212Attorney Docket No.: 308642000140 19. The compound of any of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R3and R4are independently H, C1-4 alkyl, or C1-4 haloalkyl, or R3and R4are taken together with the carbon atom to which they are attached to form a C3-6cycloalkyl or a 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl is optionally substituted with C1-4 alkyl.

20. The compound of any of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R3and R4are independently H, -CH3, or -CF3, or R3and R4are taken together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, or N-methylazetidinyl.

21. The compound of any of claims 1 or 3-20, or a pharmaceutically acceptable salt thereof, wherein R5is H, C1-2alkyl, or C1-2haloalkyl.

22. The compound of any of claims 1 or 3-21, or a pharmaceutically acceptable salt thereof, wherein R5is H, -CH3, -CH2CH3, -CH2CF3, or -CH2CF2H.

23. The compound of any of claims 1 or 3-22, or a pharmaceutically acceptable salt thereof, wherein R6is H, C1-2 alkyl, or C1-2 haloalkyl.

24. The compound of any of claims 1 or 3-23, or a pharmaceutically acceptable salt thereof, wherein R6is H, -CH3, -CH2CH3, -CH2CF3, or -CH2CF2H.

25. The compound of any of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R5and R6are each H.

26. The compound of any of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R5, and R6are each H.ny-2808889213Attorney Docket No.: 308642000140 27. The compound of any of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, and R6are each H.

28. The compound of any of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R7is a 5-6 membered heteroaryl substituted by R8and optionally substituted with one or more R9.

29. The compound of any of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R7is a 5-membered heteroaryl substituted by R8and optionally substituted with one or more R9.

30. The compound of any of claims 1-29, wherein R7is pyrazolyl, oxazolyl, or thiazolyl, wherein the pyrazolyl, oxazolyl, or thiazolyl is substituted by R8and optionally substituted with one or more R9.

31. The compound of any of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R7is a 6-membered heteroaryl substituted by R8and optionally substituted with one or more R9.

32. The compound of any of claims 1-28 or 31, or a pharmaceutically acceptable salt thereof, wherein R7is pyrimidinyl substituted by R8and optionally substituted with one or more R9.

33. The compound of any of claims 1-28, or 31, or a pharmaceutically acceptable salt thereof, wherein R7is pyridinyl, wherein the pyridinyl is substituted by R8and optionally substituted with one or more R9.

34. The compound of any of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R7is a 8-14 membered heterocyclyl substituted by R8and optionally substituted with one or more R9.ny-2808889214Attorney Docket No.: 308642000140 35. The compound of any of claims 1-27 or 34, or a pharmaceutically acceptable salt thereof, wherein R7is 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, wherein the 5,6,7,8- tetrahydropyrido[4,3-d]pyrimidine is substituted by R8and optionally substituted with one or more R9.

36. The compound of any of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R8is halo.

37. The compound of any of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R8is Cl or F.

38. The compound of any of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein R8is Cl.

39. The compound of any of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein R9is C1-4alkyl optionally substituted by one or more R9a.

40. The compound of any of claims 1-39, wherein R9ais -CN, -OR10, -C(O)-R12, -S(O)2- (R12), C3-6cycloalkyl, or 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl is optionally substituted by one of more substituents selected from the group consisting of oxo, halo, and -CH3.

41. The compound of any of claims 1-40, wherein R9ais -CN, -OH, -O(C1-4alkyl), -O(C1-4haloalkyl), -O(C3-6 cycloalkyl), -O(4-6 membered heterocyclyl), -C(O)-(C3-6 cycloalkyl), -C(O)- [N(C1-4alkyl)(C1-4alkyl)], -S(O)2-(C1-4alkyl), -S(O)2-N(C1-4alkyl)(C1-4alkyl), C3-6cycloalkyl, or 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl is optionally substituted by one of more substituents selected from the group consisting of oxo, halo, and -CH3.ny-2808889215Attorney Docket No.: 308642000140 42. The compound of any of claims 1-41, wherein R9ais selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholino, isothiazolidinyl, and 5- azaspiro[2.4]heptanyl.

43. The compound of any of claims 1-39, wherein R9is C1-4 alkyl.

44. The compound of any of claims 1-39 or 43, wherein R9is -CH3.

45. The compound of any of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein R9is C3-6cycloalkyl optionally substituted by one or more R9b.

46. The compound of any of claims 1-38 or 45, or a pharmaceutically acceptable salt thereof, wherein R9is cyclopropyl.

47. The compound of any of claims 1-29, 32 or 33, wherein48. The compound of any of claims 1-27 or 34-38, whereinoptionally substituted by 1, 2, or 3 R9groups.ny-2808889216Attorney Docket No.: 308642000140 49. The compound of any of claims 1-27 or 34-38, whereinoptionally substituted by 1 or 2 R9groups.

50. The compound of any of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R7is selected from the group consisting of:ny-2808889217Attorney Docket No.: 308642000140 ,ny-2808889218Attorney Docket No.: 30864200014051. The compound of any of claims 1, 2, 4, 6, 8, or 10-50, or a pharmaceutically acceptable salt thereof, wherein X is CR11.

52. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein R11is H or halo.

53. The compound of claim 51 or 52, or a pharmaceutically acceptable salt thereof, wherein R11is H or F.

54. The compound of any of claims 1-3, 5, 7, 9, 11 or 11-50, or a pharmaceutically acceptable salt thereof, wherein X is N.

55. A compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from compounds 1-32, and 34-189 of Table 1.

56. A compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from compounds 1-32, and 34-141 of Table 1.ny-2808889219Attorney Docket No.: 308642000140 57. A pharmaceutical composition comprising a compound of any of claims 1-56, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

58. A method for treating a disease or condition mediated by MK2, comprising administering to a subject in need thereof a compound of any of claims 1-56, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 57.

59. The method of claim 58, wherein a therapeutically effective amount of the compound is administered.

60. The method of claim 58 or 59, wherein said disease or condition mediated by MK2 is an inflammatory disorder.

61. The method of claim 58 or 59, wherein said disease or condition mediated by MK2 is ankylosing spondylitis, rheumatoid arthritis, psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn’s disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren’s syndrome, scleroderma, ulcerative colitis, asthma, uveitis, psoriatic arthritis, hidradenitis suppurativa, cryopyrin-associated periodic syndromes, or juvenile idiopathic arthritis.

62. The method of claim 58 or 59, wherein said disease or condition mediated by MK2 is ankylosing spondylitis, rheumatoid arthritis, psoriasis, Crohn’s disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren’s syndrome, scleroderma, ulcerative colitis, or asthma.

63. The method of claim 58 or 59, wherein said disease or condition mediated by MK2 is rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis, ulcerativeny-2808889220Attorney Docket No.: 308642000140 colitis, Crohn’s disease, hidradenitis suppurativa, cryopyrin-associated periodic syndromes, or juvenile idiopathic arthritis.

64. The method of claim 58 or 59, wherein said disease or condition mediated by MK2 is a cancer selected from pancreatic cancer, colorectal cancer, multiple myeloma, lung cancer, gastric cancer, breast cancer, nasopharyngeal cancer, skin cancer, bladder cancer, prostate cancer, head and neck cancer, or glioblastoma.

65. The method of claim 58 or 59, wherein said disease or condition mediated by MK2 is pancreatic cancer.

66. The method of claim 58 or 59, wherein said disease or condition mediated by MK2 is a fibrotic disease.

67. The method of claim 66, wherein the fibrotic disease is idiopathic pulmonary fibrosis.

68. The method of any of claims 58-67, wherein the subject is a human.

69. A method of inhibiting the activity of a MK2, comprising contacting a MK2 with an effective amount of a compound of any of claims 1-56, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

70. A method of covalently modifying a MK2, comprising contacting a MK2 with an effective amount of a compound of any of claims 1-56, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

71. A covalently modified MK2 formed by the method of claim 70.

72. The compound of any of claims 1-56, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 57 for use in the treatment of a MK2-mediated disease or disorder.ny-2808889221Attorney Docket No.: 308642000140 73. Use of a compound of any of claims 1-56, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 57 in the manufacture of a medicament for the treatment of a disease or disorder mediated by MK2.

74. A kit, comprising (i) a compound of any one of claims 1-56, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 57, and (ii) instructions for use in treating an MK2- mediated disease or condition in an individual in need thereof.ny-2808889222

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