Bicyclic compounds for treatment of disease and uses thereof

Abstract

Provided herein are compounds and compositions thereof for modulating hepatocyte growth factor. In some embodiments, the compounds and the compositions are provided for the treatment of diseases, including neurological disorders.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202180079749.8 (application date: November 1, 2021, invention name: Bicyclic compounds for treating diseases and their uses).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 63 / 108,660, filed on November 2, 2020, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0004] The present disclosure generally relates to compounds, compositions, and methods of making and using the same for treating diseases, such as neurodegenerative diseases. Background Art

[0005] Hepatocyte growth factor (HGF) is a pleiotropic protein factor involved in multiple biological processes including embryonic and organ development, regeneration and inflammation. HGF is a key contributing factor to the development and maturation of cortical, motor, sensory, sympathetic and parasympathetic neurons. HGF is translated and secreted as an inactive pro-HGF, but after cleavage, the α and β-subunits produced are joined by disulfide bonds to form active heterodimers. The expression of HGF mainly occurs in interstitial cells, such as fibroblasts, chondroblasts, adipocytes and endothelium. Expression has also been confirmed in the central nervous system (CNS) including neurons, astrocytes and ependymal cells (Nakamura and Mizuno, 2010). All biological activities of HGF are mediated by MET, which is a transmembrane receptor tyrosine kinase that serves as the only known receptor of HGF. It is known that MET is involved in various biological processes and has a proven role in development, regeneration and response to injury. After HGF binds to the extracellular domain of MET, the homodimerization of MET protein causes autophosphorylation of the intracellular domain. Phosphorylation of the intracellular domain of MET leads to the recruitment and phosphorylation of various effector proteins including Gab1, GRB2, phospholipase C and Stat3 (Gherardi et al., 2012; Organ and Tsao, 2011). These effector proteins then interact with downstream signal transduction pathways including PI3K / Akt, Ras / Raf / MAPK, RAC1 / CDC42, RAP / FAK, etc. to affect a series of cellular components, including gene regulation, cytoskeletal rearrangement, cell cycle progression, cell adhesion, survival and proliferation (Organ and Tsao, 2011).

[0006] Because HGF has a demonstrated role in development (Nakamura et al., 2011), homeostasis (Funakoshi and Nakamura, 2003), inhibition of cell death and regeneration (Matsumoto et al., 2014), stimulation of the HGF / MET signaling system is an ideal target for therapies for a range of disease states. Therapies involving modulation of HGF activity have been proposed for diseases and injuries in many different tissue types including liver, kidney, gastrointestinal tract, cardiovascular components, lung, skin, nervous system and muscle tissue (Matsumoto et al., 2014). However, highly effective compounds suitable for modulating HGF / MET signaling activity remain to be explored and discovered.

[0007] Despite the advances that have been made in the art, there remains a need for improved compounds and methods for treating diseases modulated by HGF. Accordingly, in one aspect, provided herein are HGF-modulating compounds for use in treating a neurodegenerative disease. Summary of the invention

[0008] In certain embodiments, compounds and compositions thereof are described herein for modulating hepatocyte growth factor (HGF) for treating disease. Non-limiting exemplary embodiments include:

[0009] Embodiment 1. A compound of formula (I):

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein:

[0012] L is a direct bond, -C(=O)-, -(CR a R b ) m -C(=O)-, -C(=O)-(CR a R b ) m -or-(CR a R b ) m -;

[0013] Each R a and R b Independently H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 Alkynyl;

[0014] R 1a and R 1b Independently H, C1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, halogen or C 6 -C 10 Arylalkyl;

[0015] R 2 is H, oxo or thioketo;

[0016] R 3 C 2 -C 6 Alkyl, C 3 -C 6 Alkenyl, C 3 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 3 -C 6 Cycloalkylalkyl, C 6 -C 10 arylalkyl, 5- to 10-membered heteroarylalkyl or 5- to 10-membered heterocyclylalkyl,

[0017] wherein the 5- to 10-membered heteroarylalkyl or the 5- to 10-membered heterocyclylalkyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen;

[0018] R 4 C 6 -C 10 aryl, 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclic group,

[0019] wherein the 5- to 10-membered heteroaryl or the 5- to 10-membered heterocyclyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen;

[0020] Each R 5 Independently for C 1 -C 6 Alkyl, oxo or halo;

[0021] R 6 H, C 1 -C 6 Alkyl or oxo;

[0022] R 7 is H or oxo;

[0023] m is 1 or 2; and

[0024] n is an integer from 0 to 3;

[0025] Among them, each C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 3 -C 12 Cycloalkylalkyl, C 6 -C 10 Aryl, C 6 -C 10 Arylalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylalkyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heterocyclylalkyl are optionally substituted with one to five substituents selected from the group consisting of hydroxy, halo, amino, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, cyano, -(C=O)NH 2 , nitro, -SO 2 (C 1 -C 6 Alkyl) and -CO 2 H.

[0026] Embodiment 2. The compound or pharmaceutically acceptable salt thereof according to Embodiment 1, wherein L is -C(=O)- or -(CR a R b ) m -.

[0027] Embodiment 3. The compound according to Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is -C(=O)-.

[0028] Embodiment 4. The compound or pharmaceutically acceptable salt thereof according to Embodiment 1 or 2, wherein L is -(CR a R b ) m -.

[0029] Embodiment 5. The compound or pharmaceutically acceptable salt thereof as described in Embodiment 4, wherein R a and R b Each is H, and m is 1.

[0030] Embodiment 6. A compound as described in any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1bare each independently H; optionally substituted by 1 to 3 groups selected from halogen, -CO 2 H and -C(=O)NH 2 Substituents substituted with C 1 -C 6 Alkyl; C 1 -C 6 alkoxy; halo; or C optionally substituted by 1 to 3 substituents selected from halo and amino 6 -C 10 Arylalkyl.

[0031] Embodiment 7. The compound or pharmaceutically acceptable salt thereof according to Embodiment 6, wherein R 1a and R 1b are each independently H, methyl, fluoro, 2-methylbutyl, -CH 2 F, methoxy, -CH 2 CO 2 H, -CH 2 C(=O)NH 2 , benzyl or 4-aminobenzyl.

[0032] Embodiment 8. The compound or pharmaceutically acceptable salt thereof according to Embodiment 6, wherein R 1a and R 1b Each independently is H or C 1 -C 3 alkyl.

[0033] Embodiment 9. The compound or pharmaceutically acceptable salt thereof as described in Embodiment 8, wherein R 1a is methyl and R 1b For H.

[0034] Embodiment 10. The compound according to Embodiment 8 or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b Each is H.

[0035] Embodiment 11. A compound as described in any one of Embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2 For H.

[0036] Embodiment 12. A compound as described in any one of Embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a thioketone group.

[0037] Embodiment 13. A compound as described in any one of Embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2 For oxygen.

[0038] Embodiment 14. A compound as described in any one of Embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 3 C 3 -C 6 Alkyl, C 3 -C 6 Alkenyl, C 3 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 3 -C 6 Cycloalkylalkyl, C 6 -C 10 The alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl are optionally substituted with one to five substituents selected from the group consisting of hydroxy, halo, amino, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, cyano, -(C=O)NH 2 , nitro, -SO 2 (C 1 -C 6 Alkyl) and -CO 2 H.

[0039] Embodiment 15. A compound as described in any one of Embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally substituted by 1 to 3 groups selected from halogen, C 1 -C 3 Alkoxy, hydroxyl, -NH 2 、-SO 2 (C 1 -C 3 alkyl) and -C(=O)NH 2 Substituents substituted with C 2 -C 6 Alkyl; C 2 -C 6 Alkenyl; C 3 -C 6 cycloalkylalkyl; 5-membered to 6-membered heteroarylalkyl; 5-membered to 6-membered heterocyclylalkyl; or C 6 Arylalkyl.

[0040] Embodiment 16. The compound or pharmaceutically acceptable salt thereof as described in Embodiment 15, wherein R 3 is selected from 1 to 31 -C 3 Alkoxy, hydroxyl, -NH 2 and-SO 2 (C 1 -C 3 Alkyl) substituted C 2 alkyl.

[0041] Embodiment 17. A compound or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 14 to 16, wherein R 3 for:

[0042]

[0043] Embodiment 18. The compound or pharmaceutically acceptable salt thereof according to Embodiment 17, wherein R 3 for:

[0044]

[0045] Embodiment 19. A compound or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 1 to 18, wherein R 4 is optionally substituted by 1 to 3 groups selected from halo, hydroxy, C 1 -C 6 Haloalkyl and C 1 -C 6 Substituents of haloalkoxy substituted C 6 -C 10 Aryl.

[0046] Embodiment 20. The compound or pharmaceutically acceptable salt thereof according to Embodiment 19, wherein R 4 is selected from 1 to 3 -CF 3 、-OCHF 2 , -OH, fluorine and chlorine substituents.

[0047] Embodiment 21. The compound or pharmaceutically acceptable salt thereof as described in Embodiment 20, wherein R 4 for:

[0048]

[0049] Embodiment 22. The compound or pharmaceutically acceptable salt thereof as described in Embodiment 21, wherein R 4 for:

[0050]

[0051] Embodiment 23. A compound as described in any one of Embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R 4is optionally substituted by 1 to 3 groups selected from halo, hydroxy, C 1 -C 6 Haloalkyl and C 1 -C 6 The substituent of the haloalkoxy group is a substituted 5- to 10-membered heteroaryl group.

[0052] Embodiment 24. The compound or pharmaceutically acceptable salt thereof as described in Embodiment 23, wherein R 4 is optionally selected from halogen, hydroxyl, C 1 -C 6 Haloalkyl and C 1 -C 6 The haloalkoxy group is substituted with 1 to 3 substituents, pyridyl or indolyl.

[0053] Embodiment 25. The compound according to Embodiment 24 or a pharmaceutically acceptable salt thereof, wherein

[0054] R 4 for

[0055] Embodiment 26. A compound according to Embodiment 25 or a pharmaceutically acceptable salt thereof, wherein

[0056] R 4 for

[0057] Embodiment 27. A compound as described in any one of Embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally substituted by 1 to 3 groups selected from halo, hydroxy, C 1 -C 6 Haloalkyl and C 1 -C 6 The substituent of the haloalkoxy group is a substituted 5- to 10-membered heterocyclic group.

[0058] Embodiment 28. The compound or pharmaceutically acceptable salt thereof as described in Embodiment 27, wherein R 4 Indolinyl.

[0059] Embodiment 29. The compound or pharmaceutically acceptable salt thereof as described in Embodiment 28, wherein R 4 for

[0060] Embodiment 30. A compound or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 1 to 26, wherein -LR 4 for:

[0061]

[0062] Embodiment 31. A compound as described in any one of Embodiments 1 to 30, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0063] Embodiment 32. A compound as described in any one of Embodiments 1 to 30, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0064] Embodiment 33. The compound or pharmaceutically acceptable salt thereof as described in Embodiment 32, wherein R 5 It is oxo or halogen.

[0065] Embodiment 34. The compound or pharmaceutically acceptable salt thereof as described in Embodiment 33, wherein R 5 is oxo or fluoro.

[0066] Embodiment 35. A compound as described in any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R 6 For H.

[0067] Embodiment 36. A compound as described in any one of Embodiments 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R 7 For oxygen.

[0068] Embodiment 37. A compound as described in any one of Embodiments 1 to 10, 13 to 31, 35 and 36, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (V):

[0069]

[0070] Embodiment 38. The compound according to Embodiment 37 or a pharmaceutically acceptable salt thereof, wherein:

[0071] L is -C(=O)- or -CH 2 -;

[0072] R 1a and R 1b are each independently H or optionally substituted by -CO 2 H substituted C 1 -C 3 alkyl;

[0073] R 3 C 4 -C 5 Alkyl, C 4 -C 5 Alkenyl or C 3 -C 5 Cycloalkyl substituted C 1 -C 3 Alkyl; and

[0074] R4 is selected from 1 to 3 -CF 3 、-OCHF 2 , -OH, fluorine and chlorine substituents, phenyl or pyridyl.

[0075] Embodiment 39. A compound selected from the compounds of Table 1A and pharmaceutically acceptable salts thereof.

[0076] Embodiment 40. A pharmaceutical composition comprising a compound as described in any one of Embodiments 1 to 39 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0077] Embodiment 41. A method for regulating hepatocyte growth factor in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as described in any one of Embodiments 1 to 39 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Embodiment 40.

[0078] Embodiment 42. The method of embodiment 41, wherein said modulation comprises treating a disease, condition or injury.

[0079] Embodiment 43. The method of embodiment 42, wherein the disease, the condition, or the injury is a neurodegenerative disease, a spinal cord injury, a traumatic brain injury, or a sensorineural hearing loss.

[0080] Embodiment 44. The method of embodiment 42 or 43, wherein the disease, the condition or the injury is a neurodegenerative disease.

[0081] Embodiment 45. The method of embodiment 44, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis (ALS).

[0082] Embodiment 46. The method of embodiment 45, wherein the neurodegenerative disease is Alzheimer's disease or Parkinson's disease.

[0083] Embodiment 47. A method for treating or slowing the progression of dementia in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as described in any one of Embodiments 1 to 39 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Embodiment 40.

[0084] Embodiment 48. The method of embodiment 47, wherein the dementia is associated with Alzheimer's disease or Parkinson's disease.

[0085] Embodiment 49. A method for preventing cognitive dysfunction in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 1 to 39, or a pharmaceutical composition as described in Embodiment 40.

[0086] Embodiment 50. A method for treating, repairing or preventing a disease, condition or injury associated with nervous tissue in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as described in any one of Embodiments 1 to 39 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Embodiment 40.

[0087] Embodiment 51. A method for treating or preventing a disease or disorder of the central nervous system, a disease or disorder of the peripheral nervous system, neuropathic pain, anxiety or depression in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as described in any one of Embodiments 1 to 39 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Embodiment 40. DETAILED DESCRIPTION

[0088] definition

[0089] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present disclosure belongs. In the following description, certain specific details are set forth in order to provide a comprehensive understanding of the various embodiments of the present disclosure. It should be understood that the foregoing general description and the following detailed description are only exemplary and explanatory and do not limit any subject matter required. In the case where any material incorporated herein by reference is inconsistent with the content of the present disclosure, the content of the expression shall prevail. In the present application, unless otherwise specifically stated, the use of the singular includes the plural. It must be noted that, unless the context clearly specifies otherwise, the singular forms "a / an" and "said" as used in this specification and the appended claims include plural indicators. In the present application, unless otherwise stated, the use of "or" means "and / or". In addition, the use of the term "including" and other forms (such as "include / includes / included") is not restrictive.

[0090] Unless the context requires otherwise, throughout this specification and claims, the word "comprise" and variations thereof (such as "comprises" and "comprising") are to be construed in an open, inclusive sense, ie, "including (but not limited to)".

[0091] In this specification, unless otherwise indicated, any concentration range, percentage range, ratio range or integer range should be understood to include any integer value within the stated range and (where appropriate) its fraction (such as one tenth and one hundredth of an integer). In addition, unless otherwise indicated, any numerical range related to any physical feature such as polymer subunits, size or thickness stated herein should be understood to include any integer within the stated range. As used herein, unless otherwise indicated, the terms "about" and "approximately" mean ±20%, ±10%, ±5% or ±1% of the indicated range, value or structure.

[0092] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0093] "Amino" refers to -NH 2 Group.

[0094] "Carboxy" or "carboxyl" refers to -CO 2 H group.

[0095] "Cyano" refers to a -CN group.

[0096] "Hydroxy" or "hydroxyl" refers to an -OH group.

[0097] "Nitro" refers to -NO 2 Group.

[0098] "Oxo" refers to a =0 substituent.

[0099] "Thioneto" refers to a =S substituent.

[0100] "Thiol" refers to a -SH substituent.

[0101] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain radical consisting solely of carbon and hydrogen atoms having from one to twelve carbon atoms (C 1 -C 12 Alkyl), preferably one to eight carbon atoms (C 1 -C 8 Alkyl), one to six carbon atoms (C 1 -C 6 Alkyl) or one to three carbon atoms (C 1 -C 3Alkyl) and which is attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, etc. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted.

[0102] "Alkenyl" refers to an unbranched or branched unsaturated hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, having from two to twelve carbon atoms (C 2 -C 12 alkenyl), preferably two to eight carbon atoms (C 2 -C 8 alkenyl) or two to six carbon atoms (C 2 -C 6 The alkenyl group is optionally substituted, unless stated otherwise specifically in the specification, and is linked to the rest of the molecule by a single bond, such as vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, etc. Unless stated otherwise specifically in the specification, the alkenyl group is optionally substituted.

[0103] "Alkynyl" refers to an unbranched or branched unsaturated hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon triple bonds, having from two to twelve carbon atoms (C 2 -C 12 Alkynyl), preferably two to eight carbon atoms (C 2 -C 8 Alkynyl) or two to six carbon atoms (C 2 -C 6 Alkynyl) and it is attached to the rest of the molecule through a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless stated otherwise specifically in the specification, alkynyl is optionally substituted.

[0104] "Alkoxy" refers to a group of the formula -OR a A group in which R a is an alkyl group as defined above containing one to twelve carbon atoms. Preferred alkoxy groups have one to six carbon atoms (i.e., C 1 -C 6 Alkoxy) or one to three carbon atoms (i.e. C 1 -C 3 Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[0105] "Aromatic ring" refers to the cyclic planar portion of a molecule (i.e., a group) of a ring with a resonant bond, which is arranged relative to other connectivity of atoms with the same group to show increased stability. In general, an aromatic ring contains a set of covalently bonded coplanar atoms and includes multiple π-electrons (e.g., alternating double bonds and single bonds) that are even numbers but not multiples of 4 (i.e., 4n+2 π-electrons, wherein n=0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthyl (naphthenyl), imidazolyl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, pyridone, pyridazinyl, pyrimidone. Unless otherwise specifically stated in this specification, "aromatic ring" includes all groups that are optionally substituted.

[0106] "Aryl" refers to a group containing 6 to 18 carbon atoms and at least one aromatic ring (i.e., C 6 -C 18 Aryl), preferably having 6 to 10 carbon atoms (i.e., C 6 -C 10 For purposes of the embodiments of the present disclosure, an aryl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, The aryl group may be substituted with chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, phenyl, pleiadene, pyrene and triphenylene. Unless otherwise specifically stated in the specification, the aryl group is optionally substituted.

[0107] "Arylalkyl" refers to a group of the formula -R b -R c A group in which R b is an alkylene chain and R c is one or more aryl groups as defined above, for example benzyl, diphenylmethyl, etc. Arylalkyl groups may contain 6 -C 10 Aryl (i.e. C 6 -C 10 Arylalkyl) C 1 -C 10Unless stated otherwise specifically in the specification, an arylalkyl group is optionally substituted.

[0108] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic carbocyclic radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms (i.e., C 3 -C 15 Cycloalkyl), preferably having three to ten carbon atoms (i.e., C 3 -C 10 Cycloalkyl) or three to six carbon atoms (i.e. C 3 -C 6 Cycloalkyl) and it is saturated or unsaturated and is connected to the rest of the molecule by a single bond. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When there are two substitution positions on the same carbon atom, cycloalkyl also includes "spirocycloalkyl". Polycyclic groups include, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo [2.2.1] heptyl etc. Unless specifically stated otherwise in this specification, cycloalkyl is optionally substituted.

[0109] "Cycloalkylalkyl" refers to a group of the formula -R b -R c A group in which R b is an alkylene chain and R c is one or more cycloalkyl groups as defined above, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, etc. The cycloalkylalkyl group may contain a 3 -C 12 Cycloalkyl (i.e. C 3 -C 12 Cycloalkylalkyl) C 1 -C 10 Alkylene chain or connected to C 3 -C 6 Cycloalkyl (i.e. C 3 -C 6 Cycloalkylalkyl) C 1 -C 10 Unless stated otherwise specifically in the specification, a cycloalkylalkyl group is optionally substituted.

[0110] "Fused" means that any ring structure described herein is fused to an existing ring structure in the compounds of the present disclosure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or the fused heteroaryl ring is replaced by a nitrogen atom.

[0111] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.

[0112] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Preferred haloalkyl groups include alkyl groups having one to six carbon atoms and substituted with one or more halo groups (i.e., C 1 -C 6 The haloalkyl groups may be all the same or the haloalkyl groups may be different. Unless otherwise specifically stated in the specification, the haloalkyl groups are optionally substituted.

[0113] "Haloalkoxy" refers to a group of the formula -OR a A group in which R a is a haloalkyl group as defined herein containing from one to twelve carbon atoms. Preferred haloalkoxy groups include haloalkyl groups having from one to six carbon atoms (i.e., C 1 -C 6 haloalkoxy) or having one to three carbon atoms (C 1 -C 3 The term "haloalkoxy" refers to an alkoxy group (e.g., a haloalkoxy group) and an alkoxy group substituted with one or more halo groups. The halo groups may all be the same or the halo groups may all be different. Unless otherwise specifically stated in the specification, the haloalkoxy group is optionally substituted.

[0114] "Heteroaryl" refers to an aromatic group (e.g., a 5- to 14-membered ring system) having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 10 ring carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur in the ring. Preferred heteroaryl groups have a 5- to 10-membered ring system (i.e., a 5- to 10-membered heteroaryl) containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered ring system (i.e., a 5- to 6-membered heteroaryl) containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur. For the purposes of the embodiments of the present disclosure, aryl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system. Examples of heteroaryl groups include pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolyl, quinuclidinyl, isoquinolyl, tetrahydroquinolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thiophenyl / thienyl. Heteroaryl groups may include one or more N-oxide (NO-) moieties, such as pyridine-N-oxide. Unless otherwise specifically stated in the specification, heteroaryl groups are optionally substituted.

[0115] "Heteroarylalkyl" refers to a group of the formula -R b -R c A group in which R b is an alkylene chain and Rc is one or more heteroaryl groups as defined above. The heteroarylalkyl group may contain a C 1 -C 10 The alkylene chain or the C 1 -C 10 Unless stated otherwise specifically in the specification, a heteroarylalkyl group is optionally substituted.

[0116] "Heterocyclyl" refers to a saturated or unsaturated cycloalkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term "heterocyclyl" includes heterocycloalkenyl (i.e., a heterocyclyl having at least one double bond), bridged heterocyclyl, fused heterocyclyl and spiro heterocyclyl. The heterocyclyl group may be a single ring or multiple rings, wherein the multiple rings may be fused, bridged or spiro, and may contain one or more oxo (C=O) moieties or N-oxide (NO-) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the connection (i.e., it may be bonded via a carbon atom or a heteroatom). In addition, regardless of the connection to the rest of the molecule, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which may be fused to an aryl or heteroaryl ring. As used herein, heterocyclyl has 1 to 10 ring carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms, and 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Preferred heterocyclyls have five to ten members in the ring system including one to four heteroatoms selected from nitrogen and oxygen (i.e., 5- to 10-membered heterocyclyls) or five to eight members in the ring system including one to four heteroatoms selected from nitrogen and oxygen (i.e., 5- to 8-membered heterocyclyls). Examples of heterocyclic groups include dioxolanyl, thienyl [1,3] dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, heterocyclic groups are optionally substituted.

[0117] "Heterocyclylalkyl" refers to a group of the formula -R b -R c A group in which R b is an alkylene chain and R cis one or more heterocyclyl groups as defined above. The heterocyclylalkyl group may contain a C 1 -C 10 The alkylene chain or the C 1 -C 10 Unless stated otherwise specifically in the specification, a heterocyclylalkyl group is optionally substituted.

[0118] In some embodiments, the term "substituted" as used herein means any of the above groups or other substituents (e.g., C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 3 -C 12 alkyl, aryl, and heteroaryl) wherein at least one hydrogen atom (e.g., 1, 2, 3, or all of the hydrogen atoms) is replaced by a bond to a non-hydrogen atom such as, but not limited to, a halogen atom such as F, Cl, Br, and I (i.e., a "halo"); an oxygen atom in a group such as hydroxy or an alkoxy group (e.g., alkoxy or haloalkoxy); a nitrogen atom in a group such as an amine (e.g., -NH 2 ), amides (e.g., -(C=O)NH 2 ) and nitro; alkyl groups including one or more halogens, such as F, Cl, Br and I (eg, haloalkyl); and cyano.

[0119] It should be understood that unless otherwise specified, L, R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Each selection of is optionally substituted as described above, with the proviso that all valences are satisfied by substitution. Specifically, unless otherwise specifically stated, L, R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 and R 7Each selection of is optionally substituted, and provided such substitution results in a stable molecule (eg, groups such as H and halo are not optionally substituted).

[0120] An "effective amount" or "therapeutically effective amount" of a compound or composition refers to the amount of the compound or composition that produces the desired result as needed based on the disclosure herein. The effective amount can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to by measuring ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (a dose lethal to 50% of the population). In some embodiments, an effective amount of a compound causes a reduction or suppression of symptoms or a prolongation of survival in a subject (ie, a human patient). Multiple doses of the compound may be required as a result.

[0121] "Treating / treatment" a disease of a subject refers to 1) preventing the disease from occurring in a patient who is susceptible to the disease or has not yet shown symptoms of the disease; 2) inhibiting the disease or curbing its development; or 3) ameliorating the disease or causing the disease to regress. As used herein, "treatment / treating" is a method for obtaining a beneficial or desired result (including a clinical result). For the purposes of this disclosure, a beneficial or desired result includes, but is not limited to, one or more of the following: alleviating one or more symptoms caused by a disease or condition; reducing the extent of a disease or condition; stabilizing a disease or condition (e.g., preventing or delaying the deterioration of a disease or condition); delaying the occurrence or recurrence of a disease or condition; delaying or slowing the progression of a disease or condition; improving the condition of a disease or condition; alleviating a disease or condition (partially or completely); reducing the dose of one or more other drugs required to treat a disease or condition; enhancing the effect of another drug used to treat a disease or condition; delaying the progression of a disease or condition; improving the quality of life; and / or prolonging the survival of a subject. "Treatment" also encompasses the mitigation of the pathological consequences of a disease or condition. The methods of the present invention encompass any one or more of these therapeutic aspects.

[0122] As used herein, the terms "individual," "subject," and "patient" mean any mammal. Examples include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, the mammal is a human.

[0123] As the term is used herein, "therapeutic effect" encompasses therapeutic benefit and / or prophylactic benefit as described herein. Therapeutic effect includes delaying or eliminating the appearance of a disease or condition; delaying or eliminating the onset of symptoms of a disease or condition; slowing, arresting or reversing the progression of a disease or condition; causing partial or complete regression of a disease or condition; or any combination thereof.

[0124] As used herein, the terms "co-administration," "administered in combination with," and grammatical equivalents thereof encompass administration of two or more agents to animals, including humans, such that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration in separate compositions at different times, or administration in a composition in which both agents are present.

[0125] "Pharmaceutically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are suitable for use in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0126] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts.

[0127] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexylaminesulfonic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethane Sulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptanoic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid and similar acids.

[0128] "Pharmaceutically acceptable base addition salts" refer to those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable. These salts are prepared by the addition of inorganic or organic bases to the free acids. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts and the like. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0129] In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts, such as quaternary ammonium alkyl halide salts (eg, methyl bromide).

[0130] As used herein, "therapeutic agent" refers to a biological, pharmaceutical or chemical compound or other moiety. Non-limiting examples include simple or complex organic or inorganic molecules, peptides, proteins, oligonucleotides, antibodies, antibody derivatives, antibody fragments, vitamin derivatives, carbohydrates, toxins or chemotherapeutic compounds. Various compounds such as small molecules and oligomers (e.g., oligopeptides and oligonucleotides) and synthetic organic compounds based on various core structures can be synthesized. In addition, various natural sources can provide compounds for screening, such as plant or animal extracts, etc.

[0131] The term "in vivo" refers to events that occur within the body of a subject.

[0132] Embodiments of the present disclosure are also intended to encompass all pharmaceutically acceptable compounds of Formula (I) that are isotopically labeled by replacing one or more atoms with atoms having a different atomic mass or mass number (i.e., "isotopic forms" of compounds of Formula (I)). Examples of isotopes that may be incorporated into compounds of Formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C.14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. These radiolabeled compounds can be used to help determine or measure the effectiveness of a compound by characterizing, for example, the site or mode of action or binding affinity to a pharmacologically important site. Certain isotopically labeled compounds of formula (I) (e.g., those incorporating a radioisotope) are useful in drug and / or substrate tissue distribution studies. The radioisotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) is particularly suitable for this purpose due to its ease of incorporation and ready means of detection.

[0133] Deuterium (i.e. 2 Substitution of heavier isotopes may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[0134] Through such 11 C. 18 F. 15 O and 13 Positron emitting isotope substitution of N may be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to the methods described in the Examples set forth below, using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously employed.

[0135] Certain embodiments are also intended to encompass in vivo metabolites of the disclosed compounds. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, which is primarily due to enzymatic processes. Therefore, embodiments include compounds produced by methods including administering a compound of the present disclosure to a mammal for a period of time sufficient to produce its metabolites. Such products are typically administered to an animal (such as a rat, mouse, guinea pig, monkey) or to a human of a detectable dose of a radiolabeled compound of the present disclosure, allowing metabolism to proceed for a sufficient time and separating its conversion products from urine, blood, or other biological samples for identification.

[0136] "Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0137] Typically crystallization produces a solvate of the disclosed compounds. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of the compound of formula (I) and one or more solvent molecules. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Therefore, the compound of formula (I) can exist as a hydrate, including a monohydrate, a dihydrate, a hemihydrate, a sesquihydrate, a trihydrate, a tetrahydrate, etc., and corresponding solvated forms. In some aspects, the compound of formula (I) is a true solvate, while in other cases, the disclosed compounds only retain exogenous water or are a mixture of water plus some exogenous solvents.

[0138] "Optional / optionally" means that the event or situation described subsequently may or may not occur, and the description includes the situation where the event or situation occurs and the situation where it does not occur. For example, "optionally substituted aryl" means that the aryl may be substituted or may not be substituted and the description includes both substituted aryl and aryl without substitution. Polymers or similar infinite structures obtained by defining substituents with other substituents attached infinitely (for example, substituted aryl with substituted alkyl, the substituted alkyl itself is substituted by substituted aryl, the substituted aryl is further substituted by substituted heteroalkyl, etc.) are not intended to be included in this article. Similarly, the above definition is not intended to include unallowed substitution patterns (for example, methyl substituted with 5 fluorines or heteroaryl with two adjacent oxygen ring atoms). Such unallowed substitution patterns are well known to those skilled in the art.

[0139] "Pharmaceutical composition" or "pharmaceutically acceptable composition" refers to a preparation of a compound of the present disclosure and a medium generally accepted in the art for delivering biologically active compounds to mammals (e.g., humans). Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients thereof.

[0140] "Pharmaceutically acceptable carriers, diluents or excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0141] The compounds of formula (I) or their pharmaceutically acceptable salts or isotopic forms thereof may contain one or more centers causing geometric asymmetry and may thus provide enantiomers, diastereomers and other stereoisomeric forms defined as (R)- or (S)- or as (D)- or (L)- for amino acids in terms of absolute stereochemistry. Embodiments therefore include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0142] "Stereoisomers" refer to compounds made up of the same atoms bonded by the same bonds but with different three-dimensional structures that are not interchangeable. The present disclosure encompasses various stereoisomers and mixtures thereof and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0143] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0144] "Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. Embodiments therefore include tautomers of the disclosed compounds.

[0145] The chemical naming schemes and structure diagrams used herein are modified forms of the IUPAC nomenclature system, which use ACD / named version 9.07 software program and / or ChemDraw Ultra version 11.0.1 software naming program (CambridgeSoft). For the complex chemical names used herein, the substituent is usually named before the group to which it is attached. For example, cyclopropylethyl includes an ethyl backbone with a cyclopropyl substituent. Unless described below, all bonds are identified in the chemical structure diagrams herein, except for all bonds on some carbon atoms, assuming that they are bonded to enough hydrogen atoms to complete the valence.

[0146] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although for clarity the invention may be described herein in the context of separate embodiments, the invention may also be implemented in a single embodiment.

[0147] Compound

[0148] In one aspect, provided herein is a compound of formula (I):

[0149]

[0150] or a pharmaceutically acceptable salt thereof, wherein:

[0151] L is a direct bond, -C(=O)-, -(CR a R b ) m -C(=O)-, -C(=O)-(CR a R b ) m -or-(CR a R b ) m -;

[0152] Each R a and R b Independently H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 Alkynyl;

[0153] R 1a and R 1b Independently H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, halogen or C 6 -C 10 Arylalkyl;

[0154] R 2 is H, oxo or thioketo;

[0155] R 3 C 2 -C 6 Alkyl, C 3 -C 6 Alkenyl, C3 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 3 -C 6 Cycloalkylalkyl, C 6 -C 10 arylalkyl, 5- to 10-membered heteroarylalkyl or 5- to 10-membered heterocyclylalkyl,

[0156] wherein the 5- to 10-membered heteroarylalkyl or the 5- to 10-membered heterocyclylalkyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen;

[0157] R 4 C 6 -C 10 aryl, 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclic group,

[0158] wherein the 5- to 10-membered heteroaryl or the 5- to 10-membered heterocyclyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen;

[0159] Each R 5 Independently for C 1 -C 6 Alkyl, oxo or halo;

[0160] R 6 H, C 1 -C 6 Alkyl or oxo;

[0161] R 7 is H or oxo;

[0162] m is 1 or 2; and

[0163] n is an integer from 0 to 3;

[0164] Among them, each C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 3 -C 12 Cycloalkylalkyl, C 6 -C 10 Aryl, C 6 -C 10 Arylalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylalkyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heterocyclylalkyl are optionally substituted with one to five substituents selected from the group consisting of hydroxy, halo, amino, C1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, cyano, -(C=O)NH 2 , nitro, -SO 2 (C 1 -C 6 Alkyl) and -CO 2 H.

[0165] In some embodiments, L is a direct bond. In some embodiments, L is -C(=O)- or -(CR a R b ) m -. In some embodiments, L is -C(=O)-. In some embodiments, L is -(CR a R b ) m -. In some embodiments, L is -(CR a R b ) m -C(=O)- or -C(=O)-(CR a R b ) m -. In some embodiments, L is -(CR a R b ) m -C(=O)-. In some embodiments, L is -C(=O)-(CR a R b ) m -.

[0166] In some embodiments, each R a and R b Independently H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 In some embodiments, each R a and R b Independently H, C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl or C 2 -C 4 In some embodiments, R a and R b Each is H. In some embodiments, R ais H. In some embodiments, R a C 1 -C 6 In some embodiments, R a C 2 -C 6 In some embodiments, R a C 2 -C 6 In some embodiments, R b is H. In some embodiments, R b C 1 -C 6 In some embodiments, R b C 2 -C 6 In some embodiments, R b C 2 -C 6 Alkynyl, such as ethynyl or propynyl.

[0167] In some embodiments, R 1a and R 1b Independently H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, halogen or C 6 -C 10 In some embodiments, R 1a is H. In some embodiments, R 1a C 1 -C 6 In some embodiments, R 1a C 2 -C 6 In some embodiments, R 1a C 2 -C 6 In some embodiments, R 1a C 1 -C 6 Alkoxy, such as methoxy, ethoxy or propoxy. In some embodiments, R 1ais a halogen group, such as fluorine, chlorine or bromine. 1a C 6 -C 10 Arylalkyl, such as benzyl. In some embodiments, R 1b is H. In some embodiments, R 1b C 1 -C 6 In some embodiments, R 1b C 2 -C 6 In some embodiments, R 1b C 2 -C 6 In some embodiments, R 1b C 1 -C 6 Alkoxy, such as methoxy, ethoxy or propoxy. In some embodiments, R 1b is a halogen group, such as fluorine, chlorine or bromine. 1b C 6 -C 10 Arylalkyl, such as benzyl.

[0168] In some embodiments, R 1a and R 1b are each independently H; optionally substituted by 1 to 3 groups selected from halogen, -CO 2 H and -C(=O)NH 2 Substituents substituted with C 1 -C 6 Alkyl; C 1 -C 6 alkoxy; halo; or C optionally substituted by 1 to 3 substituents selected from halo and amino 6 -C 10 In some embodiments, R 1a is C substituted by 1 to 3 halogen groups 1 -C 6 In some embodiments, R 1a For 1 to 3 -CO 2 H-substituted C 1 -C 6 In some variations, R 1a For 1 to 2 CO 2 H-substituted C 1 -C 3 Alkyl groups, such as -CH 2 CO 2H or -CH 2 CH 2 CO 2 H. In some embodiments, R 1a is 1 to 3 -C(=O)NH 2 C 1 -C 6 In some embodiments, R 1a 1 to 2 -C(=O)NH 2 C 1 -C 3 Alkyl groups, such as -CH 2 C(=O)NH 2 or -CH 2 CH 2 C(=O)NH 2 In some embodiments, R 1a is C substituted by 1 to 3 substituents selected from halogen and amino 6 -C 10 In some embodiments, R 1a is C substituted by 1 to 3 halogen groups 6 -C 10 Arylalkyl, such as fluorine, chlorine or bromine. In some embodiments, R 1a is C substituted by 1 to 3 amine groups 6 -C 10 In some embodiments, R 1b is C substituted by 1 to 3 halogen groups 1 -C 6 In some embodiments, R 1b For 1 to 3 -CO 2 H-substituted C 1 -C 6 In some variations, R 1b For 1 to 2 CO 2 H-substituted C 1 -C 3 Alkyl groups, such as -CH 2 CO 2 H or -CH 2 CH 2 CO 2 H. In some embodiments, R 1b is 1 to 3 -C(=O)NH 2 C 1 -C 6 In some embodiments, R 1b 1 to 2 -C(=O)NH 2 C1 -C 3 Alkyl groups, such as -CH 2 C(=O)NH 2 or -CH 2 CH 2 C(=O)NH 2 In some embodiments, R 1b is C substituted by 1 to 3 substituents selected from halogen and amino 6 -C 10 In some embodiments, R 1b is C substituted by 1 to 3 halogen groups 6 -C 10 Arylalkyl, such as fluorine, chlorine or bromine. In some embodiments, R 1b is C substituted by 1 to 3 amine groups 6 -C 10 In some embodiments, R 1a and R 1b are each independently H, methyl, fluoro, 2-methylbutyl, -CH 2 F, methoxy, -CH 2 CO 2 H, -CH 2 C(=O)NH 2 , benzyl or 4-aminobenzyl. In some embodiments, R 1a and R 1b Each independently is H or C 1 -C 3 In some embodiments, R 1a is methyl and R 1b is H. In some embodiments, R 1a and R 1b Each is H. In some embodiments, R 1a and R 1b One of them is H and the other is C 1 -C 3 An alkyl group, such as a methyl group.

[0169] In some embodiments, R 2 is H, oxo or thioketo. In some embodiments, R 2 is H. In some embodiments, R 2 In some embodiments, R 2 It is a thioketone group.

[0170] In some embodiments, R 3 C 3 -C 6 Alkyl, C 3 -C6 Alkenyl, C 3 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 3 -C 6 Cycloalkylalkyl, C 6 -C 10 In some embodiments, R 3 C 3 -C 6 In some embodiments, R 3 C 4 -C 6 In some embodiments, R 3 C 3 -C 6 In some embodiments, R 3 C 4 -C 6 In some embodiments, R 3 C 3 -C 6 In some embodiments, R 3 C 4 -C 6 In some embodiments, R 3 C 3 -C 12 Cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 3 C 3 -C 6 In some embodiments, R 3 C 3 -C 6 Cycloalkylalkyl, such as -(CH 2 ) 1-3 (C 3 -C 6 In some embodiments, R 3 C 6 -C 10 Arylalkyl, such as benzyl. In some embodiments, R 3 is a 5- to 10-membered heteroarylalkyl group, such as -(CH 2 ) 1-3 (5- to 10-membered heteroaryl) or -(CH 2 ) 1-3(5-membered to 6-membered heteroaryl). In some embodiments, the 5-membered to 10-membered heteroarylalkyl contains 1 to 2 nitrogen atoms. In some embodiments, R 3 is a 5- to 10-membered heterocyclylalkyl group, such as -(CH 2 ) 1-3 (5- to 10-membered heterocyclic group) or -(CH 2 ) 1-2 (5- to 6-membered heterocyclyl). In some embodiments, the 5- to 10-membered heterocyclylalkyl contains 1 to 2 nitrogen atoms.

[0171] In some embodiments, R 3 is optionally substituted by 1 to 3 groups selected from halogen and -C(=O)NH 2 Substituents substituted with C 3 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 3 -C 6 In some embodiments, R 3 is optionally substituted by 1 to 3 groups selected from halogen, C 1 -C 3 Alkoxy, hydroxyl, -NH 2 、-SO 2 (C 1 -C 3 alkyl) and -C(=O)NH 2 Substituents substituted with C 2 -C 6 Alkyl; C 2 -C 6 Alkenyl; C 3 -C 6 cycloalkylalkyl; 5-membered to 6-membered heteroarylalkyl; 5-membered to 6-membered heterocyclylalkyl; or C 6 In some embodiments, R 3 is selected from 1 to 3 1 -C 3 Alkoxy, hydroxyl, -NH 2 and-SO 2 (C 1 -C 3 Alkyl) substituted C 2 In some embodiments, R 3 for:

[0172]

[0173] In some embodiments, R 3 for:

[0174]

[0175] In some embodiments, R 3 It is 2-methylbutyl.

[0176] In some embodiments, R 4 C 6 -C 10 In some embodiments, R 4 C 6 -C 10 In some embodiments, R 4 is a 5- to 10-membered heteroaryl group containing 1 to 2 nitrogen atoms. 4 is a 5- to 10-membered heterocyclic group. 4 is a 5- to 9-membered heterocyclic group containing 1 to 2 nitrogen atoms. 4 is a 5- to 9-membered heterocyclic group containing 1 to 2 oxygen atoms. 4 It is a 5- to 9-membered heterocyclic group containing 1 nitrogen atom and 1 oxygen atom.

[0177] In some embodiments, R 4 is optionally substituted by 1 to 3 groups selected from halo, hydroxy, C 1 -C 6 Haloalkyl and C 1 -C 6 Substituents of haloalkoxy substituted C 6 -C 10 In some embodiments, R 4 is selected from 1 to 3 -CF 3 、-OCHF 2 In some embodiments, R 4 for:

[0178]

[0179] In some embodiments, R 4 for:

[0180]

[0181] In some embodiments, R 4 is optionally substituted by 1 to 3 groups selected from halo, hydroxy, C 1 -C 6 Haloalkyl and C 1-C 6 In some embodiments, R 4 is optionally substituted by 1 to 3 groups selected from halo, hydroxy, C 1 -C 6 Haloalkyl and C 1 -C 6 In some embodiments, R 4 for In some embodiments, R 4 is substituted by 1 to 3 groups selected from halogen, hydroxyl, C 1 -C 6 Haloalkyl and C 1 -C 6 In some embodiments, R 4 for In some embodiments, R 4 is optionally substituted by 1 to 3 groups selected from halo, hydroxy, C 1 -C 6 Haloalkyl and C 1 -C 6 In some embodiments, R 4 Indolinyl

[0182] In some embodiments, -LR 4 -CH 2 (phenyl) or -C(O)(phenyl), wherein the phenyl group is replaced by 1 to 3 groups selected from C 1 -C 3 Haloalkyl, C 1 -C 3 In some embodiments, -LR 4 -CH 2 (pyridinyl) or -C(O)(pyridinyl), wherein the pyridinyl group is replaced by 1 to 3 groups selected from C 1 -C 3 Haloalkyl, C 1 -C 3 In some embodiments, -LR 4 for:

[0183]

[0184] In some embodiments, each R 5 Independently for C 1 -C 6In some embodiments, R 5 C 1 -C 6 In some embodiments, R 5 In some embodiments, R 5 is a halogen group, such as fluorine, chlorine or bromine. 5 In some embodiments, R 5 is oxo or fluoro.

[0185] In some embodiments, R 6 H, C 1 -C 6 In some embodiments, R 6 is H. In some embodiments, R 6 C 1 -C 6 In some embodiments, R 6 For oxygen.

[0186] In some embodiments, R 7 is H or oxo. In some embodiments, R 7 is H. In some embodiments, R 7 For oxygen.

[0187] In some embodiments, m is 1. In other embodiments, m is 2.

[0188] In some embodiments, n is 0. In other embodiments, n is an integer from 1 to 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0189] In any embodiment of Formula (I) or its variations, each C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 3 -C 12 Cycloalkylalkyl, C 6 -C 10 Aryl, C 6 -C 10The arylalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylalkyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heterocyclylalkyl groups are optionally substituted with one to three substituents selected from hydroxy, halo (such as fluorine, chlorine, or bromine), amino, C 1 -C 6 Haloalkyl (such as -CF 3 or -CHF 2 ), C 1 -C 6 Alkoxy (such as methoxy or ethoxy), C 1 -C 6 Haloalkoxy (such as -OCHF 2 or -OCF 3 ) and -(C=O)NH 2 .

[0190] In some embodiments, the compound of formula (I) is a compound of formula (II), (IIa), (IIb), (IIc), (IId), or (IIe):

[0191]

[0192] or a pharmaceutically acceptable salt thereof, wherein L, R 1a , R 1b , R 3 , R 4 , R 5 , R 6 , R 7 and n are as described for formula (I). In some embodiments, the compound has formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula (IIa) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula (IIb) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula (IIc) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula (IId) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula (IIe) or a pharmaceutically acceptable salt thereof.

[0193] In some embodiments, the compound of formula (I) is a compound of formula (IIIa), (IIIb), (IIIc) or (IIId):

[0194]

[0195]

[0196] or a pharmaceutically acceptable salt thereof, wherein R 1a , R 1b , R 3, R 5 , R 6 and n is as described for formula (I), and R represents one or more optionally selected substituents such as hydroxy, halo, amino, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy, as described for formula (I). In some embodiments, the compound has formula (IIIa) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula (IIIb) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula (IIIc) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula (IIId) or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, the compound of formula (I) is a compound of formula (IVa), (IVb), (IVc) or (IVd):

[0198]

[0199] or a pharmaceutically acceptable salt thereof, wherein R 5 and n is as described for formula (I), and R represents one or more optionally selected substituents such as hydroxy, halo, amino, C 1 -C 6 Haloalkyl, C 1 -C 6 In some embodiments, the compound has the formula (IVa) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the formula (IVb) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the formula (IVc) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the formula (IVd) or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments, the compound of formula (I) is a compound of formula (V):

[0201]

[0202] or a pharmaceutically acceptable salt thereof, wherein L, R 1a , R 1b , R 3 and R 4 As described for formula (I). In some embodiments, L is -C(=O)- or -CH 2 -; R 1a and R 1b is independently H or optionally -CO 2 H substituted C 1-C 3 Alkyl; R 3 C 4 -C 5 Alkyl, C 4 -C 5 Alkenyl or C 3 -C 5 Cycloalkyl substituted C 1 -C 3 alkyl; and R 4 is selected from 1 to 3 -CF 3 、-OCHF 2 , -OH, fluorine and chlorine substituted phenyl or pyridinyl. In some variations, R 1a and R 1b One of them is H and the other is C 1 -C 3 An alkyl group, such as a methyl group.

[0203] In the descriptions herein, it is understood that each description, variation, embodiment or aspect of a portion can be combined with each description, variation, embodiment or aspect of other portions, just as each combination of descriptions is specifically and individually listed. For example, each description, variation, embodiment or aspect provided herein with respect to L of formula (I) can be combined with R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 Each description, variation, embodiment or aspect combination of and n is as specific and individually listed each combination. It should also be understood that, when applicable, all descriptions, variations, embodiments or aspects of formula (I) are equally applicable to other formulas described in detail herein, and are described equally, as each description, variation, embodiment or aspect is listed individually and individually for all formulas. For example, when applicable, all descriptions, variations, embodiments or aspects of formula (I) are equally applicable to any one of the formulas described in detail herein, such as formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd) and (V), and are described equally, as each description, variation, embodiment or aspect is listed individually and individually for all chemical formulas.

[0204] In some embodiments, a compound or a pharmaceutically acceptable salt thereof is provided that is selected from the compounds in Table 1. Although certain compounds described in the present disclosure, including compounds in Table 1, are presented as specific stereoisomers and / or non-stereochemical forms, it is understood that any or all stereochemical forms (including any enantiomeric or diastereomeric forms) and any tautomeric or other forms of any of the compounds of the present disclosure, including compounds in Table 1, are described herein.

[0205] Table 1.

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214] or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, the compound of Formula (I) is not compound 3a, 3b, 9, 10, 13, 15, 16, 18, 21, 23-29, 31-41, 43-48, 50, 52 or 54.

[0216] In some embodiments, a compound selected from the compounds in Table 1A or a pharmaceutically acceptable salt thereof is provided. Although certain compounds described in the present disclosure, including compounds in Table 1A, are presented as specific stereoisomers and / or non-stereochemical forms, it is understood that any or all stereochemical forms (including any enantiomeric or diastereomeric forms) and any tautomeric or other forms of any of the compounds of the present disclosure, including compounds in Table 1A, are described herein.

[0217] Table 1A.

[0218]

[0219]

[0220]

[0221] or a pharmaceutically acceptable salt thereof.

[0222] It is understood that in the present specification, combinations of substituents and / or variables of the depicted chemical formulas are permissible only if such actions result in stable compounds.

[0223] In addition, all compounds of formula (I) in free base or free acid form can be converted to their pharmaceutically acceptable salts by methods known to those skilled in the art by treatment with appropriate inorganic or organic bases or inorganic or organic acids. The salts of compounds of formula (I) can be converted to their free base or free acid forms by standard techniques.

[0224] Synthesis method

[0225] The compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer can be prepared by using organic chemical synthesis methods known in the art. In general, the starting components can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI and Fluorochem USA or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described herein.

[0226] General reaction scheme 1.

[0227]

[0228] General Reaction Scheme 1 provides an exemplary method for preparing compounds of formula (I). R in General Reaction Scheme 1 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L and n are as defined herein. X is a reactive moiety selected to facilitate the desired reaction (e.g., a halide). 1 and P 2 is a suitable protecting group. L' is selected so that the desired L portion is composed of L'-R 4 The compound of structure A1 can be purchased or prepared according to methods known in the art. Under appropriate coupling conditions (e.g., T 3The reaction of A1 and A2 under suitable coupling conditions (e.g., T and base) produces the product of the coupling reaction between A1 and A2 and A3. A3 is then reacted under suitable coupling conditions (e.g., T 3 P and base) with A4 to give compound A5. Compound A5 is then cyclized (e.g., using formic acid) and deprotected (e.g., using piperidine) to give compound A6. Compound A6 is then reacted with compound A7 to give the final compound of formula (I) as shown.

[0229] General reaction scheme 2.

[0230]

[0231] An alternative method for synthesizing compounds of formula (I) is depicted in General Reaction Scheme 2. R in General Reaction Scheme 2 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L and n are as defined herein. 2 is a suitable protecting group. Each X is a selected reactive moiety (e.g., a halide) that promotes the desired reaction. L' is selected so that the desired L moiety consists of L'-R 4 The reaction between the secondary amine and the protective group P can be removed. 3 (e.g., p-methoxybenzyl) as R 3 The intermediate A5 is prepared by cyclizing (e.g., using formic acid) and deprotecting (e.g., using piperidine) to obtain the compound A9. The compound A9 is then reacted with A7 to obtain the compound A10. The compound A10 is then deprotected (e.g., using cerium ammonium nitrate) to obtain the compound A11. The compound A11 is then reacted with A12 to provide the final compound of formula (I).

[0232] General reaction scheme 3.

[0233]

[0234] A method related to that shown in General Reaction Scheme 2 is depicted in General Reaction Scheme 3. In this method, the two amine nitrogen atoms of the bicyclic core are deprotected to provide compound A10, which is then reacted with A7 to give compound A11. Subsequent reaction with A12 provides the final compound of formula (I).

[0235] It should be noted that various alternative strategies for preparing compounds of formula (I) are available to those of ordinary skill in the art. For example, other compounds of formula (I) can be prepared according to similar methods using appropriate starting materials.

[0236] It will also be appreciated by those skilled in the art that in the method for preparing the compounds described herein, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Such functional groups may include hydroxyl, amino and carboxylic acid. Suitable protecting groups for hydroxyl include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino and amidino include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for carboxylic acids include alkyl, aryl or arylalkyl esters. Protecting groups are optionally added or removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, TW and PGM Wutz, Protective Groups in Organic Synthesis (1999), 3rd edition, Wiley. As will be appreciated by those skilled in the art, protecting groups may also be polymer resins, such as Wang resins, Rink resins or 2-chlorotrityl chloride resins.

[0237] Pharmaceutical compositions and preparations

[0238] In yet another aspect, a pharmaceutical composition is provided herein. The pharmaceutical composition comprises any (or multiple) of the aforementioned compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In other more embodiments, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, and an additional therapeutic agent. Non-limiting examples of such therapeutic agents are described below.

[0239] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, aural, nasal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracerebroventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0240] In certain embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is applied in a local rather than systemic manner, for example, often in the form of a reservoir formulation or a sustained release formulation via direct injection of the compound into an organ. In a specific embodiment, the long-acting preparation is administered by implantation (for example, subcutaneous or intramuscular) or by intramuscular injection. In addition, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome targets an organ and is selectively absorbed by the organ. In yet other embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is provided in a quick release formulation, in an extended release formulation, or in an intermediate release formulation. In yet other embodiments, the compound described herein is applied topically.

[0241] Formula (I) compound or its pharmaceutically acceptable salt, isotopic form or stereoisomer is effective in a wide range of dosages. For example, in the treatment of adults, 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg / day and 5 to 40 mg / day dosages are examples of dosages used in some embodiments. An exemplary dosage is 10 to 30 mg / day. The exact dosage will depend on the route of administration, the form of administration of the compound, the subject to be treated, the weight of the subject to be treated and the preference and experience of the attending physician.

[0242] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is administered in a single dose form. Typically, such administration will be performed by injection, such as intravenous injection, so as to quickly introduce the agent. However, other routes are used when appropriate. A single dose of the disclosed compounds can also be used to treat acute conditions (e.g., traumatic brain injury).

[0243] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is administered in multiple doses. In some embodiments, administration is about once, twice, three times, four times, five times, six times or more than six times a day. In other embodiments, administration is about once a month, once every two weeks, once a week or once every other day. In another embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer and another therapeutic agent are administered together about once a day to about 6 times a day. In another embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer and therapeutic agent are administered for less than about 7 days. In another embodiment, administration is continued for more than about 6 days, 10 days, 14 days, 28 days, two months, six months or one year. In some cases, continuous administration is achieved and maintained as long as needed.

[0244] The compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer can be continuously administered as long as needed. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is administered for more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days or 28 days. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is administered for less than 28 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is administered for a long time on an uninterrupted basis, for example, for the treatment of chronic effects (e.g., dementia).

[0245] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is administered in doses. It is known in the art that due to the variability in the pharmacokinetics of the compound between subjects, the optimal therapy requires the personalization of the dosing regimen. The administration of the compound can be found by routine experiments according to the present disclosure.

[0246] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is formulated into a pharmaceutical composition. In a specific embodiment, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, which include excipients and adjuvants that help the active compound to be processed into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients are suitable for formulating the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999).

[0247] Provided herein are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, and a pharmaceutically acceptable diluent, excipient or carrier. Also provided herein are methods for administering a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, and a pharmaceutically acceptable diluent, excipient or carrier.

[0248] In certain embodiments, the compound is administered as a pharmaceutical composition, wherein the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is mixed with other therapeutic agents, such as in combination therapy. All combinations of active ingredients described in the following method parts and throughout this disclosure are contemplated herein. In specific embodiments, the pharmaceutical composition includes one or more compounds of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer.

[0249] As used herein, a pharmaceutical composition refers to a mixture of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients. In certain embodiments, a pharmaceutical composition helps to administer a compound to an organism. In some embodiments, in order to practice the treatment or use methods provided herein, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof provided herein is administered to a mammal suffering from a disease, illness or medical condition to be treated in the form of a pharmaceutical composition. In a specific embodiment, the mammal is a human. In some embodiments, the therapeutically effective amount depends on the following factors: the severity of the disease, the age and relative health of the subject, the efficacy of the compound used, and other factors. The compounds described herein are used alone or in combination with one or more therapeutic agents as components of a mixture.

[0250] In one embodiment, one or more compounds of formula (I) or pharmaceutically acceptable salts, isotopic forms or stereoisomers thereof are formulated in an aqueous solution. In specific embodiments, for example only, the aqueous solution is selected from a physiologically compatible buffer, such as Hank's solution, Ringer's solution or a saline buffer. In other embodiments, one or more compounds of formula (I) or pharmaceutically acceptable salts, isotopic forms or stereoisomers thereof are formulated for transmucosal administration. In specific embodiments, transmucosal preparations include permeants suitable for the barrier to be penetrated (e.g., the blood-brain barrier). In other embodiments in which the compounds described herein are formulated for other parenteral injections, suitable preparations include aqueous or non-aqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and / or excipients.

[0251] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is formulated for oral administration. The compound is formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is formulated into an oral dosage form, including (for example only) tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, etc.

[0252] In certain embodiments, the pharmaceutical preparation for oral use is obtained by mixing one or more solid excipients with one or more compounds of formula (I) or pharmaceutically acceptable salts, isotopic forms or stereoisomers thereof; optionally grinding the resulting mixture; and optionally, after adding suitable adjuvants, treating the mixture of particles to obtain tablets or dragee cores. In particular, suitable excipients are fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In a particular embodiment, a disintegrant is optionally added. Disintegrants include, by way of example only, cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

[0253] In one embodiment, dosage forms such as dragee cores and tablets have one or more layers of suitable coatings. In a particular embodiment, concentrated sugar solution coated dosage forms are used. Sugar solution optionally contains additional components, such as (for example only) gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer liquid and suitable organic solvent or solvent mixture. Dye and / or pigment are also optionally added to the coating for identification purposes. In addition, dye and / or pigment are optionally used to characterize the different combinations of active compound dosage.

[0254] In certain embodiments, a therapeutically effective amount of a compound of formula (I) or at least one of its pharmaceutically acceptable salts, isotopic forms or stereoisomers is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). In a particular embodiment, the push-fit capsule contains the active ingredient blended with one or more fillers. Fillers include, by way of example only, lactose, binders (such as starch) and / or lubricants (such as talc or magnesium stearate) and optionally selected stabilizers. In other embodiments, soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more oils, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0255] In other embodiments, a therapeutically effective amount of at least one compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, an isotopic form or a stereoisomer thereof is formulated for buccal or sublingual administration. Preparations suitable for buccal or sublingual administration include (for example only) tablets, lozenges or gels. In yet other embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, an isotopic form or a stereoisomer thereof is formulated for parenteral injection, including preparations suitable for bolus injection or continuous infusion. In a specific embodiment, the preparation for injection is provided in a unit dosage form (e.g., ampoule) or in a multidose container. A preservative is optionally added to the injection preparation. In yet other embodiments, the pharmaceutical composition is formulated into a form suitable for parenteral injection, such as a sterile suspension, solution or emulsion in an oily or aqueous vehicle. Parenteral injection preparations optionally contain a preparatoner, such as a suspending agent, a stabilizer and / or a dispersant. In a specific embodiment, the pharmaceutical preparation for parenteral administration includes an aqueous solution of an active compound in a water-soluble form. In additional embodiments, the suspension of the active compound or compound (e.g., a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof) is prepared as an oily injection suspension when appropriate. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, oils and fats, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or polydextrose. Optionally, the suspension contains a suitable stabilizer or an agent that increases the solubility of the compound to allow the preparation of a highly concentrated solution. Alternatively, in other embodiments, the active ingredient is in powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

[0256] In yet other embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof is applied topically. The compound is formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, creams, medicinal sticks, balms, creams or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tension enhancers, buffers and preservatives.

[0257] In other embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is formulated for transdermal administration. In a specific embodiment, the transdermal preparation adopts a transdermal delivery device and a transdermal delivery patch and can be a lipophilic emulsion or a buffered aqueous solution dissolved and / or dispersed in a polymer or an adhesive. In various embodiments, such patches are constructed for continuous, pulsed or on-demand delivery of pharmaceutical agents. In additional embodiments, the transdermal delivery of the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is completed by means of an iontophoresis patch, etc. In certain embodiments, a transdermal patch provides controlled delivery of the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer. In a specific embodiment, the absorption rate is slowed down by using a rate-controlled membrane or by trapping the compound in a polymer matrix or a gel. In an alternative embodiment, absorption is increased using an absorption enhancer. An absorption enhancer or a carrier includes an absorbable pharmaceutically acceptable solvent that helps pass through the skin. For example, in one embodiment, the transdermal device is in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with a carrier, an optionally present rate controlling barrier that delivers the compound to the skin of the host at a controlled and predetermined rate over an extended period of time, and means for securing the device to the skin.

[0258] In other embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, sprays or powders. Any pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is suitably delivered in an aerosol spray presentation form from a pressurized package or sprayer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In a specific embodiment, the dosage unit of the pressurized aerosol is determined by providing a valve for delivering a quantitative amount. In certain embodiments, capsules and cartridges such as (for example only) gelatin for use in an inhaler or insufflator are formulated to contain a powder mixture of the compound and a suitable powder matrix (such as lactose or starch).

[0259] In still other embodiments, the compounds of formula (I) or pharmaceutically acceptable salts, isotopic forms or stereoisomers thereof are formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, etc. In suppository forms of the compositions, a low melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.

[0260] In certain embodiments, the pharmaceutical composition is formulated in any conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that help to process the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. When suitable, any pharmaceutically acceptable technology, carrier and excipient are optionally used. The pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof is manufactured in a conventional manner, such as (for example only) by means of conventional mixing, dissolving, granulating, sugar-coated pill making, water grinding, emulsification, encapsulation, embedding or compression methods.

[0261] The pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, diluent or excipient and at least one compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer, described herein as an active ingredient. The active ingredient is in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also referred to as polymorphs) and active metabolites of these compounds with the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. In addition, the compound formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer covers non-solvated and solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, etc. It is also believed that the solvated forms of the compounds presented herein are disclosed herein. In addition, the pharmaceutical composition optionally includes other medical or pharmaceutical agents, carriers, adjuvants (such as preservatives, stabilizers, wetting agents or emulsifiers), solubilizers, salts for regulating osmotic pressure, buffers and / or other substances of therapeutic value.

[0262] Methods for preparing compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof include formulating the compound with one or more inert pharmaceutically acceptable excipients or carriers to form a solid, semisolid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets and suppositories. Liquid compositions include solutions in which the compound is dissolved; emulsions containing the compound; or solutions containing liposomes, micelles or nanoparticles containing the compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof. Semisolid compositions include, but are not limited to, gels, suspensions and creams. The pharmaceutical compositions described herein are in the form of liquid solutions or suspensions, solid forms suitable for dissolving or suspending in a liquid prior to use, or emulsions. These compositions also optionally contain small amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, and the like.

[0263] In some embodiments, when the agent is in the form of a solution, a suspension, or both, the pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof is illustratively in liquid form. Typically, when the composition is administered in the form of a solution or a suspension, the first portion of the agent is in the form of a solution and the second portion of the agent is suspended in a liquid matrix in the form of particles. In some embodiments, the liquid composition includes a gel formulation. In other embodiments, the liquid composition is an aqueous solution.

[0264] In certain embodiments, suitable aqueous suspensions contain one or more polymers as suspending agents. Suitable polymers include water-soluble polymers, such as cellulose polymers, for example hydroxypropyl methylcellulose, and water-insoluble polymers, such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein include mucoadhesive polymers selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and polydextrose.

[0265] Applicable pharmaceutical compositions also optionally include solubilizers to assist the solubility of the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer. The term "solubilizer" generally includes agents that form micellar solutions or true solutions of agents. Some acceptable nonionic surfactants (e.g., polysorbate 80) are suitable for use as solubilizers, and ophthalmologically acceptable glycols, polyethylene glycols (e.g., polyethylene glycol 400) and glycol ethers are also suitable for use as solubilizers.

[0266] In addition, suitable pharmaceutical compositions optionally contain one or more pH adjusters or buffers, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and trishydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in amounts required to maintain the pH of the composition within an acceptable range.

[0267] In addition, suitable compositions optionally also contain one or more salts in an amount necessary to bring the weight molar osmotic concentration of the composition into an acceptable range. Such salts include salts having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0268] Other suitable pharmaceutical compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[0269] Other suitable compositions contain one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octoxynol 10, octoxynol 40.

[0270] Still other suitable compositions optionally contain one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0271] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case a preservative is typically included in the composition.

[0272] In alternative embodiments, other delivery systems for hydrophobic drug compounds are used. Liposomes and emulsions are examples of delivery vehicles or carriers applicable herein. In certain embodiments, organic solvents, such as N-methylpyrrolidone, are also used. In additional embodiments, sustained release systems are used, such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agents to deliver formula (I) compounds or their pharmaceutically acceptable salts, isotopic forms or stereoisomers. Various sustained release materials are applicable herein. In some embodiments, sustained release capsules release compounds for several weeks to more than 100 days. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies can be used for protein stabilization.

[0273] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizers. Examples of such stabilizers include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0274] In some embodiments, the concentration of the compound of formula (I) provided in the pharmaceutical composition of the present disclosure is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.1% or less. 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v or v / v.

[0275] In some embodiments, the concentration of the compound of formula (I) provided in the pharmaceutical compositions of the present disclosure is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 16.25%, 17.75%, 17.50%, 17 ... 5.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07% , 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w / w, w / v or v / v.

[0276] In some embodiments, the concentration of the compound of Formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof provided in the pharmaceutical composition ranges from about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.0 From about 7% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12% or from about 1% to about 10% w / w, w / v or v / v.

[0277] In some embodiments, the concentration of the compound of Formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof provided in the pharmaceutical composition ranges from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1% or about 0.1% to about 0.9% w / w, w / v or v / v.

[0278] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof provided in the pharmaceutical composition is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.3 5g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.00 6g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g or 0.0001g.

[0279] In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer provided in the pharmaceutical composition of the present disclosure exceeds 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0010 g, 0.0011 g, 0.0012 g, 0.0013 g, 0.0014 g, 0.0015 g, 0.0016 g, 0.0017 g, 0.0018 g, 0.0019 g, 0.010 g, 0.011 g, 0.012 g, 0.013 g, 0.0 015g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.00 6g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0 .02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g , 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4 g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5 g, 2g, 2.5g, 3g, 3.5g, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g or 10g.

[0280] In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer provided in the pharmaceutical composition ranges from 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g or 1-3 g.

[0281] Medicine Boxes / Products

[0282] Also provided are kits and articles for use in therapeutic applications described herein. In some embodiments, such kits include a carrier, a package, or a container separated to accommodate one or more containers (such as vials, tubes, etc.), each of which includes one of the individual elements to be used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The container is formed of a variety of materials such as glass or plastic.

[0283] The article provided herein contains packaging material. The packaging material for packaging drug products includes, for example, packaging materials found in U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. The example of drug packaging material includes, but is not limited to, blister packaging, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles and any packaging material suitable for selected preparations and expected administration and treatment modes. For example, the container includes one or more compounds described herein, which are optionally in the form of a composition or in combination with another agent as disclosed herein. The container optionally has a sterile access port (for example, the container is an intravenous solution bag or a vial with a stopper that can be pierced by a hypodermic needle). Such medicine boxes optionally include compounds, which have identification descriptions or labels or instructions related to their use in the method described herein.

[0284] For example, a kit typically includes one or more additional containers, each of which has one or more of a variety of materials (such as reagents, optionally in concentrated form, and / or devices) required for use of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof from a commercial and user perspective. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carriers, packaging, containers, vials, and / or tube labels listing the contents and / or instructions for use and package inserts with instructions for use. A set of instructions is also typically included. The label is optionally attached to or associated with the container. For example, when letters, numbers, or other characters forming the label are attached, molded, or etched into the container itself, the label is attached to the container; when the label is present in a receiver or carrier that also contains the container, the label is associated with the container, such as a package insert. In addition, the label is used to indicate the contents for a specific therapeutic application. In addition, the label indicates the contents such as instructions for use in the methods described herein. In certain embodiments, the pharmaceutical composition is presented in one or more packaging or dispenser devices containing unit dosage forms of the compounds provided herein. The packaging, for example, contains metal or plastic foil, such as a blister pack. Alternatively, the packaging or dispenser device is accompanied by instructions for use. Alternatively, the packaging or dispenser is accompanied by precautions associated with the container in a form specified by a government agency that regulates the manufacture, use or sale of pharmaceuticals, which precautions reflect that the agency approves the drug form for human or veterinary administration. Such precautions are, for example, labels approved by the U.S. Food and Drug Administration for prescription drugs, or approved product inserts. In some embodiments, a composition containing a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof formulated in a compatible pharmaceutical carrier is prepared, placed in an appropriate container and labeled for use in treating the indicated condition.

[0285] Use / treatment methods

[0286] Embodiments of the present disclosure provide methods for regulating hepatocyte growth factor in a subject in need thereof, the methods comprising administering to the subject an effective amount of a compound as disclosed herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof). In some embodiments, the compounds described herein activate hepatocyte growth factor. Regulating (e.g., inhibiting or activating) hepatocyte growth factor can be assessed and confirmed by a wide variety of methods known in the art. Kits and commercially available assays can be used to determine whether to regulate (e.g., inhibit or activate) hepatocyte growth factor and to what extent hepatocyte growth factor is regulated.

[0287] In some embodiments, provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof for use in regulating hepatocyte growth factor in a subject in need thereof. In some embodiments, provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of a medicament for regulating hepatocyte growth factor in a subject in need thereof.

[0288] Applicants have found that compound formula (I) exhibits promising activity associated with certain diseases of interest. Therefore, in one aspect, a method for regulating hepatocyte growth factor in a subject in need is provided herein, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof. In some embodiments, a method for activating hepatocyte growth factor in a subject in need is provided herein, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof.

[0289] In certain more specific embodiments, modulation includes treating a disease, condition, or injury (e.g., traumatic brain injury). By way of non-limiting example, the disease, condition, or injury includes a neurodegenerative disease, traumatic brain injury, memory loss or loss of function, spinal cord injury, sensorineural hearing loss, nerve damage, etc. In some embodiments, the disease, condition, or injury is a neurodegenerative disease, spinal cord injury, traumatic brain injury, or sensorineural hearing loss.

[0290] In a more specific embodiment, the disease, condition or injury is a neurodegenerative disease. For example, in some embodiments, the neurodegenerative disease is Alzheimer's disease, dementia, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis (ALS). In a more specific embodiment, the neurodegenerative disease is Alzheimer's disease or Parkinson's disease.

[0291] Also provided herein is a method for treating or slowing the progression of dementia in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof. In a specific embodiment, the dementia is associated with Alzheimer's disease or Parkinson's disease.

[0292] In another aspect, provided herein is a method for preventing cognitive dysfunction in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof.

[0293] Another related embodiment provides a method for treating, repairing or preventing a disease, condition or injury associated with nervous tissue in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof.

[0294] In other aspects, a method of treating a neuropsychiatric disease or condition is provided herein, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof. Non-limiting examples of neuropsychiatric diseases or conditions include, but are not limited to, depression and anxiety.

[0295] In other aspects, a method for treating a disease or condition of the central nervous system is provided herein, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof to a subject in need. In some embodiments, a method for preventing a disease or condition of the central nervous system is provided herein, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof to a subject in need. A non-limiting example of a disease or condition of the central nervous system is traumatic brain injury.

[0296] In other aspects, a method for treating a disease or condition of the peripheral nervous system is provided herein, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof to a subject in need thereof. In some embodiments, a method for preventing a disease or condition of the peripheral nervous system is provided herein, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof to a subject in need thereof. A non-limiting example of a disease or condition of the peripheral nervous system is neuropathic pain.

[0297] Embodiments of the methods described above include administering to a mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. The methods disclosed herein generally involve administering a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to treat, protect, or reverse diseases and injuries associated with neural cells or the nervous system. That is, embodiments of the present disclosure relate to treating, preventing, or reversing neurodegenerative diseases, including treating dementia; repairing traumatic injuries; and / or preventing cognitive dysfunction.

[0298] In some embodiments, the disclosure provides a method of regulating protein activity (e.g., hepatocyte growth factor) in subjects including but not limited to rodents and mammals (e.g., humans) by administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to a subject. In some embodiments, the regulation of hepatocyte growth factor is the activation of hepatocyte growth factor. In some embodiments, the percentage of regulation exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the percentage of inhibition exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0299] In some embodiments, the present disclosure provides a method of regulating the activity of hepatocyte growth factor in a cell by contacting the cell with a certain amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof sufficient to regulate the activity of hepatocyte growth factor. In some embodiments, the present disclosure provides a method of regulating the activity of hepatocyte growth factor in a tissue by contacting the tissue with a certain amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof sufficient to regulate the activity of hepatocyte growth factor in the tissue. In some embodiments, the present disclosure provides a method of regulating the activity of hepatocyte growth factor in an organism by contacting the organism with a certain amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof sufficient to regulate the activity of hepatocyte growth factor in the organism. In some embodiments, the present disclosure provides a method of regulating the activity of hepatocyte growth factor in an animal by contacting an animal with a certain amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof sufficient to regulate the activity of hepatocyte growth factor in the animal. In some embodiments, the present disclosure provides a method for regulating the activity of hepatocyte growth factor in a mammal by contacting the mammal with a certain amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof sufficient to regulate the activity of hepatocyte growth factor in the mammal. In some embodiments, the present disclosure provides a method for regulating the activity of hepatocyte growth factor in a human body by contacting a human with a certain amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof sufficient to regulate the activity of hepatocyte growth factor in the human body. In other embodiments, the present disclosure provides a method for treating a disease mediated by the activity of hepatocyte growth factor in a subject in need of such treatment. In some variations, regulating hepatocyte growth factor by a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof involves activating hepatocyte growth factor.

[0300] Other embodiments provide methods for combination therapy, wherein therapeutic agents known to regulate other pathways, or other components of the same pathway, or even overlapping target enzyme groups are used in combination with compounds of formula (I) or pharmaceutically acceptable salts, isotopic forms or stereoisomers thereof. In one aspect, such therapies include, but are not limited to, combinations of one or more compounds of formula (I) or pharmaceutically acceptable salts, isotopic forms or stereoisomers thereof with therapeutic agents, therapeutic antibodies and other therapeutic modalities to provide synergistic or additional therapeutic effects.

[0301] Many therapeutic agents are currently known in the art and can be used in combination with a compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof. In some embodiments, the therapeutic agent is selected from memantine, cholinesterase inhibitors, antidepressants, antianxiety agents and / or antipsychotic drugs. Some embodiments include the use of therapies including reminiscence therapy, cognitive stimulation therapy, reality orientation training, physical activity, etc.

[0302] Exemplary cholinesterase inhibitors may include donepezil, galantamine, and rivastigmine, which help slow the decomposition of brain chemicals related to memory and judgment. Memantine can help control different brain chemicals required for learning and memory. In certain aspects, memantine can also be used with donepezil in a combination drug for moderate to severe dementia. Antidepressants may include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs). Antianxiety agents may include, but are not limited to, lorazepam (Ativan) or oxazepam (oxazepam) (Serax). Some embodiments of the methods described herein may include the use or administration of antipsychotic drugs such as aripiprazole (Abilify), haloperidol (Haldol), olanzapine (olanzapine) (Zyprexa), and risperidone (risperdal).

[0303] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof is formulated or administered with a liquid or solid tissue barrier also referred to as a lubricant. Examples of tissue barriers include, but are not limited to, polysaccharides, polysaccharides, biological membranes, anti-adhesion membranes, and hyaluronic acid.

[0304] In some embodiments, the therapeutic agent administered with the compound of Formula (I) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof includes any suitable therapeutic agent effectively delivered by inhalation, for example: analgesics, such as codeine, dihydromorphine, ergotamine, fentanyl or morphine; angina preparations, such as diltiazem; antiallergic agents, such as cromoglycate, ketotifen or nedocromil; Anti-infective agents, such as cephalosporin, penicillin, streptomycin, sulphonamide, tetracycline, or pentamidine; antihistamines, such as methapyrilene; anti-inflammatory agents, such as beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide, acetonide or fluticasone; cough suppressants such as noscapine; bronchodilators such as ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol , rimiterol, salbutamol, salmeterol, terbutalin, isoetharine, tulobuterol, orciprenaline, or (-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridyl)ethoxy]hexyl]-amino]methyl]benzyl alcohol; a diuretic such as amiloride; an anticholinergic such as ipratropium, atropine, or oxitropium;Hormones, such as cortisone, hydrocortisone or prednisolone; xanthines, such as aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, such as insulin or glucagon. Those skilled in the art will appreciate that, where appropriate, the therapeutic agent is used in salt form (e.g., in alkali metal or amine salt form or in acid addition salt form) or in ester form (e.g., lower alkyl ester) or in solvate form (e.g., hydrate) to optimize the activity and / or stability of the therapeutic agent. ;

[0305] Other therapeutic agents that can be combined with a compound of formula (I), or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, are found in Goodman and Gilman, "The Pharmacological Basis of Therapeutics", Tenth Edition, edited by Hardman, Limbird and Gilman, or the Physician's Desk Reference, both of which are incorporated herein by reference in their entirety.

[0306] Depending on the condition being treated, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer can be used in combination with the therapeutic agent disclosed herein. Therefore, in some embodiments, one or more compounds of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer will be co-administered with other therapeutic agents as described above. When used in combination therapy, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer is administered simultaneously with the second therapeutic agent or is administered alone. This combined administration may include simultaneous administration with the same dosage form, simultaneous administration with a separate dosage form, and administration alone. That is, any one of the compounds of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer and the therapeutic agent described above can be formulated together with the same dosage form and administered simultaneously. Alternatively, any one of the compounds of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer and the therapeutic agent described above can be administered simultaneously, wherein both are present in a separate preparation. In another alternative, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer may be administered just after any one of the therapeutic agents described above, or vice versa. In some embodiments of the separate administration regimen, the compound of formula (I) or its pharmaceutically acceptable salt, isotopic form or stereoisomer and any one of the therapeutic agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.

[0307] The examples and preparation methods provided below further illustrate and illustrate the compounds of formula (I) or their pharmaceutically acceptable salts, isotopic forms or stereoisomers and methods for preparing such compounds. It should be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparation methods. In the following examples and throughout the specification and claims, unless otherwise indicated, molecules with a single stereocenter exist as a racemic mixture. Unless otherwise indicated, those molecules with two or more stereocenters exist as a racemic mixture of diastereomers. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

[0308] Example

[0309] The following examples are provided for illustrative purposes.Methods for preparing compounds of formula (I) or pharmaceutically acceptable salts, isotopic forms or stereoisomers thereof are provided herein or can be deduced by one of ordinary skill in the art.

[0310] The examples and preparations provided below further illustrate and exemplify the compounds of the present disclosure and methods for testing such compounds.It should be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples.

[0311] The chemical reactions in the described embodiments can be easily adapted to prepare many other compounds disclosed herein, and alternative methods for preparing the disclosed compounds are considered to be within the scope of the present disclosure. For example, the synthesis of unexemplified compounds according to the present disclosure can be performed by modifications apparent to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making conventional modifications to reaction conditions, reagents, and starting materials. Alternatively, other reactions disclosed herein or known in the art will be considered to be applicable to the preparation of other compounds of the present disclosure.

[0312] Unless otherwise indicated, in the following examples, the compounds were isolated as racemic mixtures.

[0313] The following abbreviations may be associated with this application.

[0314] abbreviation

[0315] AcOH: acetic acid

[0316] CAN: Cerium Ammonium Nitrate

[0317] DAST: Diethylaminosulfur trifluoride

[0318] DCM: dichloromethane

[0319] DIPEA: N,N-diisopropylethylamine

[0320] DMEM: Dulbecco's modified Eagle's medium

[0321] DMF: dimethylformamide

[0322] DMSO: dimethyl sulfoxide

[0323] EMEM: Eagle's Minimum Essential Medium

[0324] EtOAc: Ethyl acetate

[0325] EtOH: ethanol

[0326] FBS: Fetal bovine serum

[0327] Fmoc: fluorenylmethoxycarbonyl

[0328] HATU: (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0329] LC / MS: Liquid chromatography mass spectrometry

[0330] Me:Methyl

[0331] MeOH: Methanol

[0332] PBS: Phosphate buffered saline

[0333] Pic-BH 3 :Methylpyridine borane

[0334] PMB: p-methoxybenzyl ether

[0335] Prep HPLC: Preparative High Performance Liquid Chromatography

[0336] rt or RT: room temperature

[0337] TFA: trifluoroacetic acid

[0338] TLC: Thin layer chromatography

[0339] T 3 P: Propane phosphoric anhydride

[0340] Synthesis Example

[0341] Example S1. Synthesis of (6S)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. The synthetic route for preparing this starting material compound is shown in Scheme 1.

[0342] Solution 1.

[0343]

[0344] Step 1: Synthesis of (2S)-1-((2,2-dimethoxyethyl)(2-methylbutyl)amino)-1-oxopropan-2-ylcarbamate (9H-fluoren-9-yl)methyl ester. To a stirred solution of compound (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanoic acid (5.0 g, 16.07 mmol) in dichloromethane (100 mL) was added T 3 P (15.2mL, 24.1) and DIPEA (5.6mL, 32.1mmol). The reaction mixture was stirred at room temperature for 15min and N-(2,2-dimethoxyethyl)-2-methylbutan-1-amine (2.81g, 32.1mmol) was added and continued to stir at room temperature for 8 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was quenched with ice-cold water (100mL) and extracted with dichloromethane (2×100mL). The combined organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried, filtered and concentrated under reduced pressure to give a crude compound. The crude compound was purified by flash column chromatography (100-200 mesh silica gel, eluted with 40% ethyl acetate / petroleum ether) to give a pure compound (2S)-(9H-fluoren-9-yl)methyl 1-((2,2-dimethoxyethyl)(2-methylbutyl)amino)-1-oxopropan-2-ylcarbamate (5.2 g, 69.1%) as a gummy compound.

[0345] Step 2: Synthesis of (2S)-2-amino-N-(2,2-dimethoxyethyl)-N-(2-methylbutyl)acrylamide. To a stirred solution of (2S)-1-((2,2-dimethoxyethyl)(2-methylbutyl)amino)-1-oxopropan-2-ylcarbamic acid (9H-fluoren-9-yl)methyl ester (34.0 g, 72.6 mmol) in DMF (230 mL) was added 20% piperidine in DMF (70 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was complete, excess DMF (100 mL) was added, followed by washing with excess n-hexane (3×200 mL). The DMF layer was collected and poured into ice-cold water (1000 mL), followed by extraction with 10% methanol-dichloromethane (3×500 mL). The combined organic layers were purified by anhydrous Na2 SO 4 Dry, filter and concentrate under reduced pressure to give (2S)-2-amino-N-(2,2-dimethoxyethyl)-N-(2-methylbutyl)propanamide (20.4 g, 68.4%) as a gummy solid.

[0346] Step 3: Synthesis of (9H-fluoren-9-yl)methyl 3-((2S)-1-((2,2-dimethoxyethyl)(2-methylbutyl)amino)-1-oxopropan-2-ylamino)-3-oxopropylcarbamate. To a stirred solution of 3-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanoic acid (20.2 g, 81.2 mmol) in dichloromethane (500 mL) at room temperature was added T. 3 P (80mL, 121.8mmol) and DIPEA (28.6mL, 160.4mmol) were added and the mixture was stirred for 10 minutes. To this mixture was added (2S)-2-amino-N-(2,2-dimethoxyethyl)-N-(2-methylbutyl)propionamide (25.53mL, 81.2mmol) and stirring was continued at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was quenched with water (500mL) and the mixture was extracted with dichloromethane (2×500mL). The combined organic layers were purified by Na 2 SO 4 The mixture was dried, filtered and concentrated under reduced pressure to give a crude product. The crude compound was purified by flash column chromatography (100-200 mesh silica gel, eluted with 70% ethyl acetate / petroleum ether) to give the pure compound 3-((2S)-1-((2,2-dimethoxyethyl)(2-methylbutyl)amino)-1-oxopropan-2-ylamino)-3-oxopropylcarbamic acid (9H-fluoren-9-yl)methyl ester (21.2 g, 78.6%) as a gummy compound.

[0347] Step 4: Synthesis of (6S)-(9H-fluoren-9-yl)methyl 6-methyl-8-(2-methylbutyl)-4,7-dioxooctahedral-1H-pyrazino[1,2-a]pyrimidine-1-carboxylate. To a stirred solution of (9H-fluoren-9-yl)methyl 3-((2S)-1-((2,2-dimethoxyethyl)(2-methylbutyl)amino)-1-oxopropan-2-ylamino)-3-oxopropylcarbamate (21.0 g, 38.9 mmol) was added formic acid (105 mL). The reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure to give a crude compound. The crude compound was dissolved in saturated aqueous NaHCO 3(200 mL) solution, followed by extraction with ethyl acetate (3×500 mL). The combined organic layers were washed with brine solution (500 mL), and then the combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried, filtered and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (100-200 mesh silica gel, eluted with 50% ethyl acetate / petroleum ether) to give the pure compound 6-methyl-8-(2-methylbutyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxylic acid (6S)-(9H-fluoren-9-yl)methyl ester (25 g, 69.0%) as a gum.

[0348] Step 5: Synthesis of (6S)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione. To a stirred solution of (6S)-(9H-fluoren-9-yl)methyl 6-methyl-8-(2-methylbutyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxylate (14.0 g, 29.4 mmol) in DMF (70 mL) at 0 °C was added 20% piperidine in DMF (30 mL). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was monitored by TLC. After complete consumption of the starting material, additional DMF (50 mL) was added, followed by washing the mixture with excess n-hexane (3×200 mL). The DMF layer was poured into ice-cold water (1000 mL) and extracted with 10% methanol-dichloromethane (3×500 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to provide the desired crude compound (6S)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (6.25 g, 83.8%) as a solid.

[0349] Example S2. Synthesis of Compound 1a. The synthetic route for preparing Compound 1a is shown in Scheme 2.

[0350] Solution 2.

[0351]

[0352] To a solution of 4-(trifluoromethyl)benzoic acid (0.232 g, 0.91 mmol) in dichloromethane (20 mL) stirred at room temperature was added T 3P (1.2 mL, 1.37 mmol) and DIPEA (0.42 mL, 1.82 mmol) were added and the mixture was stirred for 15 minutes. To this mixture was added (6S)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (0.310 g, 0.91 mmol) and stirring was continued for 8 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the mixture was quenched with water (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The crude compound was purified by preparative HPLC. The pure fractions were combined and concentrated under reduced pressure, followed by lyophilization to give 1a (0.340 g, 65.3%) as a solid. Preparative HPLC method: Mobile phase A: 10 mM ammonium bicarbonate / water; Mobile phase B: acetonitrile; Column: X-Select Phenyl Hexyl (150×19 mm 5μ); Flow rate: 16 mL / min. MS (ESI) m / z [M+H] + :426.05.

[0353] Example S3. Synthesis of Compound 2a. The synthetic route for preparing Compound 2a is shown in Scheme 3.

[0354] Solution 3.

[0355]

[0356] To a solution of 4-(difluoromethoxy)benzoic acid (0.37 g, 1.968 mmol) in dichloromethane (15 mL) at room temperature were added DIPEA (0.8 ml, 5.904 mmol) and T 3 P (2.0 mL, 3.936 mmol). The mixture was stirred for 30 min, then (6S)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.4 g, 1.578 mmol) was added, and stirring was continued for 16 hours. The progress of the reaction was monitored by TLC and LC / MS. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (50 mL) and saturated sodium chloride solution (50 mL), then dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC. Pure fractions were collected and lyophilized to give 2a (380 mg, 46%) as a solid. Preparative HPLC conditions: mobile phase A: 10 mM ammonium bicarbonate / water; mobile phase B: acetonitrile; column: Kromosil phenyl (150×25 mm 10μ); flow rate: 25 mL / min. MS (ESI) m / z [M+H] +:424.11.

[0357] Example S4. Synthesis of Compound 3a. The synthetic route for preparing Compound 3a is shown in Scheme 4.

[0358] Solution 4.

[0359]

[0360] To a solution of (6S)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (0.500 g, 1.97 mmol) stirred in methanol (20 mL) at room temperature was added 4-hydroxybenzaldehyde (0.289 g, 1.97 mmol) and acetic acid (0.23 mL, 3.95 mmol). The reaction mixture was stirred at room temperature for 5 minutes. To this mixture was added methylpyridine borane (0.253 g, 2.37 mmol) and stirring was continued for 48 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice-cold water (50 mL) and the mixture was extracted with 10% methanol-dichloromethane (3×40 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The crude compound was purified by preparative HPLC. The pure fractions were combined and concentrated under reduced pressure, followed by lyophilization to afford 3a (0.180 g, 46.09%) as a solid. Preparative HPLC method: Mobile phase A: 10 mM ammonium bicarbonate / water; Mobile phase B: acetonitrile; Column: Kromosil phenyl (150×25 mm 10μ); Flow rate: 25 mL / min. MS (ESI) m / z [M+H] + :360.11.

[0361] Example S5. Synthesis of Compound 4a. The synthetic route for preparing Compound 4a is shown in Scheme 5.

[0362] Solution 5.

[0363]

[0364] To a solution of 6-hydroxynicotinic acid (0.340 g, 2.446 mmol) in DMF (15 mL) at room temperature was added DIPEA (1.30 mL, 7.338 mmol) and HATU (1.39 g, 3.669 mmol). The resulting reaction mixture was stirred for 30 min, followed by the addition of (6S)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.495 g, 1.956 mmol), and the mixture was stirred for 16 hours. The progress of the reaction was monitored by TLC and LC / MS (TLC system: 10% methanol / dichloromethane, Rf: 0.15, detection: UV). The reaction mixture was quenched with cold water (100 mL) and extracted with 10% methanol / dichloromethane (3×100 mL). The combined organic layers were washed with cold water (50 mL) and cold brine solution (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC. Pure fractions were collected and lyophilized to give 4a (160 mg, 21.8%) as a solid. Preparative HPLC method: Mobile phase A: 0.01 mM ammonium bicarbonate / water; Mobile phase B: acetonitrile; Column: X-Select Phenyl Hexyl (150×19 mm 5μ); Flow rate: 15 mL / min. MS (ESI) m / z [M+H] + :375.05.

[0365] Example S6. Synthesis of Compound 5a. The synthetic route for preparing Compound 5a is shown in Scheme 6.

[0366] Solution 6.

[0367]

[0368] To a solution of (6S)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (0.5 g, 1.97 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.470 g, 1.97 mmol) in DMF (20 mL) stirred at room temperature was added K 2 CO 3 (0.546 g, 3.95 mmol), and the mixture was stirred for 8 hours. The reaction progress was monitored by TLC. After completion, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with Na 2 SO 4Dry, filter and concentrate under reduced pressure. The crude compound was purified by preparative HPLC. The pure fractions were combined and concentrated under reduced pressure, followed by lyophilization to give 5a (0.270 g, 63.8%) as a gum. Preparative HPLC method: Mobile phase A: 10 mM ammonium bicarbonate / water; Mobile phase B: acetonitrile; Column: Kromosil C 18 (150×25mm 10μ); flow rate: 25mL / min. MS (ESI) m / z [M+H] + :412.2.

[0369] Example S7. Synthesis of Compound 6a. The synthetic route for preparing Compound 6a is shown in Scheme 7.

[0370] Solution 7.

[0371]

[0372] To a solution of (6S)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (0.500 g, 1.97 mmol) and 1-(bromomethyl)-4-(difluoromethoxy)benzene (0.466 g, 1.97 mmol) in DMF (20 mL) stirred at room temperature was added K 2 CO 3 (0.546 g, 9.95 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The crude compound was purified by preparative HPLC. The pure fractions were combined and concentrated under reduced pressure, followed by lyophilization to afford 6a (0.178 g, 41.5%) as a semisolid. Preparative HPLC method: Mobile phase A: 10 mM ammonium bicarbonate / water; Mobile phase B: acetonitrile; Column: X-Select C 18 (250×19mm, 5μ); flow rate: 18mL / min. MS (ESI) m / z [M+H] + :410.11.

[0373] Example S8. Synthesis of Compound 7a. The synthetic route for preparing Compound 7a is shown in Scheme 8.

[0374] Solution 8.

[0375]

[0376] To a solution of compound (6S)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (0.500 g, 1.97 mmol) stirred in methanol (20 mL) at room temperature, 6-hydroxynicotinaldehyde (0.243 g, 1.97 mmol) and acetic acid (0.25 mL, 3.95 mmol) were added, and the mixture was stirred for 5 min. To this mixture was added methylpyridine borane (0.318 g, 2.96 mmol) and stirring was continued for 96 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice-cold water (50 mL) and extracted with 10% methanol-dichloromethane (3×40 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The crude compound was purified by preparative HPLC. The pure fractions were collected and concentrated under reduced pressure, followed by lyophilization to afford 7a (0.164 g, 42%) as a solid. Preparative HPLC method: Mobile phase A: 10 mM ammonium bicarbonate / water; Mobile phase B: acetonitrile; Column: X-BRIDGE C 18 (250×19mm, 5μ); flow rate: 18mL / min. MS (ESI) m / z [M+H] + :361.11.

[0377] Example S9. Synthesis of Compound 8a. The synthetic route for preparing Compound 8a is shown in Scheme 9.

[0378] Solution 9.

[0379]

[0380] Step 1: Synthesis of (6S)-1-(4-(benzyloxy)benzoyl)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a solution of 4-(benzyloxy)benzoic acid (0.360 g, 1.42 mmol) in dichloromethane (20 mL) stirred at room temperature was added T 3 P (1.2 mL, 1.7 mmol) and DIPEA (0.55 mL, 2.84 mmol) were added and the mixture was stirred for 15 min. To this mixture was added (6S)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (0.400 g, 1.42 mmol) and stirring was continued at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were purified by Na 2 SO4 Dried, filtered and concentrated under reduced pressure to afford 0.9 g of crude material. Analysis of crude material by LC / MS showed 54.59% of desired product. The crude material was used in the next step without purification.

[0381] Step 2: Synthesis of compound 8a. 2 To a solution of (6S)-1-(4-(benzyloxy)benzoyl)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (0.900 g) stirred in methanol (20 mL) at room temperature was added 10% Pd—C (0.200 g) under atmospheric pressure. The reaction mixture was stirred at room temperature under H 2 The reaction mixture was stirred for 8 hours under a balloon. The reaction progress was monitored by TLC. After completion, the reaction mixture was filtered through diatomaceous earth and evaporated under reduced pressure to obtain the crude compound. The crude compound was dissolved in dichloromethane (50 mL) and precipitated with NaHCO 3 The filtrate was washed with aqueous solution (20 mL) and brine solution (20 mL). 2 SO 4 Dry, filter and concentrate under reduced pressure. The crude compound was triturated with ether to give 8a (0.330 g, 82%) as a solid. MS (ESI) m / z [M+H] + :374.11.

[0382] Example S10. Synthesis of Compound 9. The synthetic route for preparing Compound 9 is shown in Scheme 10.

[0383] Solution 10.

[0384]

[0385] Step 1: Synthesis of (9H-fluoren-9-yl)methyl 2-(sec-butyl(2,2-dimethoxyethyl)amino)-2-oxoethylcarbamate. To a stirred solution of 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)acetic acid (10 g, 33.6 mmol) in dichloromethane (100 mL) cooled to 0°C was added DIPEA (11.88 mL, 67.3 mmol), N-(2,2-dimethoxyethyl)butan-2-amine (10.84 g, 67.3 mmol) and T 3 P (53.0 mL, 84.1 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, ice-cold water (100 mL) was added and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with anhydrous Na 2 SO 4The crude product was purified by flash column chromatography (100-200 mesh silica gel) and eluted with 20-25% ethyl acetate / petroleum ether to afford (9H-fluoren-9-yl)methyl 2-(sec-butyl(2,2-dimethoxyethyl)amino)-2-oxoethylcarbamate (10.8 g, 72.9%) as a solid.

[0386] Step 2: Synthesis of 2-amino-N-sec-butyl-N-(2,2-dimethoxyethyl)acetamide. To a solution of 2-(sec-butyl(2,2-dimethoxyethyl)amino)-2-oxoethylcarbamic acid (9H-fluoren-9-yl)methyl ester (10.8 g, 24.5 mmol) in DMF (20 mL) cooled to 0°C was added piperidine (2.4 mL), and the reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After TLC indicated that the starting material was completely consumed, the reaction mixture was diluted with petroleum ether (2×100 mL), followed by the addition of water and the separation of the mixture. The aqueous layer was extracted with dichloromethane (2×150 mL). The combined organic layers were purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the desired pure product 2-amino-N-sec-butyl-N-(2,2-dimethoxyethyl)acetamide (3.6 g, 67.2%) as a solid.

[0387] Step 3: Synthesis of (9H-fluoren-9-yl)methyl-3-(2-(sec-butyl(2,2-dimethoxyethyl)amino)-2-oxoethylamino)-3-oxopropylcarbamate. To a stirred solution of 2-amino-N-sec-butyl-N-(2,2-dimethoxyethyl)acetamide (3.6 g, 16.5 mmol) in dichloromethane (40 mL) at 0°C was added DIPEA (31.91 mL, 49.5 mmol), 3-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanoic acid (5.14 g, 16.5 mmol) and T 3 P (39.13 g, 33 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, reaction water (100 mL) was added and the organic phase was separated. The aqueous phase was extracted with dichloromethane (2×150 mL). The combined organic layer was purified by Na 2 SO 4The mixture was dried, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography using silica gel (230-400 mesh; 23% to 25% ethyl acetate / petroleum ether as eluent). The collected pure fractions were concentrated under reduced pressure to give (9H-fluorene-9-yl)methyl-3-(2-(sec-butyl(2,2-dimethoxyethyl)amino)-2-oxoethylamino)-3-oxopropylcarbamate (4.1 g, 48.6%) in a gelatinous state.

[0388] Step 4: Synthesis of 8-sec-butyl-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxylic acid (9H-fluoren-9-yl)methyl ester. A solution of (9H-fluoren-9-yl)methyl-3-(2-(sec-butyl(2,2-dimethoxyethyl)amino)-2-oxoethylamino)-3-oxopropylcarbamate (4.1 g, 8.01 mmol) in acetic acid (2 mL) was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After TLC indicated that the starting material was completely consumed, the reaction mixture was concentrated and the resulting mass was diluted with water and extracted with dichloromethane (2×100 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the product (9H-fluoren-9-yl)methyl 8-sec-butyl-4,7-dioxooctahhydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxylate (3.2 g, 89.3%) as a gum.

[0389] Step 5: Synthesis of 8-sec-butyltetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione. To a solution of 8-sec-butyl-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxylic acid (9H-fluoren-9-yl)methyl ester (3.2 g, 7.1 mmol) in DMF (20 mL) cooled to 0 °C was added piperidine (0.7 mL, 1.0 eq), and the reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After TLC indicated that the starting material was completely consumed, the reaction mixture was washed with petroleum ether (2×50 mL) to remove non-polar impurities. Cold water was added and extracted with dichloromethane (2×100 mL). The combined organic layers were purified by Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give the pure product 8-sec-butyltetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (900 mg, 55.9%) as a solid.

[0390] Step 6: Synthesis of compound 9. To a stirred solution of (8-(sec-butyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.500 g, 2.2 mmol) and 4-hydroxybenzaldehyde (0.271 g, 2.2 mmol) in methanol (10 mL) was added acetic acid (0.27 mL, 2.0 eq.) and methylpyridine borane (0.285 g, 2.6 mmol) at room temperature. The reaction mixture was stirred at room temperature for 48 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were purified by Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a crude product. The crude compound was analyzed by LC / MS. Crude LC / MS data showed 8.28% of the desired blocks. The crude compound was purified by silica gel column chromatography (100 to 200), and 50-70% ethyl acetate / petroleum ether eluted the desired compound. The LC / MS of the eluted fractions showed 72.16% of the desired blocks, which were further purified by preparative HPLC. After preparative HPLC purification, the fractions were collected and concentrated under reduced pressure, followed by lyophilization to give 9 (0.168 g, 22.8%) as a solid. Preparative HPLC method: Mobile phase A: 10 mM ammonium bicarbonate / water; Mobile phase B: acetonitrile; Column: X-BRIDGE C 18 (150×19mm 5μ); flow rate: 18mL / min. MS (ESI) m / z [M+H] + :332.2.

[0391] Example S11. Synthesis of Compound 10. The synthetic route for preparing Compound 10 is shown in Scheme 11.

[0392] Solution 11.

[0393]

[0394] To a solution of 6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (250 mg, 0.98 mmol) and 4-chlorobenzoic acid (170 mg, 1.09 mmol) in DMF (4 mL) at 0 ° C., HATU (413 mg, 1.08 mmol) was added, followed by DIPEA (0.35 mL, 1.97 mmol). The reaction mixture was stirred at room temperature for 12 h. After completion, the reaction mixture was quenched with ice-cold water (50 mL) and the aqueous layer was extracted with EtOAc (50 mL×2). The organic layer was washed with cold H 2 O (30 mL), then washed with saturated brine (30 mL), and2 SO 4 The mixture was dried and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (silica gel 100-200 mesh; 30% EtOAc / hexane) to give 1-(4-chlorobenzoyl)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione 10 (150 mg, 0.383 mmol, 39.2% yield) as a solid. MS (ESI) m / z [M+H] + :392.05. 1 H NMR (400 MHz, DMSO-d 6 )δ0.66-0.89(m,6H)0.91-1.42(m,4H)1.57-1.78(m,1H)2.16-2.35(m,2H)2.55-2.65(m,2H)3.08-3. 23(m,2H)3.28-3.40(m,1H)3.51-3.64(m,2H)4.76-4.89(m,1H)5.88-6.02(m,1H)7.46-7.56(m,4H).

[0395] Example S12. Synthesis of Compound 11. The synthetic route for preparing Compound 11 is shown in Scheme 12.

[0396] Solution 12.

[0397]

[0398] To a solution of 6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (250 mg, 0.98 mmol) and 4-fluorobenzoic acid (153 mg, 1.09 mmol) in DMF (4 mL) at 0 ° C., HATU (413 mg, 1.08 mmol) was added, followed by DIPEA (0.35 mL, 1.97 mmol). The reaction mixture was stirred at room temperature for 12 h. After completion, the reaction mixture was quenched with ice-cold water (50 mL) and the aqueous layer was extracted with EtOAc (50 mL×2). The organic layer was washed with cold H 2 O (30 mL), then washed with saturated brine (30 mL), and 2 SO 4The mixture was dried and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (silica gel 100-200 mesh; 30% EtOAc / hexane) to give 1-(4-fluorobenzoyl)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione 11 (140 mg, 0.37 mmol, 38.0% yield) as a solid. MS (ESI) m / z [M+H] + :376.05. 1 H NMR(400MHz, DMSO-d6)δ0.69-0.81(m,3H)0.86(t,J=7.23Hz,3H)0.95-1.14(m,2H)1.20-1.43(m,4H)1.59-1.80(m,2H)2.26(d,J=16.95Hz,1H) 2.55-2.72(m,1H)3.20-3.31(m,2H)3.35-3.39(m,1H)3.52-3.70(m,2H) 4.73-4.89(m,1H)7.33(t,J=8.73Hz,2H)7.61(dd,J=8.23,5.73Hz,2H).

[0399] Example S13. Synthesis of Compound 12. The synthetic route for preparing Compound 12 is shown in Scheme 13.

[0400] Solution 13.

[0401]

[0402] To a solution of 6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (250 mg, 0.98 mmol) and 3-chloro-4-(trifluoromethyl)benzoic acid (242 mg, 1.09 mmol) in DMF (4 mL) at 0 ° C., HATU (413 mg, 1.08 mmol) was added, followed by DIPEA (0.35 mL, 1.97 mmol). The reaction mixture was stirred at room temperature for 12 h. After completion, the reaction mixture was quenched with ice-cold water (50 mL) and the aqueous layer was extracted with EtOAc (50 mL×2). The organic layer was washed with cold H 2 O (30 mL), then washed with saturated brine (30 mL), and 2 SO 4The mixture was dried and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (silica gel 100-200 mesh; 30% EtOAc / hexane) to give 1-(3-chloro-4-(trifluoromethyl)benzoyl)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione 12 (250 mg, 0.55 mmol, 55.2% yield) as a solid. MS (ESI) m / z [M+H] + :460.0. 1 H NMR(400MHz,DMSO-d6)δ0.74-0.93(m,6H)0.98-1.19(m,2H)1.28-1.46(m, 3H)1.64-1.81(m,1H)2.22(d,J=17.45Hz,1H)2.57-2.70(m,1H)3.14(dd,J= 13.21,6.23Hz,1H)3.25-3.31(m,2H)3.44-3.57(m,1H)3.61-3.87(m,2H)4. 78-4.90(m,1H)5.89-6.05(m,1H)7.72(d,J=7.98Hz,1H)7.90-8.02(m,2H).

[0403] Example S14. Synthesis of intermediate compound 8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. The synthetic route for preparing this intermediate compound is shown in Scheme 14.

[0404] Solution 14.

[0405]

[0406] Step 1: Synthesis of 2,2-diethoxy-N-(4-methoxybenzyl)ethan-1-amine. A 500 mL round-bottom flask was charged with anisaldehyde (12 mL, 90.22 mmol) and 2,2-diethoxyethylamine (10 g, 75.18 mmol). The reaction mixture was heated at 100 °C for 1 h. The reaction mixture was cooled at room temperature and EtOH (100 mL) was added to the reaction mixture, followed by NaBH 4 (4.28 g, 112.7 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. After the starting material was completely consumed (monitored by TLC), the reaction mixture was concentrated under reduced vacuum. The obtained crude material was dissolved in EtOAc (300 mL). The organic layer was washed with brine (100 mL) and purified by Na 2 SO 4Dry and concentrate in vacuo to obtain a crude product. The obtained crude product was purified by column chromatography (silica gel 100-200 mesh; 70% EtOAc / hexane) to obtain 2,2-diethoxy-N-(4-methoxybenzyl)ethan-1-amine (15 g, 59.28 mmol, 78% yield) as a liquid. MS (ESI) m / z [M+H] + :254.3.

[0407] Step 2: (9H-fluoren-9-yl)methyl (1-((2,2-diethoxyethyl)(4-methoxybenzyl)amino)-1-oxopropan-2-yl)carbamate. To a stirred solution of (((9H-fluoren-9-yl)methoxy)carbonyl)alanine (32 g, 102.76 mmol) in anhydrous DMF (140 mL) maintained at 0°C was added HATU (42 g, 110.67 mmol), DIPEA (21.06 mL, 118.57 mmol), followed by 2,2-diethoxy-N-(4-methoxybenzyl)ethan-1-amine (20 g, 79.05 mmol). The reaction mixture was stirred at room temperature for 16 h. After complete consumption of the starting material, the reaction mixture was quenched with ice-cold water (300 mL) and the aqueous layer was extracted with EtOAc (200 mL×2). The organic layer was washed with cold H 2 O (200 mL), followed by brine (100 mL), and then Na 2 SO 4 The reaction mixture was dried and concentrated under reduced pressure to give a crude product. The crude material obtained was purified by column chromatography (silica gel 100-200 mesh; 50% EtOAc / hexane) to give (9H-fluoren-9-yl)methyl (1-((2,2-diethoxyethyl)(4-methoxybenzyl)amino)-1-oxopropan-2-yl)carbamate (28 g, 51.22 mmol, 64.8% yield) as a colloidal liquid. MS (ESI) m / z [M+H-EtOH] + :501.2.

[0408] Step 3: Synthesis of 2-amino-N-(2,2-diethoxyethyl)-N-(4-methoxybenzyl)propionamide. To (9H-fluoren-9-yl)methyl (1-((2,2-diethoxyethyl)(4-methoxybenzyl)amino)-1-oxopropan-2-yl)carbamate (28 g, 51.22 mmol) was added in CH 2 Cl 2To the solution in 4% paraformaldehyde (30 mL) was added diethylamine (200 mL). The reaction mixture was stirred at room temperature for 3 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated and the obtained crude material was purified by column chromatography (silica gel 100-200 mesh; 5% MeOH / DCM) to give 2-amino-N-(2,2-diethoxyethyl)-N-(4-methoxybenzyl)propanamide (14.5 g, 44.75 mmol, 87% yield) as a viscous liquid. MS (ESI) m / z [M+H-EtOH] + :279.05.

[0409] Step 4: Synthesis of (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(4-methoxybenzyl)amino)-1-oxopropan-2-yl)amino)-3-oxopropyl)carbamate. To a stirred solution of 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (14.78 g, 47.53 mmol) in anhydrous DMF (120 mL) maintained at 0°C was added HATU (18.06 g, 47.53 mmol), DIPEA (9.21 mL, 51.85 mmol) followed by 2-amino-N-(2,2-diethoxyethyl)-N-(4-methoxybenzyl)propanamide (14 g, 43.20 mmol). The reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with ice-cold water (200 mL) and the aqueous layer was extracted with EtOAc (200 mL×2). The organic layer was washed with cold H 2 O (500 mL), followed by saturated brine (200 mL), and Na 2 SO 4 The mixture was dried and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (silica gel 100-200 mesh; 30% EtOAc / hexane) to give (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(4-methoxybenzyl)amino)-1-oxopropan-2-yl)amino)-3-oxopropyl)carbamate (18 g, 29.14 mmol, 67.44% yield) as a viscous liquid. MS (ESI) m / z [M+H-EtOH] + :572.

[0410] Step 5: Synthesis of (9H-fluoren-9-yl)methyl 8-(4-methoxybenzyl)-6-methyl-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate. A solution of (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(4-methoxybenzyl)amino)-1-oxopropan-2-yl)amino)-3-oxopropyl)carbamate (18 g, 29.14 mmol) in formic acid (120 mL) was stirred at room temperature for 12 h. After completion, the reaction mixture was concentrated and the obtained crude material was purified by column chromatography (silica gel 100-200 mesh; 30% EtOAc / hexane) to give 8-(4-methoxybenzyl)-6-methyl-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylic acid (9H-fluoren-9-yl)methyl ester (14.5 g, 27.58 mmol, 94% yield) as a solid. MS (ESI) m / z [M+H] + :526.

[0411] Step 6: Synthesis of 8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. 8-(4-methoxybenzyl)-6-methyl-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylic acid (9H-fluoren-9-yl)methyl ester (14 g, 26.63 mmol) was added to CH 2 Cl 2 To the solution in 4% paraformaldehyde (150 mL) was added diethylamine (100 mL), and the reaction mixture was stirred at room temperature for 3 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated and the obtained crude material was purified by column chromatography (silica gel 100-200 mesh 5% MeOH / DCM) to give 8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (7 g, 23.07 mmol, 87% yield) as a viscous solid. MS (ESI) m / z [M+H] + :304.

[0412] Example S15. Synthesis of intermediate compound 8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. The synthetic route for preparing this intermediate compound is shown in Scheme 15.

[0413] Solution 15.

[0414]

[0415] Step 1: Synthesis of 8-(4-methoxybenzyl)-6-methyl-1-(4-(trifluoromethyl)benzoyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a solution of 4-(trifluoromethyl)benzoic acid (5.26 g, 27.69 mmol) in DMF (100 mL) maintained at 0°C was added HATU (10.52 g, 27.69 mmol), DIPEA (12.30 mL, 69.23 mmol), followed by 8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (7 g, 23.07 mmol), and the reaction mixture was stirred at room temperature for 12 h. After completion, the reaction mixture was quenched with ice-cold water (200 mL) and the aqueous layer was extracted with EtOAc (200 mL×2). The organic layer was washed with cold H 2 O (200 mL), then washed with saturated brine (150 mL), and 2 SO 4 The mixture was dried and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (silica gel 100-200 mesh; 30% EtOAc / hexane) to give 8-(4-methoxybenzyl)-6-methyl-1-(4-(trifluoromethyl)benzoyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (9 g, 18.92 mmol, 82.04% yield) as a solid. MS (ESI) m / z [M+H] + :476.15 and MS (ESI) m / z [M+Na] + :498.05.

[0416] Step 2: Synthesis of 6-methyl-1-(4-(trifluoromethyl)benzoyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. 8-(4-methoxybenzyl)-6-methyl-1-(4-(trifluoromethyl)benzoyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (9 g, 18.92 mmol) was added to a 0°C solution of CH 3 CN:H 2 CAN (31.15 g, 56.82 mmol) was added to a solution of 4% paraformaldehyde (2:1, 150 mL) and the reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was washed with saturated NaHCO 3 The solution was quenched with aqueous solution (200 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were washed with H 2 O (200 mL), followed by washing with saturated brine solution (150 mL), and 2 SO4 The mixture was dried and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (silica gel 100-200 mesh; 10% MeOH / DCM) to give 6-methyl-1-(4-(trifluoromethyl)benzoyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (3.5 g, 9.85 mmol, 52.8% yield) as a solid. MS (ESI) m / z [M+H+CH 3 CN] + :397.0. 1 H NMR(400MHz, DMSO-d6)δ1.25-1.46(m,3H)2.15-2.30(m,1H)2.56-2.69(m,1H)3.16(d,J=4.99Hz,1H)3.22-3.30(m,1 H)3.42-3.72(m,2H)4.70-4.87(m,1H)5.85-5.95(m,1H)7.75(d,J=7.98Hz,2H)7.86(d,J=7.98Hz,2H)8.11(brs,1H).

[0417] Example S16. General procedure A for the synthesis of final compounds.

[0418] To a solution of 6-methyl-1-(4-(trifluoromethyl)benzoyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (200 mg, 0.56 mmol) in DMF (2 mL) was added KO t Bu (1 M in THF, 1.69 mmol, 1.69 mL) was added followed by the addition of alkyl halide (1.12 mmol) and the reaction mixture was exposed to microwave irradiation at 120 °C for 1 h. The reaction mixture was cooled to room temperature and treated with H 2 The reaction mixture was quenched with 4% paraformaldehyde (25 mL) and 0.04% paraformaldehyde (25 mL). The aqueous layer was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine and concentrated. The obtained crude product was purified by CombiFlash.

[0419] Example S17. Synthesis of Compound 15.

[0420] Compound 15 was synthesized by General Procedure A using (bromomethyl)cyclopentane as the alkyl halide. MS (ESI) m / z [M+H] + :438.65. 1 H NMR (400 MHz, DMSO-d 6)δ1.02-1.26(m,3H)1.28-1.42(m,2H)1.44-1.76(m,6H)1.80-2.08-2.33( m,2H)2.55-2.71(m,1H)3.22(dd,J=12.96,7.48Hz,1H)3.26-3.32(m,1H)3 .39(d,J=6.98Hz,1H)3.49-3.57(m,1H)3.59-3.74(m,1H)3.76-3.91(m,1H )4.80-4.90(m,1H)5.95-6.05(m,1H)7.72-7.79(m,2H)7.84-7.91(m,2H).

[0421] Example S18. Synthesis of compound 16.

[0422] Compound 16 was synthesized by General Procedure A using bromomethylcyclobutane as the alkyl halide. MS (ESI) m / z [M+H] + :424.15. 1 H NMR (400 MHz, DMSO-d 6 )δ1.29-1.44(m,2H)1.58-1.89(m,4H)1.90-2.08(m,2H)2.16-2.31(m,1H)2.55-2.70(m,2H)3.18-3.31(m,1H)3.25-3.26(m,1H)3.34-3.42 (m,1H)3.36-3.57(m,2H)3.60-3.69(n,1H)3.71-3.83(m,1H)4.75-4.89(m,1H)5.90-6.05(m,1H)7.70-7.79(m,2H)7.87(d,J=8.31Hz,2H).

[0423] Example S19. Synthesis of Compound 19.

[0424] Compound 19 was synthesized by General Procedure A using (2-bromoethyl)cyclopentane as the alkyl halide. MS (ESI) m / z [M+H] + :452.35. 1 H NMR (400 MHz, DMSO-d 6)δ0.94-1.18(m,3H)1.26-1.61(m,9H)1.66-1.83(m,2H)2.16-2.31(m,1H)2.56-2.70(m,1H)3.16-3.28(m,1H)3.35-3.56(m ,3H)3.60-3.73(m,1H)3.77-3.90(m,1H)4.72-4.92(m,1H)5.94-6.06(m,1H)7.77(d,J=7.98Hz,2H)7.87(d,J=7.98Hz,2H).

[0425] Example S20. Synthesis of Compound 20.

[0426] Compound 20 was synthesized by General Procedure A using (2-bromoethyl)cyclobutane as the alkyl halide. MS (ESI) m / z [M+H] + :438.25. 1 H NMR (400 MHz, DMSO-d 6 )δ1.27-1.44(m,3H)1.50-1.71(m,4H)1.71-1.88(m,2H)1.93-2.09(m,2H)2.13-2.34(m,2H)2.56-2.70(m,2H)3.25-3.32(m,1H)3.35-3.42 (m,1H)3.45-3.55(m,1H)3.59-3.72(m,1H)3.74-3.90(m,1H)4.75-4.89(m,1H)5.94-6.05(m,1H)7.71-7.79(m,2H)7.87(d,J=8.31Hz,2H).

[0427] Example S21. Synthesis of Compound 21.

[0428] Compound 21 was synthesized by General Procedure A using 1-bromobutane as the alkyl halide. MS (ESI) m / z [M+H] + :412.20. 1 H NMR (400 MHz, DMSO-d 6 )δ0.81-0.97(m,3H)1.15-1.57(m,7H)2.15-2.31(m,1H)2.57-2.69(m,1H)3.14-3.28(m,1H)3.35-3.60(m,3H)3.6 2-3.73(m,1H)3.74-3.92(m,1H)4.75-4.91(m,1H)5.94-6.06(m,1H)7.76(d,J=7.34Hz,2H)7.87(d,J=7.83Hz,2H).

[0429] Example S22. Synthesis of Compound 22.

[0430] Compound 22 was synthesized by General Procedure A using 4-bromobut-1-ene as the alkyl halide. MS (ESI) m / z [M+H] + :410.20. 1 H NMR (400 MHz, DMSO-d 6 )δ1.28-1.45(m,3H)2.14-2.38(m,3H)2.55-2.69(m,1H)3.36-3.57(m,4H)3.58-3.72(m,1H)3.75-3.89(m,1H)4.7 5-4.90(m,1H)4.98-5.19(m,2H)5.69-5.84(m,1H)5.93-6.05(m,1H)7.76(d,J=7.98Hz,2H)7.88(d,J=7.98Hz,2H).

[0431] Example S23. Synthesis of Compound 23.

[0432] Compound 23 was synthesized by General Procedure A using 1-bromo-2-methylpropane as the alkyl halide. MS (ESI) m / z [M+H] + :412.25. 1 H NMR (400 MHz, DMSO-d 6 )δ0.80-0.96(m,6H)1.30-1.48(m,3H)1.85-2.03(m,1H)2.15-2.31(m, 1H)2.57-2.70(m,1H)3.06-3.16(m,1H)3.18-3.28(m,1H)3.36-3.45(m ,1H)3.44-3.57(m,1H)3.60-3.74(m,1H)3.73-3.87(m,1H)4.77-4.92( m,1H)5.93-6.07(m,1H)7.76(d,J=7.48Hz,2H)7.87(d,J=7.48Hz,2H).

[0433] Example S24. Synthesis of Compound 24.

[0434] Compound 24 was synthesized by General Procedure A using 2-bromopropane as the alkyl halide. MS (ESI) m / z [M+H] + :398.55. 1 H NMR (400 MHz, DMSO-d 6)δ1.10(d,J=5.49Hz,6H)1.28-1.45(m,3H)2.16-2.24(m,1H)2.56-2.71(m,1H)3.34-3.40(m,1H)3.44-3. 79(m,3H)4.59-4.72(m,1H)4.75-4.90(m,1H)5.86-6.00(m,1H)7.79(d,J=7.98Hz,2H)7.83-7.92(m,2H).

[0435] Example S25. Synthesis of Intermediate Compound 1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. The synthetic route for preparing this intermediate compound is shown in Scheme 16.

[0436] Solution 16.

[0437]

[0438] Step 1: Synthesis of 1-(4-(difluoromethoxy)benzoyl)-8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a solution of 4-(difluoromethoxy)benzoic acid (1.71 g, 9.08 mmol) in DMF (25 mL) maintained at 0°C was added HATU (3.45 g, 9.08 mmol), DIPEA (4.34 mL, 24.8 mmol), followed by 8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (2.5 g, 8.25 mmol), and the reaction mixture was stirred at room temperature for 12 h. After completion, the reaction mixture was quenched with ice-cold water (50 mL) and the aqueous layer was extracted with EtOAc (100 mL×2). The organic layer was washed with cold H 2 O (100 mL), then washed with saturated brine (100 mL), 2 SO 4 The mixture was dried and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (silica gel 100-200 mesh; 30% EtOAc / hexane) to give 1-(4-(difluoromethoxy)benzoyl)-8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (3.5 g, 7.38 mmol, 89.5% yield) as a solid. MS (ESI) m / z [M+H] + :474.12.

[0439] Step 2: Synthesis of 1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. 1-(4-(difluoromethoxy)benzoyl)-8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (3.0 g, 6.34 mmol) was added to a 0°C solution of CH 3 CN:H 2 CAN (12.0 g, 21.90 mmol) was added to a solution of 4% paraformaldehyde (2:1, 45 mL) and the reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was washed with saturated NaHCO 3 The solution was quenched with aqueous solution (100 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were washed with H 2 O (250 mL), followed by washing with saturated brine solution (250 mL), 2 SO 4 The mixture was dried and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (silica gel 100-200 mesh; 10% MeOH / DCM) to give 1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (2.0 g, 5.66 mmol, 89.6% yield) as a solid. MS (ESI) m / z [M+H] + :353.95. 1 H NMR (400 MHz, DMSO-d 6 )δ1.10-1.39(m,3H)2.17-2.18(m,1H)2.52-2.68(m,1H)3.18-3.27(m,2H)3.44-3.71(m,2H)4.69-4.83(m ,1H)5.75-5.92(m,1H)7.24(d,J=7.83Hz,2H)7.32(t,J=72.0Hz,1H)7.57(d,J=8.31Hz,2H)8.04(brs,1H).

[0440] Example S26. General procedure B for the synthesis of final compounds.

[0441] To a solution of 1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (200 mg, 0.56 mmol) in DMF (4 mL) maintained at 0°C was added NaH (122 mg, 2.8 mmol, 55% dispersion in mineral oil) and the reaction mixture was stirred at the same temperature for 15 minutes. To this reaction mixture was added alkyl halide (1.6 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for 3 h. After completion, the mixture was heated to room temperature with ice-cold H 2 The reaction mixture was quenched with 1% O (15 mL) and the aqueous layer was extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine and concentrated. The obtained crude product was purified by CombiFlash.

[0442] Example S27. Synthesis of Compound 13.

[0443] Compound 13 was synthesized by General Procedure B using (bromomethyl)cyclopentane as the alkyl halide. MS (ESI) m / z [M+H] + :436.05. 1 H NMR (400 MHz, DMSO-d 6 )δ1.07-1.16(m,3H)1.32(d,J=6.48Hz,3H)1.41-1.73(m,7H)2.06-2.21( m,1H)2.21-2.34(m,1H)2.54-2.70(m,1H)3.14-3.29(m,1H)3.35-3.45(m ,1H)3.52-3.69(m,1H)3.75-3.93(m,1H)4.75-4.91(m,1H)5.88-5.99(m, 1H)7.27(d,J=8.48Hz,2H)7.35(t,J=72.0Hz,1H)7.61(d,J=8.98Hz,2H).

[0444] Example S28. Synthesis of Compound 14.

[0445] Compound 14 was synthesized by General Procedure B using (bromomethyl)cyclobutane as the alkyl halide. MS (ESI) m / z [M+H] + :421.14. 1 H NMR (400 MHz, DMSO-d 6)δ1.16-1.25(m,1H)1.27-1.43(m,3H)1.54-1.73(m,2H)1.73-1.86(m,2H)1.8 9-2.03(m,2H)2.24(d,J=17.12Hz,1H)2.53-2.69(m,2H)3.20-3.28(m,1H)3.2 9-3.40(m,1H)3.40-3.66(m,2H)3.69-3.87(m,1H)4.75-4.86(m,1H)5.74-6.0 2(m,1H)7.26(d,J=8.31Hz,2H))7.33(t,J=72.0Hz,1H)7.59(d,J=8.31Hz,2H).

[0446] Example S29. Synthesis of Compound 17.

[0447] Compound 20 was synthesized by General Procedure B using 1-bromobutane as the alkyl halide. MS (ESI) m / z [M+H] + :410.0. 1 H NMR (400 MHz, DMSO-d 6 )δ0.81-0.96(m,3H)1.15-1.39(m,4H)1.40-1.55(m,2H)2.26(d,J=16.95Hz,1H)2.53-2.70(m,2H)3.12-3.30(m,2H)3.38-3.46(m,1H)3.56- 3.74(m,2H)3.75-3.92(m,1H)4.84(q,J=6.81Hz,1H)5.86-6.06(m,1H)7.28(d,J=7.98Hz,2H)7.36(t,J=72.0Hz,1H)7.62(d,J=8.48Hz,2H).

[0448] Example S30. Synthesis of Compound 18.

[0449] Compound 18 was synthesized by General Procedure B using 4-bromobut-1-ene as the alkyl halide. MS (ESI) m / z [M+H] + :408.06. 1 H NMR (400 MHz, DMSO-d 6)δ1.16-1.45(m,3H)2.18-2.33(m,3H)2.53-2.70(m,1H)3.36-3.46(m,3H)3.51-3.72(m,2H)3.74-3.90(m,1H)4.84(q,J=6.65Hz ,1H)4.91-5.15(m,2H)5.67-5.84(m,1H)5.86-6.03(m,1H)7.29(d,J=8.48Hz,2H)7.36(t,J=72.0Hz,1H)7.61(d,J=8.48Hz,2H).

[0450] Example S31. Synthesis of Compound 27.

[0451] Compound 27 was synthesized by General Procedure B using 2-(bromomethyl)tetrahydrofuran as the alkyl halide. MS (ESI) m / z [M+H] + :438.1. 1 H NMR (400 MHz, CDCl 3 )δ7.48-7.55(m,2H),7.20-7.30(m,2H),6.40-6.76(m,1H),5.90-6.20(m,1H),5.16-5.26(m,1H),4.06-4.17(m, 2H),3.82-3.92(m,4H),3.61-3.77(m,2H),2.83-2.99(m,1H),2.47-2.59(m,2H),2.01-2.12(m,4H),1.49(s,3H).

[0452] Example S32. Synthesis of Compound 28.

[0453] Compound 28 was synthesized by General Procedure B using (2-bromoethyl)benzene as the alkyl halide. MS (ESI) m / z [M+H] + :458.10. 1 H NMR (400 MHz, CDCl 3 )δ7.40-7.50(m,2H),7.20-7.28(m,2H),7.33-7.43(m,5H),6.40-6.76(m,1H),5.90-6.20(m,1H),5.16-5.26(m,1H),3.72-3.96(m, 2H),3.44-3.52(m,1H),3.25-3.35(m,2H),2.83-2.99(m,2H),2.47-2.59(m,1H),2.42-2.60(m,1H),2.30-2.57(m,1H),1.49(s,3H).

[0454] Example S33. Synthesis of Compound 29.

[0455] Compound 29 was synthesized by General Procedure B using 4-(2-bromoethyl)pyridine as the alkyl halide. MS (ESI) m / z [M+H] + :459.10. 1 H NMR (400 MHz, CDCl 3 )δ8.50-8.58(m,2H),7.24-7.46(m,4H),7.18(d,J=7.99Hz,2H),6.40-6.76(m,1H),5.90-6.20(m,1H),5.16-5.26(m,1H),3.72-3.96( m,2H),3.44-3.52(m,1H),3.25-3.35(m,2H),2.83-2.99(m,2H),2.47-2.59(m,1H),2.42-2.60(m,1H),2.30-2.57(m,1H),1.49(s,3H).

[0456] Example S34. Synthesis of Compound 30.

[0457] Compound 30 was synthesized by General Procedure B using (3-bromopropyl)cyclopropane as the alkyl halide. MS (ESI) m / z [M+H] + :459.10. 1 H NMR (400 MHz, CDCl 3 )δ8.50-8.58(m,2H),7.24-7.46(m,4H),7.18(d,J=7.99Hz,2H),6.40-6.76(m,1H),5.90-6.20(m,1H),5.16-5.26(m,1H),3.72-3.96( m,2H),3.44-3.52(m,1H),3.25-3.35(m,2H),2.83-2.99(m,2H),2.47-2.59(m,1H),2.42-2.60(m,1H),2.30-2.57(m,1H),1.49(s,3H).

[0458] Example S35. Synthesis of Compound 31.

[0459] Compound 31 was synthesized by General Procedure B using (2-bromoethyl)cyclopropane as the alkyl halide. MS (ESI) m / z [M+H] + :422.2. 1 H NMR (400 MHz, CDCl 3)δ7.48(d,J=8.01Hz,2H),7.20-7.28(m,2H),6.40-6.76(m,1H),5.90-6.20(m,1H),5.16-5.26(m,1H),3.72- 3.96(m,1H),3.46-3.64(m,5H),2.46-2.64(m,2H),1.43-1.56(m,5H),0.43-0.65(m,2H),0.75-0.85(m,2H).

[0460] Example S36. Synthesis of Compound 32.

[0461] Compound 32 was synthesized by General Procedure B using 1-bromo-2-methoxyethane as the alkyl halide. MS (ESI) m / z [M+H] + :412.1. 1 H NMR (400 MHz, DMSO-d 6 )δ7.52-7.62(m,2H),7.16-7.34(m,3H),5.85-5.95(m,1H),4.80-4.90(m,1H),3.85-3.95(m,1H),3. 70-3.80(m,2H),3.25-3.46(m,5H),3.22(s,3H),2.62-2.72(m,1H),2.20-2.30(m,1H),1.49(s,3H).

[0462] Example S37. Synthesis of compound 33.

[0463] Compound 33 was synthesized by General Procedure B using 1-bromo-3-methoxypropane as the alkyl halide. MS (ESI) m / z [M+H] + :426.20. 1 H NMR (400 MHz, DMSO-d 6 )δ7.52-7.62(m,2H),7.16-7.34(m,3H),5.85-5.95(m,1H),4.80-4.90(m,1H),3.85-3.95(m,1H),3.70-3.80( m,2H),3.58-3.68(m,2H),3.45-3.55(m,4H),3.22(s,3H),2.62-2.72(m,1H),2.20-2.30(m,2H),1.49(s,3H).

[0464] Example S38. Synthesis of compound 36.

[0465] Compound 36 was synthesized by General Procedure B using (2-bromoethyl)methylsulfone as the alkyl halide. MS (ESI) m / z [M+H] + :459.95. 1 H NMR (400 MHz, chloroform) δ 7.49 (d, J = 8.01 Hz, 2H), 7.15-7.26 (m, 2H), 6.40-6.76 (m, 1H), 5.90-6.20 (m, 1H), 5.15-5.25 (m, 1H), 3.86-3.97 (m, 3H), 3.66-3.77 (m, 2H), 3.38-3.49 (m, 3H), 2.97 (s, 3H), 2.59-2.69 (m, 2H), 1.49 (s, 3H).

[0466] Example S39. Synthesis of compound 34.

[0467] Step 1. To a solution of 1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.300 g, 0.849 mmol) in DMF (6 mL) at 0 °C was added Cs 2 CO 3 (0.827 g, 2.547 mmol), followed by addition of (2-bromoethoxy)(tert-butyl)dimethylsilane (0.243 g, 1.018 mmol), and the reaction mixture was heated in a sealed tube at 120 ° C for 1 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was slowly quenched with ice-cold water (30 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with ice-cold brine solution (3 × 30 mL) and purified by Na 2 SO 4 Dry and concentrate under reduced pressure to give 8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.250 g, crude material). The crude compound was used as is in the next reaction without further purification. MS (ESI) m / z [M+H] + :512.10.

[0468] Step 2. To a solution of 8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.250 g, 0.4886 mmol) in THF (5 mL) was added TBAF (3 mL) at 0°C. The reaction mixture was allowed to reach room temperature and stirred for 6 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was slowly quenched with ice-cold water (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with ice-cold brine solution (10 mL), purified by Na 2 SO 4 Drying and concentration under reduced pressure gave a crude compound. The obtained crude compound was purified by column chromatography (silica gel 60-120 mesh; 10% MeOH / DCM) to give 1-(4-(difluoromethoxy)benzoyl)-8-(2-hydroxyethyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.102 g, 52% yield) as a white solid. MS (ESI) m / z [M+H] + :398.2. 1 H NMR (400 MHz, DMSO-d 6 )δ7.52-7.62(m,2H),7.16-7.34(m,3H),5.92-6.02(m,1H),6.78-6.88(m,2H),3.86-3.92(m, 1H),3.47-3.62(m,6H),3.21-3.31(m,1H),2.57-2.67(m,1H),2.25-3.35(m,1H),1.49(s,3H).

[0469] Example S40. Synthesis of compound 35.

[0470] Step 1. To a solution of 1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.300 g, 0.849 mmol) in DMF (6 mL) was added NaH (0.050 g, 1.274 mmol) at 0 °C, followed by 2-bromoacetonitrile (0.112 g, 0.933 mmol), and the reaction mixture was allowed to stand at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was slowly quenched with ice-cold water (70 mL) and extracted with EtOAc (100 mL). The combined organic layers were washed with ice-cold brine solution (100 mL) and purified by Na 2 SO 4Dry and concentrate under reduced pressure to give the crude compound. The obtained crude compound was purified by column chromatography (silica gel 60-120 mesh; 10% MeOH / DCM) to give 2-(1-(4-(difluoromethoxy)benzoyl)-6-methyl-4,7-dioxooctahydro-8H-pyrazino[1,2-a]pyrimidin-8-yl)acetonitrile (0.120 g, 36% yield) as a white solid. MS (ESI) m / z [M+H] + :393.05.

[0471] Step 2. To a solution of 2-(1-(4-(difluoromethoxy)benzoyl)-6-methyl-4,7-dioxooctahydro-8H-pyrazino[1,2-a]pyrimidin-8-yl)acetonitrile (0.120 g, 0.305 mmol) in ethanol (5 mL) was added concentrated HCl (0.100 mL) at room temperature followed by platinum oxide (0.012 g, 0.030 mmol) and the reaction mixture was heated under hydrogen atmosphere for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a pad of celite. The celite pad was washed with ethanol (20 mL) and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n-pentane to give 8-(2-aminoethyl)-1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.110 g, 90% yield) as a white solid. MS (ESI) m / z [M+H] + :397.05. 1 H NMR (400 MHz, DMSO 6 )δ7.96(s,2H),7.55-7.65(m,2H),7.20-7.35(m,3H),5.90-6.20(m,1H),4.85-4.95(m,1H),3.82-3.92(m,1H) ,3.55.-3.85(m,2H),3.35-3.45(m,3H),2.95-3.05(m,2H),2.60-2.70(m,1H),2.20-2.30(m,1H),1.35(s,3H).

[0472] Example S41. General procedure C for the synthesis of final compounds.

[0473] To a solution of 1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.200 g, 0.566 mmol) in DMF (5 mL) at 0 °C was added Cs 2 CO 3(0.735 g, 2.264 mmol, 4 eq), followed by addition of alkyl halide (0.679 mmol, 1.2 eq), and the reaction mixture was heated at 50 ° C under microwave irradiation for 1 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was slowly quenched with ice-cold water (6 mL) and extracted with EtOAc (20 mL × 3). The combined organic layer was washed with saturated brine solution (10 mL) and purified by Na 2 SO 4 Dry and concentrate under reduced pressure to get the crude compound. The crude compound was purified by column chromatography to get the final compound.

[0474] Example S42. Synthesis of Compound 25.

[0475] Compound 25 was synthesized by General Procedure C using 2-(2-iodoethyl)furan as the alkyl halide. MS (ESI) m / z [M+H] + :448.10. 1 H NMR: δ7.40-7.50(m,2H),7.28-7.38(m,1H),7.15-7.25(m,2H),6.39-6.78(m,1H),6.25-6.35(m,1H),5.90-6.12(m,2H),5.25-5.35(m ,1H),5.10-5.20(m,1H),3.70-3.80(m,1H),3.50-3.60(m,1H),3.20-3.40(m,2H),2.95-3.05(m,3H),2.45-2.60(m,2H),1.59(s,3H).

[0476] Example S43. Synthesis of Compound 26.

[0477] Compound 26 was synthesized by General Procedure C using 2-(2-bromoethyl)thiophene as the alkyl halide. MS (ESI) m / z [M+H] + :464.1. 1 H NMR (400 MHz, CDCl 3 )δ7.40-7.48(m,2H),7.15-7.26(m,3H),6.85-6.95(m,2H),6.39-6.95(m,2H),5.90-6.20(m,1H),5.15-5.25(m, 1H),3.72-3.96(m,2H),3.47-3.54(m,1H),3.32-3.42(m,3H),3.10-3.20(m,2H),2.42-2.56(m,2H),1.49(s,3H).

[0478] Example S44. Synthesis of intermediate compound 1-(4-(difluoromethoxy)benzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione.

[0479]

[0480] Step 1: Synthesis of 6-methyl-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylic acid (9H-fluoren-9-yl)methyl ester. A solution of 8-(4-methoxybenzyl)-6-methyl-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylic acid (9H-fluoren-9-yl)methyl ester (1.0 g, 26.63 mmol) in TFA (10 mL) was stirred at 130 ° C in a microwave for 2 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated under vacuum and the crude product was extracted with ethyl acetate (100 ml) and saturated sodium bicarbonate solution. The organic layer was purified by anhydrous Na 2 SO 4 Dry and concentrate under vacuum, and purify by column chromatography (silica gel 100-200 mesh; 5% MeOH / DCM) to give 6-methyl-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylic acid (9H-fluoren-9-yl)methyl ester (300 mg, 42% yield) as a sticky solid. MS (ESI) m / z [M+H] + :406.

[0481] Step 2: Synthesis of 6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. 6-methyl-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylic acid (9H-fluoren-9-yl)methyl ester (300 mg, 0.74 mmol) was added to CH 2 Cl 2 To the solution in 4% paraformaldehyde (5 mL), diethylamine (6 mL) was added. The reaction mixture was stirred at room temperature for 3 h. After the starting material was completely consumed (monitored by TLC), the reaction mixture was concentrated and the crude product was purified by column chromatography (silica gel 100-200 mesh; 10% MeOH / DCM) to give 6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (120 g, 92% yield) as a white solid. MS (ESI) m / z[M+H] + :184.

[0482] Step 3: Synthesis of 1-(4-(difluoromethoxy)benzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a solution of 6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.700 g, 3.820 mmol) in DMF (8.0 mL) was added K 2 CO 3 (1.58g, 11.46mmol) and stirred for 10min. 1-(bromomethyl)-4-(difluoromethoxy)benzene (1.086g, 4.584mmol) was added to the resulting reaction mixture, and the reaction mixture was heated at 80°C for 6h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, quenched with water (50mL) and extracted with EtOAc (50mL×2). The combined organic layer was washed with saturated brine solution (20mL) and purified by Na 2 SO 4 The mixture was dried and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh; 5% MeOH / DCM) to give 1-(4-(difluoromethoxy)benzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.550 g, 43.0% yield) as an off-white solid. MS (ESI) m / z [M+H] + :340.34.

[0483] Example S45. General procedure D for the synthesis of final compounds.

[0484] To a solution of 1-(4-(difluoromethoxy)benzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.100 g, 0.2949 mmol) in DMF (2 mL) was added NaH (0.021 g, 0.8847 mmol) at 0°C, followed by the appropriate alkyl halide (2 eq.), and the reaction mixture was allowed to warm to room temperature and stirred for 5 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was washed with saturated NaHCO 3 The solution was quenched with aqueous solution (2 mL) and extracted with EtOAc (10 mL×2). The combined organic layers were washed with H 2 O (5 mL), followed by washing with saturated brine (5 mL), 2 SO 4 Dry and concentrate under reduced pressure.The crude material was purified by combiflash column chromatography (5% MeOH / DCM) to give the final product.

[0485] Example S46. Synthesis of compound 37.

[0486] Compound 37 was synthesized by General Procedure D using 4-bromo-1,1,1-trifluorobutane as the alkyl halide. MS (ESI) m / z [M+H] + :354.2. 1 H NMR (400 MHz, CDCl 3 ): δ1.41(d,J=7.13Hz,3H),1.71-1.86(m,2H),2.01-2.15(m,2H),2.26-2. 35(m,1H),2.60-2.67(m,1H),2.89-3.01(m,1H),3.07-3.15(m,1H),3.21-3 .34(m,2H),3.46-3.65(m,2H),3.81-3.95(m,2H),4.35-4.41(m,1H),5.20- 5.29(m,1H),6.53(t,J=72.0Hz,1H),7.08-7.16(m,2H),7.30-7.36(m,2H).

[0487] Example S47. Synthesis of compound 38.

[0488] Compound 38 was synthesized by General Procedure D using (2-bromoethyl)cyclopentane as the alkyl halide. MS (ESI) m / z [M+H] + :436.2. 1 H NMR (400 MHz, CDCl 3 )δ1.01-1.15(m,2H),1.41(d,J=7.13Hz,3H),1.45-1.62(m,8H),1.66-1.80(m,2H),2. 23-2.34(m,1H),2.58-2.72(m,1H),2.89-2.98(m,1H),3.04-3.18(m,2H),3.23-3.33(m ,1H),3.43-3.54(m,1H),3.55-3.65(m,1H),3.78-3.93(m,1H),4.31-4.39(m,1H),5.1 5-5.26 (m, 1H), 6.53 (t, J = 72.0Hz, 1H), 7.13 (d, J = 8.50Hz, 2H), 7.34 (d, J = 8.50Hz, 2H).

[0489] Example S48. Synthesis of compound 39.

[0490] Compound 39 was synthesized by General Procedure D using 4-bromobut-1-ene as the alkyl halide. MS (ESI) m / z [M+H] + :394.2. 1H NMR (400 MHz, CDCl 3 )δ1.41(d,J=7.13Hz,3H),2.23-2.35(m,3H),2.60-2.71(m,1H),2.92-3.0 1(m,1H),3.06-3.14(m,1H),3.22-3.46(m,3H),3.53-3.64(m,1H),3.79-3. 93(m,2H),4.28-4.38(m,1H),4.91-5.00(m,2H),5.16-5.26(m,1H),5.64- 5.76(m,1H),6.52(t,J=72.0Hz,1H),7.10-7.16(m,2H),7.30-7.36(m,2H).

[0491] Example S49. Synthesis of Compound 40.

[0492] Compound 40 was synthesized by General Procedure D using (2-bromoethyl)cyclobutene as the alkyl halide. MS (ESI) m / z [M+H] + :422.25. 1 H NMR (400 MHz, CDCl 3 )δ1.41(d,J=7.13Hz,3H),1.56-1.65(m,4H),1.73-1.92(m,2H),1.95-2.07(m,2H),2. 14-2.25(m,1H),2.26-2.35(m,1H),2.59-2.72(m,1H),2.91-2.99(m,1H),3.04-3.14(m ,2H),3.23-3.43(m,2H),3.53-3.63(m,1H),3.87(q,J=13.38Hz,2H),4.29-4.39(m,1H) ,5.17-5.24(m,1H),6.53(t,J=72.0Hz,1H),7.13(d,J=8.63Hz,2H),7.30-7.37(m,2H).

[0493] Example S50. Synthesis of Compound 41.

[0494] Compound 41 was synthesized by General Procedure D using 1-bromobutane as the alkyl halide. MS (ESI) m / z [M+H] + :396.05. 1 H NMR (400 MHz, DMSO-d 6)δ0.86(t,J=7.34Hz,3H),1.14-1.24(m,2H),1.24-1.30(m,2H),1.38-1.50(m,2H ),1.98-2.10(m,1H),2.53-2.61(m,2H),2.64-2.77(m,2H),3.07-3.25(m,3H),3.3 2-3.41(m,1H),3.62-3.73(m,1H),3.87-3.93(m,2H),4.49-4.58(m,1H),4.84-4. 94(m,1H),7.15(d,J=8.56Hz,2H),7.22(t,J=72.0Hz,1H),7.43(d,J=8.56Hz,1H).

[0495] Example S51. Synthesis of Compound 52.

[0496] Compound 52 was synthesized by General Procedure D using 2-trifluoromethyl-1-bromoethane as the alkyl halide. MS (ESI) m / z [M+H] + :420.16. 1 H NMR (400 MHz, CDCl 3 )δppm 7.31-7.38(m,2H),7.11-7.16(m,2H),6.31-6.73(m,1H),5.26(q,J=7.21Hz,1H),4.23 -4.44(m,2H),3.98-4.13(m,1H),3.80-3.93(m,3H),3.59(t,J=11.07Hz,1H),3.10(dd ,J=11.51,3.75Hz,1H),2.90-2.99(m,1H),2.62-2.72(m,1H),2.32(dd,J=4.38,2.38H z, 1H), 2.28 (dd, J = 4.31, 2.31Hz, 1H), 1.48 (d, J = 7.25Hz, 1H), 1.41 (d, J = 7.13Hz, 3H).

[0497] Example S52. General procedure E for the synthesis of final compounds.

[0498] To a solution of 6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.300 g, 1.184 mmol) in DMF (6 mL) stirred in a flask immersed in an ice / water bath, cesium carbonate (0.771 g, 2.368 mmol, 2 eq.) was added, followed by the appropriate alkyl halide (1.1 eq.). The flask was removed from the bath and stirred until TLC indicated that the starting material was completely consumed. The reaction mixture was poured into ice-cold water (70 mL) and the aqueous layer was extracted with EtOAc (100 mL). The organic layer was washed with ice-cold brine (50 mL×3) and dried over anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure.The crude product was purified by preparative HPLC to give the final compound.

[0499] Example S53. Synthesis of Compound 42.

[0500] Compound 42 was synthesized by General Procedure E using 4-(bromomethyl)-2-chloro-1-(trifluoromethyl)benzene as the alkyl halide. MS (ESI) m / z [M+H] + :362.2. 1 H NMR (400 MHz, DMSO-d 6 )δ0.75-0.89(m,3H),0.82-0.87(m,3H),0.96-1.13(m,1H),1.23-1.31(m,4H),1. 64-1.75(m,1H),2.06-2.09(m,1H),2.55-2.62(m,1H),2.65-2.76(m,1H),3.05-3 .15(m,1H),3.15-3.26(m,3H),3.64-3.74(m,1H),3.84-3.95(m,2H),4.52-4.60( m, 1H), 4.86-4.94 (m, 1H), 7.17 (t, J = 8.76Hz, 2H), 7.41 (dd, J = 8.19, 5.82Hz, 2H).

[0501] Example S54. Synthesis of compound 43.

[0502] Compound 43 was synthesized by General Procedure E using 4-(bromomethyl)-2-chloro-1-(trifluoromethyl)benzene as the alkyl halide. MS (ESI) m / z [M+H] + :446.2. 1 H NMR (400 MHz, DMSO-d 6)0.72-0.80(m,3H),0.80-0.87(m,3H),0.96-1.10(m,1H),1.21-1.27(m,1H),1.28-1 .34(m,3H),1.62-1.79(m,1H),2.00-2.13(m,1H),2.53-2.65(m,1H),2.66-2.76(m,1 H),3.00-3.10(m,1H),3.17-3.29(m,3H),3.62-3.72(m,1H),4.00-4.08(m,2H),4.55 -4.65(m,1H),4.85-4.95(m,1H),7.52-7.60(m,1H),7.73(s,1H),7.80-7.88(m,1H).

[0503] Example S55. Synthesis of compound 44.

[0504] To a solution of 6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.420 g, 1.657 mmol) and 1H-indole-3-carbaldehyde (0.264 g, 1.823 mmol) in DCE (15 mL) was added acetic acid (1 mL, 1.657 mmol) and the reaction mixture was heated at 80 °C for 1 h. To the resulting reaction mixture was added NaBH 4 (0.188 g, 4.973 mmol) and the reaction mixture was heated and stirred at 80 ° C for 4 h. When TLC analysis (5% MeOH / DCM) indicated that the starting material was completely consumed, the reaction mixture was diluted with water (40 mL) and the aqueous layer was extracted with DCM (100 mL). The organic layer was washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 The obtained crude material was purified by column chromatography (silica gel 100-200 mesh; 5% MeOH / DCM), then washed with water (30 mL) and dried under reduced pressure to give compound 44 (0.250 g, 39% yield) as an off-white solid. MS (ESI) m / z [M+H] + :383.4. 1 H NMR (400 MHz, DMSO-d 6)δ0.70(t,J=7.09Hz,3H),0.75-0.82(m,3H),0.91-1.11(m,1H),1.22-1.31(m,3H),1.57-1.72(m,1H) ),1.97-2.07(m,1H),2.55-2.70(m,2H),2.83(dt,J=10.91,2.74Hz,1H),2.95-3.07(m,1H),3.10-3. 26(m,3H),3.54-3.69(m,1H),3.96-4.04(m,1H),4.06-4.15(m,1H),4.54-4.64(m,1H),4.84-4.95(m ,1H),6.94-7.02(m,1H),7.04-7.13(m,1H),7.29-7.40(m,2H),7.65(d,J=7.95Hz,1H),10.95(s,1H).

[0505] Example S55. Synthesis of intermediate compound 1-(4-fluorobenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)dione.

[0506] To a solution of 6-methylhexahydro-4H-pyrazine [1,2-a] pyrimidine-4,7 (6H) -dione (250 mg, 1.40 mmol) in DMF (3 mL) was added potassium carbonate (580 mg, 4.20 mmol), followed by 4-fluorobenzyl bromide (0.320 g, 1.70 mmol) and stirred at 80 ° C for 3 h. After completion, the reaction mixture was monitored by TLC (5% MeOH / DCM). The reaction mixture was poured into ice-cold water (50 mL) and the aqueous layer was extracted with EtOAc (50 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (silica gel 100-200 mesh; 5% MeOH / DCM) to give 1-(4-fluorobenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)dione (160 mg, 70% yield) as a white solid. MS (ESI) m / z [M+H] + :292.

[0507] Example S56. Synthesis of Compound 45.

[0508] To a solution of 1-(4-fluorobenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)dione (80 mg, 0.2739 mmol) in DMF (3 mL) at 0 °C under an ice-cold bath was added NaH (20 mg, 0.2739 mmol) and stirred for 20 min, followed by (2-bromoethyl)cyclobutane (67 mg, 0.41 mmol) after 3 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (silica gel 100-200 mesh; 5% MeOH / DCM) to give 8-(2-cyclobutylethyl)-1-(4-fluorobenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)dione (13 mg, 16% yield) as a gummy liquid. MS (ESI) m / z [M+H] + :374. 1 H NMR (400MHz, CD 3 Cl 3 ): δ7.30-7.40(m,2H),7.00-7.10(m,2H),5.15-5.25(m,1H),4.25-4.35(m,1H),3.80-3.95(m,2H),3.55-3.65(m,1H),3.25-3.45(m,2H ),3.05-3.20(m,2H),2.90-3.0(m,1H),2.60-2.70(m,1H),2.15-2.40(m,2H),1.75-2.10(m,4H),1.55-1.65(m,4H),1.20-1.30(m,3H).

[0509] Example S57. Synthesis of compound 46.

[0510] To a solution of 1-(4-fluorobenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)dione (80 mg, 0.2739 mmol) in DMF (3 mL) at 0°C under an ice-cold bath was added NaH (20 mg, 0.2739 mmol) and stirred for 20 min, followed by the addition of (2-bromoethyl)cyclopentane (72 mg, 0.41 mmol) after 3 hours, after complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4The crude obtained was purified by column chromatography (silica gel 100-200 mesh; 5% MeOH / DCM) to give 8-(2-cyclopentylethyl)-1-(4-fluorobenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)dione as a gummy liquid.

[0511] Example S58. Synthesis of intermediate compound 6-(fluoromethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione hydrochloride.

[0512] Step 1: Synthesis of N-(2,2-diethoxyethyl)-2-methylbutan-1-amine. To neat 2,2-diethoxyethyl-1-amine (20.0 g, 0.137 mmol) was added 2-methylbutanal (11.60 g, 0.137 mmol) at room temperature, and the reaction mixture was heated to 100 °C for 3 h. Ethanol (200 mL) was slowly added to the resulting reaction mixture at room temperature, followed by NaBH 4 (15.40 g, 0.413 mmol), and the reaction mixture was stirred for 16 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and washed with saturated NH 4 Cl solution (100 mL) was slowly quenched. The aqueous layer was extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (400 mL) and then purified by Na 2 SO 4 Dry and concentrate under reduced pressure to obtain the crude compound. The obtained crude material was purified by column chromatography (silica gel 100-200 mesh; 10% MeOH / DCM) to obtain N-(2,2-diethoxyethyl)-2-methylbutan-1-amine (25.8 g, 88% yield) as a colorless liquid. MS (ESI) m / z [M+H] + :204.3. 1 HNMR(400MHz, DMSO-d6)δ0.80-0.89(m,6H)1.11(t,J=6.98Hz,6H)1.35-1.48(m,2H)2.28-2.32(m,1H )2.41-2.45(m,1H)2.55(d,J=5.49Hz,2H)3.42-3.52(m,2H)3.57-3.65(m,2H)4.49(t,J=5.49Hz,1H).

[0513] Step 2: (9H-fluoren-9-yl)methyl (1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-3-hydroxy-1-oxopropan-2-yl)carbamate. To a stirred solution of (((9H-fluoren-9-yl)methoxy)carbonyl)serine (15.0 g, 45.81 mmol) in anhydrous DMF (150 mL) maintained at 0°C was added HATU (26.0 g, 68.80 mmol), DIPEA (23.92 mL, 137.61 mmol), followed by N-(2,2-diethoxyethyl)-2-methylbutan-1-amine (12.10 g, 59.63 mmol). The reaction mixture was stirred at room temperature for 4 h. After complete consumption of the starting material, the reaction mixture was quenched with ice-cold water (500 mL) and the aqueous layer was extracted with EtOAc (250 mL×2). The combined organic layers were washed with cold H 2 O (200 mL), followed by brine (200 mL), and then Na 2 SO 4 The mixture was dried and concentrated under reduced pressure to give a crude product. The crude material was purified by column chromatography (silica gel 100-200 mesh; 80% EtOAc / hexane) to give (9H-fluoren-9-yl)methyl (1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-3-hydroxy-1-oxopropan-2-yl)carbamate (21.0 g, 89.43% yield) as a yellow viscous solid. MS (ESI) m / z [M+Na] + :535.35.

[0514] Step 3: Synthesis of 2-amino-N-(2,2-diethoxyethyl)-3-hydroxy-N-(2-methylbutyl)acrylamide. To a stirred solution of (9H-fluoren-9-yl)methyl (1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-3-hydroxy-1-oxopropan-2-yl)carbamate (21.0 g, 41.01 mmol) in anhydrous DCM (110 mL) maintained at 0°C was added diethylamine (58 mL, 2.80 volumes), and the reaction mixture was stirred at room temperature for 3 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give the crude product. The obtained crude material was purified by column chromatography (silica gel 100-200 mesh; 5% MeOH / DCM) to give 2-amino-N-(2,2-diethoxyethyl)-3-hydroxy-N-(2-methylbutyl)acrylamide (9.50 g, 80% yield) as a yellow sticky solid. MS (ESI) m / z [M+H] + :291.4.

[0515] Step 4: Synthesis of (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-3-hydroxy-1-oxopropan-2-yl)amino)-3-oxopropyl)carbamate. To a stirred solution of 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (9.50 g, 30.54 mmol) in anhydrous DMF (95 mL) maintained at 0°C was added HATU (17.40 g, 45.81 mmol), DIPEA (16.0 mL, 91.62 mmol) followed by 2-amino-N-(2,2-diethoxyethyl)-3-hydroxy-N-(2-methylbutyl)propanamide (13.20 g, 45.81 mmol) at room temperature and the reaction mixture was stirred for 16 h. After completion, the reaction mixture was quenched with ice-cold water (200 mL) and the aqueous layer was extracted with EtOAc (200 mL×2). The organic layer was washed with cold H 2 O (500 mL), followed by saturated brine (200 mL), and Na 2 SO 4 The mixture was dried and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel 100-200 mesh; 80% EtOAc / hexanes) to give (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-3-hydroxy-1-oxopropyl-2-yl)amino)-3-oxopropyl)carbamate (8.0 g, 31.0% yield) as a viscous yellow oil. MS (ESI) m / z [MH] - :582.2.

[0516] Step 5: Synthesis of (9H-fluoren-9-yl)methyl 6-(hydroxymethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate. A stirred solution of (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-3-hydroxy-1-oxopropan-2-yl)amino)-3-oxopropyl)carbamate (8.0 g, 13.77 mmol) in formic acid (48.0 mL, 6.0 volumes) at room temperature and the reaction mixture was stirred for 16 h. After completion, the reaction mixture was concentrated under reduced pressure to give (9H-fluoren-9-yl)methyl 6-(hydroxymethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (6.0 g, crude material) as a brown semisolid. The crude compound was used as is in the next reaction without further purification. MS (ESI) m / z [M+H] + :492.2.

[0517] Step 6: Synthesis of 6-(hydroxymethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. 6-(hydroxymethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylic acid (9H-fluoren-9-yl)methyl ester (6.0 g, 12.20 mmol) was added to CH 2 Cl 2 To the solution in (36.0mL) was added diethylamine (18.0mL), and the reaction mixture was stirred at room temperature for 3h. After the starting material was completely exhausted (monitored by TLC), the reaction mixture was concentrated under reduced pressure to obtain a crude compound. The crude material was purified by column chromatography (silica gel 100-200 mesh; 5% MeOH / DCM) to obtain 6-(hydroxymethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (3.0g, 93.75% yield) as a viscous colorless oil. MS (ESI) m / z[M+H] + :270.20.

[0518] Step 7: Synthesis of tert-butyl 6-(hydroxymethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate. 6-(Hydroxymethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (3.0 g, 11.15 mmol) was added to CH 2 Cl 2 In the solution of 4% paraformaldehyde (60mL), triethylamine (4.5mL, 33.45mmol) was added, followed by Boc anhydride (3.78mL, 16.72mmol), and the reaction mixture was stirred at room temperature for 16h. After the starting material was completely exhausted (monitored by TLC), the reaction mixture was slowly quenched with ice-cold water (30mL) and extracted with DCM (40mL). The organic layer was washed with brine (30mL) and purified by Na 2 SO 4 The mixture was dried and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel 100-200 mesh; 10% MeOH / DCM) to give tert-butyl 6-(hydroxymethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (8.0 g, 31.0% yield) as a viscous yellow oil. MS (ESI) m / z [M+H] + :370.25.

[0519] Step 8: Synthesis of tert-butyl 6-(fluoromethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate. To a solution of 6-(hydroxymethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (1.50 g, 4.065 mmol) in DCM (30 mL) was added DAST (1.97 g, 12.19 mmol) at -78 °C and stirred for 15 min. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. After the reaction was complete (monitored by TLC), the mixture was heated to 40 °C with saturated NaHCO 3 The reaction mixture was quenched with 1% paraformaldehyde (100 mL) and the aqueous layer was extracted with EtOAc (100 mL×2). The combined organic layers were washed with saturated brine (50 mL) and purified by Na 2 SO 4 Dry and concentrate under reduced pressure to obtain the crude compound. The crude material was purified by column chromatography (silica gel 100-200 mesh; 5% MeOH / DCM) to give tert-butyl 6-(fluoromethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (0.800 g, 72.0% yield) as a colorless viscous oil. MS (ESI) m / z [M+H] + :372.2.

[0520] Step 9: Synthesis of 6-(fluoromethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione hydrochloride. To a stirred solution of tert-butyl 6-(fluoromethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (1.0 g, 2.695 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in dioxane (5 mL) at 0°C, and the reaction mixture was stirred at room temperature for 3 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (10 mL), filtered through Na 2 SO 4 The mixture was dried and concentrated under reduced pressure to give 6-(fluoromethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione hydrochloride (0.630 g, crude material) as a brown viscous oil. MS (ESI) m / z [M+H] + Free base: 271.00.

[0521] Example S59. Synthesis of Compound 47.

[0522] To a solution of 6-(fluoromethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione hydrochloride (0.150 g, 0.550 mmol) in DMF (1.5 mL) was added K 2 CO 3 (0.381 g, 2.760 mmol), followed by the addition of 1-(bromomethyl)-4-(difluoromethoxy)benzene (0.261 g, 1.100 mmol), and the reaction mixture was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was slowly quenched with ice-cold water (6 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with saturated saline solution (10 mL) and purified by Na 2 SO 4 Dry and concentrate under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC to give 1-(4-(difluoromethoxy)benzyl)-6-(fluoromethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.040 g, 17.0% yield) as a white solid. MS (ESI) m / z [M+H] + :428.10. 1 H NMR (400 MHz, CDCl 3 )δ7.34(d,J=8.01,2H),7.11(d,J=8.01,2H),6.32-6.69(m,1H),5.14-5. 25(m,2H),4.60-4.76(m,2H),3.84-3.97(m,2H),3.35-3.45(m,2H),3.12- 3.40(m,4H),2.85-3.05(m,1H),2.65-2.75(m,1H),2.29-2.34(m,1H),1. 65-1.75(m,1H),1.30-1.40(m,1H),1.05-1.18(m,1H),0.80-0.90(m,6H).

[0523] Example S60. Synthesis of Compound 48.

[0524] To a solution of 6-(fluoromethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione hydrochloride (0.340 g, 1.253 mmol) in DMF (3.4 mL) was added Cs 2 CO 3(0.814 g, 2.506 mmol), followed by the addition of 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.598 g, 2.506 mmol), and the reaction mixture was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was slowly quenched with ice-cold water (6 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with saturated brine solution (10 mL) and purified by Na 2 SO 4 Dry and concentrate under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC to give 6-(fluoromethyl)-8-(2-methylbutyl)-1-(4-(trifluoromethyl)benzyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.045 g, 8.0% yield) as a white solid. MS (ESI) m / z [M+H] + :430.10. 1 H NMR (400 MHz, CDCl 3 )δ7.34(d,J=8.01,2H),7.11(d,J=8.01,2H),5.14-5.25(m,2H),4.60-4.76(m,2H),3.84-3.97(m,2H),3.35-3.45(m,2H),3.12-3.40(m,4 H),2.85-3.05(m,1H),2.65-2.75(m,1H),2.29-2.34(m,1H),1.65-1.75(m,1H),1.30-1.40(m,1H),1.05-1.18(m,1H),0.80-0.90(m,6H).

[0525] Example S61. Synthesis of intermediate compound 2-(1-(4-(difluoromethoxy)benzyl)-8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetate.

[0526] Step 1: Synthesis of methyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate. To a solution of 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-methoxy-4-oxobutanoic acid (1.90 g, 9.475 mmol) stirred in anhydrous DMF (30 mL) at 0°C was added HATU (3.60 g, 1.137 mmol) followed by DIPEA (2.70 mL, 1.895 mmol), and the reaction mixture was stirred at the same temperature for 10 min. To the resulting reaction mixture was added N-(2,2-diethoxyethyl)-2-methylbutan-1-amine (3.50 g, 9.475 mmol), and the mixture was then warmed to room temperature and stirred for 6 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with ice-cold water (100 mL) and the aqueous layer was extracted with EtOAc (50 mL×2). The combined organic layers were washed with cold H 2 O (50 mL), followed by brine (50 mL), and then Na 2 SO 4 The mixture was dried and concentrated under reduced pressure to give a crude product. The crude material was purified by CombiFlash column chromatography using 50% EtOAc / n-hexane to give methyl 3-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate (4.30 g, 83.0% yield) as a white solid. MS (ESI) m / z [M+H-EtOH] + :509.2.

[0527] Step 2: Synthesis of methyl 3-amino-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate. Methyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate (1.36 g, 2.451 mmol) was added to CH 2 Cl 2 4-nitro-4-nitro-2-nitropropene (0.700g, 86% yield) was obtained. The mixture was stirred for 3 hours at 4 ℃ for 1 h. After the starting material was completely exhausted (monitored by TLC), the reaction mixture was concentrated under reduced pressure to obtain a crude compound. The crude compound was purified by CombiFlash column chromatography using 5% MeOH / DCM to obtain 3-amino-4-((2,2-diethoxyethyl) (2-methylbutyl) amino)-4-oxobutanoic acid methyl esters (0.700g, 86% yield) in a yellow viscous liquid. MS (ESI) m / z [M+H-EtOH]+ :287.68.

[0528] Step 3: Synthesis of methyl 3-(3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propionamido)-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate. To a stirred solution of 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (0.490 g, 1.594 mmol) in anhydrous DMF (10 mL) maintained at 0°C was added HATU (0.720 g, 1.913 mmol), DIPEA (0.555 mL, 3.188 mmol) followed by methyl 3-amino-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate (0.530 g, 1.594 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 6 h. After completion, the reaction mixture was quenched with ice-cold water (20 mL) and the aqueous layer was extracted with EtOAc (20 mL×2). The organic layer was washed with cold H 2 O (10 mL), then washed with saturated brine (20 mL), and 2 SO 4 The mixture was dried and concentrated under reduced pressure. The crude compound was purified by Combiflash column chromatography using 5% MeOH / DCM to give methyl 3-(3-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)propionamido)-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate (0.630 g, 70% yield) as an off-white solid. MS (ESI) m / z [M+H-EtOH] + :580.20.

[0529] Step 4: Synthesis of (9H-fluoren-9-yl)methyl 6-(2-methoxy-2-oxoethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate. To a stirred solution of methyl 3-(3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propionamido)-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate (0.300 g, 0.4794 mmol) was added formic acid (1.5 mL) at room temperature and the reaction mixture was stirred for 16 h. After completion, the reaction mixture was concentrated and the obtained crude material was purified by column chromatography (silica gel 100-200 mesh; 0-5% MeOH / DCM) to afford (9H-fluoren-9-yl)methyl 6-(2-methoxy-2-oxoethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (0.200 g, 80% yield) as a yellow solid. MS (ESI) m / z [M+H] + :534.67.

[0530] Step 5: Synthesis of methyl 2-(8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetate. To methyl 6-(2-methoxy-2-oxoethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (9H-fluoren-9-yl)acetate (0.240 g, 0.4499 mmol) was added to CH 2 Cl 2 To the solution in 4% paraformaldehyde (0.5 mL) was added diethylamine (0.280 mL), and the reaction mixture was stirred at room temperature for 3 h. After the starting material was completely consumed (monitored by TLC), the reaction mixture was concentrated and the crude material was purified by combiflash column chromatography using 0-5% MeOH / DCM to give methyl 2-(8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetate (0.130 g, 93% yield) as a white solid. MS (ESI) m / z [MH] + :310.4.

[0531] Step 6: Synthesis of methyl 2-(1-(4-(difluoromethoxy)benzyl)-8-(2-methylbutyl)-4,7-dioxoocthydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetate. To a solution of methyl 2-(8-(2-methylbutyl)-4,7-dioxoocthydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetate (3.08 g, 9.890 mmol) in DMF (30 mL) was added K 2 CO 3 (4.10 g, 29.66 mmol), and the reaction mixture was stirred at 80 ° C for 15 min. 1- (bromomethyl) -4- (difluoromethoxy) benzene (3.48 g, 14.36 mmol) was added to the resulting reaction mixture, and the stirred mixture was heated to 80 ° C for 2 h. After completion, the reaction mixture was quenched with ice-cold water (200 mL) and the aqueous layer was extracted with EtOAc (200 mL × 2). The organic layer was washed with cold H 2 O (200 mL), then washed with saturated brine (150 mL), and 2 SO 4 The mixture was dried and concentrated under reduced pressure. The crude compound obtained was purified by Combiflash column chromatography (5% MeOH / DCM) to give methyl 2-(1-(4-(difluoromethoxy)benzyl)-8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetate (2.20 g, 48% yield) as a yellow solid. MS (ESI) m / z [M-CH 3 ] + :454.10.

[0532] Example S61. Synthesis of Compound 49.

[0533] To a solution of methyl 2-(1-(4-(difluoromethoxy)benzyl)-8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetate (2.20 g, 4.705 mmol) in THF (22.0 mL) was added NaOH (0.560 g, 14.11 mmol), followed by water (4 mL), and the reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in water (10 mL), slowly acidified with 6N HCl (10 mL) and stirred for 5 min. The resulting solid precipitate was filtered through a Buchner funnel and dried under reduced pressure to give 2-(1-(4-(difluoromethoxy)benzyl)-8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetic acid (0.85 g, 40% yield) as a white solid. MS (ESI) m / z [M+H] + :454.10. 1 H NMR (400 MHz, CDCl 3 )δ7.28-7.38(m,2H),7.11(d,J=7.99Hz,2H),6.33-6.71(m,1H),5.36-5.40(m ,1H),4.70-4.80(m,1H),4.65-4.75(m,1H),3.80-4.00(m,2H),3.55-3.65(m, 1H),3.35-3.45(m,1H),2.85-3.30(m,6H),2.70-2.80(m,1H),2.25-2.35(m,1 H),1.65-1.76(m,1H),1.25-1.35(m,1H),1.10-1.20(m,1H),0.8-0.9(m,6H).

[0534] Example S62. Synthesis of Compound 50.

[0535] To a solution of 2-(1-(4-(difluoromethoxy)benzyl)-8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetic acid (0.470 g, 1.036 mmol) in THF (5 mL) was added 1,1'-carbonyldiimidazole (0.500 g, 3.109 mmol) at room temperature and the reaction mixture was stirred for 15 min. To the resulting reaction mixture was added NH 3Aqueous solution (10mL) and the reaction mixture was stirred at room temperature for 3h. The reaction progress was monitored by TLC. After completion, the reaction mixture was slowly quenched with ice-cold water (6mL) and extracted with EtOAc (20mL×3). The combined organic layer was washed with saturated brine solution (10mL) and washed with Na 2 SO 4 Drying and concentrating under reduced pressure provided the crude compound. The crude compound obtained was purified by Combiflash column chromatography using 5% MeOH / DCM followed by preparative HPLC to afford 2-(1-(4-(difluoromethoxy)benzyl)-8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetamide (0.070 g, 15% yield) as a white solid. MS (ESI) m / z [M+H] + :453.20. 1 H NMR (400 MHz, CDCl 3 )δ7.30-7.40(m,2H),7.05-7.15(m,2H),6.39-6.70(m,1H),5.20-5.40(m,2H),4. 75-4.85(m,1H),3.95-4.05(m,1H),3.75-3.85(m,1H),3.50-3.60(m,1H),3.30-3. 40(m,1H),3.05-3.25(m,2H),2.85-2.95(m,2H),2.55-2.70(m,1H),2.25-2.35(m ,1H),1.70-1.80(m,2H),1.30-1.40(m,2H),1.05-1.20(m,2H),0.75-0.90(m,6H).

[0536] Example S63. Synthesis of intermediate compound 1-(3-chloro-4-(trifluoromethyl)benzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione.

[0537] To a solution of 6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (500 mg, 2.732 mmol) in DMF (7 mL) was added potassium carbonate (1.13 g, 8.196 mmol), followed by 4-(bromomethyl)-2-chloro-1-(trifluoromethyl)benzene (0.894 g, 3.278 mmol), and stirred at 80 ° C for 12 h. After the reaction was completed, the reaction mixture was poured into ice-cold water (50 mL) and the aqueous layer was extracted with EtOAc (50 mL) by monitoring by TLC (5% MeOH / DCM). The organic layer was washed with anhydrous Na 2 SO4 The mixture was dried and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (silica gel 100-200 mesh; 5% MeOH / DCM) to give 1-(3-chloro-4-(trifluoromethyl)benzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)dione (320 mg, 42% yield) as a white solid. MS (ESI) m / z [M+H] + :376.34.

[0538] Example S64. General procedure F for the synthesis of final compounds.

[0539] To a solution of 1-(3-chloro-4-(trifluoromethyl)benzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (150 mg, 0.400 mmol) in DMF (2 mL) at 0 °C was added Cs 2 CO 3 (4 eq) and stirred for 20 min, then the appropriate alkyl halide (1.2 eq) was added at room temperature, and the reaction mixture was heated and stirred at 80 ° C for 12 h. After the starting material was consumed (monitored by TLC), the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure.The crude material obtained was purified by column chromatography (silica gel 100-200 mesh; 5% MeOH / DCM) to afford the final compound.

[0540] Example S65. Synthesis of Compound 51.

[0541] Compound 51 was synthesized by General Procedure F using (2-bromoethyl)cyclobutane as the alkyl halide. MS (ESI) m / z [M+H] + :458.2. 1 H NMR (400 MHz, CDCl 3)δppm 7.70(d,J=8.07Hz,1H),7.54(s,1H),7.33(d,J=8.68Hz,1H),4.34(dd,J=10.64 ,3.55Hz,1H),3.87-3.99(m,2H),3.61(t,J=11.13Hz,1H),3.25-3.42(m,2H),3. 08-3.19(m,2H),2.89-2.98(m,1H),2.64-2.74(m,1H)2.29-2.38(m,1H)2.17-2. 27(m,1H)1.97-2.09(m,2H)1.72-1.92(m,3H)1.58-1.66(m,4H)1.55(br.s,3H).

[0542] Example S66. Synthesis of Compound 54.

[0543] Compound 54 was synthesized by General Procedure F using (2-bromoethyl)cyclopentane as the alkyl halide. MS (ESI) m / z [M+H] + :472.15. 1 H NMR (400 MHz, CDCl 3 )δppm 7.69(d,J=8.11Hz,1H)7.52-7.56(m,1H)7.33(d,J=7.89Hz,1H),5.23(q,J=7.23Hz,1H),4.36(dd,J=10. 52,3.29Hz,1H),3.87-3.98(m,2H),3.63(t,J=11.07Hz,1H),3.46-3.56(m,1H),3.25-3.35(m,1H),3.12- 3.23(m,2H),2.87-2.97(m,1H),2.60-2.70(m,1H),2.29-2.37(m,1H),1.66-1.82(m,2H),1.54-1.63(m,1 H),1.51(d,J=,2.63Hz,2H),1.42(d,J=7.23Hz,3H),1.26(br.s,2H)1.04-1.16(m,2H)0.80-0.92(m,2H).

[0544] Example S67. Synthesis of Compound 53.

[0545] Step 1: Synthesis of (9H-fluoren-9-yl)methyl 1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate. To a stirred solution of (((9H-fluoren-9-yl)methoxy)carbonyl)leucine (20.0 g, 56.58 mmol) in anhydrous DMF (200 mL) at 0°C was added HATU (21.50 g, 56.58 mmol) followed by DIPEA (10.62 mL, 61.10 mmol) and the reaction mixture was stirred at the same temperature for 10 min. To the resulting reaction mixture was added N-(2,2-diethoxyethyl)-2-methylbutan-1-amine (11.48 g, 56.58 mmol) at room temperature and the reaction mixture was stirred for 3 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with ice-cold water (100 mL) and the aqueous layer was extracted with EtOAc (50 mL×4). The combined organic layers were washed with cold H 2 O (50 mL x 2), followed by brine (50 mL), 2 SO 4 Dry and concentrate under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using 5% MeOH / DCM to give (9H-fluoren-9-yl)methyl (1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (14.5 g, 47.57 yield) as a white solid. MS (ESI) m / z [M+H] + :539.04.

[0546] Step 2: Synthesis of 2-amino-N-(2,2-diethoxyethyl)-4-methyl-N-(2-methylbutyl)pentanamide. At room temperature, (9H-fluoren-9-yl)methyl (1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (8.50 g, 15.77 mmol) was added to CH 2 Cl 2 In the solution of 4-nitro-2-nitro-2-nitro-4 ... + :272.10.

[0547] Step 3: Synthesis of (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-methyl-1-oxopentan-2-yl)amino)-3-oxopropyl)carbamate. To a stirred solution of 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (3.80 g, 12.28 mmol) in anhydrous DMF (35 mL) maintained at 0°C was added HATU (6.48 g, 17.05 mmol) and DIPEA (4.90 mL, 28.42 mmol) followed by 2-amino-N-(2,2-diethoxyethyl)-4-methyl-N-(2-methylbutyl)pentanamide (3.60 g, 11.37 mmol). The reaction mixture was allowed to reach room temperature and stirred for 3 h. After completion, the reaction mixture was quenched with ice-cold water (20 mL) and the aqueous layer was extracted with EtOAc (30 mL×2). The organic layer was washed with cold H 2 O (10 mL), then washed with saturated brine (20 mL), and 2 SO 4 The mixture was dried and concentrated under reduced pressure. The crude compound was purified by Combiflash column chromatography using 5% MeOH / DCM to give (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-methyl-1-oxopentan-2-yl)amino)-3-oxopropyl)carbamate (3.8 g, 55% yield) as an off-white solid. MS (ESI) m / z [M+H-EtOH] + :565.30.

[0548] Step 4: Synthesis of 6-isobutyl-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylic acid (9H-fluoren-9-yl)methyl ester. To a stirred solution of 6-isobutyl-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)carboxylic acid (9H-fluoren-9-yl)methyl ester (3.80 g, 6.231 mmol) was added formic acid (20 mL) at room temperature, and the reaction mixture was stirred for 16 h. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel 100-200 mesh; 0-5% MeOH / DCM) to give (9H-fluoren-9-yl)methyl 6-isobutyl-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (3.60 g, 94% yield) as a yellow solid. MS (ESI) m / z [M+H] + :518.23.

[0549] Step 5: Synthesis of 6-isobutyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. 6-isobutyl-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylic acid (9H-fluoren-9-yl)methyl ester (3.60 g, 6.954 mmol) was added to CH 2 Cl 2 To a solution of 4-nitropropene (36 mL) in 4% paraformaldehyde (5% paraformaldehyde) was added diethylamine (6.8 mL, 69.54 mmol), and the reaction mixture was stirred at room temperature for 16 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated under reduced pressure, and the crude material was purified by combiflash column chromatography using 10-50% ethyl acetate / n-hexane to give 6-isobutyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (1.20 g, 60% yield) as a white solid. MS (ESI) m / z[M+H] + :296.10.

[0550] Step 6: Synthesis of 1-(4-(difluoromethoxy)benzyl)-6-isobutyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a solution of 6-isobutyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.170 g, 0.576 mmol) in DMF (5 mL) was added K 2 CO 3 (0.159 g, 1.152 mmol), and the reaction mixture was stirred for 10 min. 1-(bromomethyl)-4-(difluoromethoxy)benzene (0.150 g, 0.632 mmol) was added to the resulting reaction mixture at room temperature and stirred for 3 h. After completion, the reaction mixture was quenched with ice-cold water (200 mL) and the aqueous layer was extracted with EtOAc (20 mL × 2). The organic layer was washed with cold H 2 O (20 mL), then washed with saturated brine (15 mL), and 2 SO 4 The mixture was dried and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 1-(4-(difluoromethoxy)benzyl)-6-isobutyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.103 g, 40% yield) as a white solid. MS (ESI) m / z [M+H] + :452.3. 1H NMR (400 MHz, DMSO d 6 )δ7.42(d,J=8.8Hz,2H),7.14-7.24(m,3H),5.0-5.10(m,1H),4.50-4.60(m,1H),3.90-4.00(m,2H),3.60-3.70(m,1H),3.02- 3.40(m,4H),2.70-2.85(m,2H),2.0-2.10(m,1H),1.50-1.70(m,4H),1.20-1.35(m,1H),1.0-1.10(m,1H),0.70-0.98(m,12H).

[0551] Biological Examples

[0552] Example B1. PhosphoMET ELISA.

[0553] Compounds were screened for potency on the HGF / MET system using the phosphorylated MET (pMET) ELISA kit (Cell Signaling).pMET levels were detected in samples with low (1 ng / mL) and high (10 ng / mL) concentrations of HGF.

[0554] The cells were cultured by passage into 6-well multiplates and maintained at 37°C, 5% CO 2 HEK293 cells were prepared by growing in DMEM + 10% FBS until approximately 90% confluence. Cells were then starved in serum-free growth medium for at least 8 hours.

[0555] Exemplary compounds were prepared in DMEM + 0.1% FBS, diluted and added to treatment medium with 1 ng / mL recombinant HGF protein (R&D Systems). Cells were maintained at 37°C and 5% CO. 2 Next, incubate in triplicate for 15 minutes. Then treat the sample with 180 μL ice-cold RIPA (radioimmunoprecipitation assay) buffer and lyse the cells on ice for 15 minutes. Remove the lysate and retain the supernatant by centrifugation at 16,000-g for 15 minutes. Use the BCA assay of the lysate to normalize the sample to determine the protein concentration in the sample.

[0556] 50 to 100 μg of total protein lysate was loaded into the ELISA wells in the pMET sandwich ELISA kit (Cell Signaling catalog number 7227C) to ensure equal protein loading in each well. The ELISA was processed according to the manufacturer's instructions. After color development, the absorbance was read at 450 nm on an optical plate reader.

[0557] Peak efficacy was used to determine potency measurements by scaling test compound dose treatments along a scale of 1 to 10 between 1 ng / mL and 10 ng / mL HGF doses according to the following formula:

[0558] y=1+(xA)*(10-1) / (BA)

[0559] Where y is the normalized data point, x is the original data point, A is the average HGF at 1 ng / mL, and B is the average HGF at 10 ng / mL. The results of the calculated potency are shown in Table 2.

[0560] Table 2. Potency of exemplary compounds.

[0561] Compound Effectiveness Compound No. Effectiveness 1a ++++ 2a ++ 3a - 4a + 5a + 6a + 7a ++ 8a + 9 - 10 - 11 +++ 12 ++ 13 - 14 ++++ 15 - 16 - 17 +++ 18 - 19 +++ 20 + 21 - 22 +++ 23 - 24 - 25 - 26 - 27 - 28 - 29 - 30 +++ 31 - 32 - 33 - 34 - 35 - 36 - 37 - 38 - 39 - 40 - 41 - 42 ++++ 43 - 44 - 45 - 46 - 47 - 48 - 49 ++++ 50 - 51 +++ 52 - 53 ++ 54 -

[0562] - The indicated compound failed to significantly enhance MET phosphorylation

[0563] +Indicates maximum potency at or above 100 nM

[0564] ++ indicates maximum potency at or above 10 nM

[0565] +++ indicates maximum potency at or above 1 nM

[0566] ++++ indicates maximum potency at or above 0.1 nM

[0567] Example B2. Cell scattering behavior assay.

[0568] MDCK cells are grown under normal conditions and observed to form a tight colony spontaneously when it propagates. MDCK cells are reacted to the HGF processing by moving away from each other (dispersion), and it is quantitatively evaluated to assess the amount of HGF / MET activation in the cell colony. In this experiment, MDCK cells are plated with 96 well formats, with HGF and exemplary compound processing, through fluorescent staining, large visual field imaging, and quantitative dispersion behavior. Determine quantitative results by analyzing the number (normalized particle count) of the continuous groups of the cell compared with the total staining area imaged.

[0569] MDCK cells were plated at low density in black wall imaging plates and maintained at 37 °C and 5% CO. 2 The cells were attached overnight in DMEM + 10% FBS at 37 ° C. The cells were then starved for 2 hours in DMEM without FBS ("starvation medium"). Samples containing exemplary compounds were prepared in DMEM without FBS and included 5 ng / mL HGF protein ("treatment medium"). A control curve was also made for each plate using HGF concentrations of 0, 5, 10 and 20 ng / mL. The starvation medium was replaced by the treatment medium and the cells were incubated at 37 ° C. and 5% CO.2 Incubate for 24 hours.

[0570] After incubation, the cells were fixed by replacing the treatment medium with cold ethanol and incubating at 4°C for 20 minutes. The cells were then rehydrated by washing with PBS and then with a staining solution (fluorescent wheat germ agglutinin; PBS containing 20 μg / mL WGA488). The cells were incubated with the staining solution at room temperature for 30 minutes, after which the staining solution was replaced with fresh PBS.

[0571] Use iCyte high content imager to image the cell area in green wavelength.Image is converted into binary and analyzes the particle diameter and particle count of image.For the purpose of analysis, individual cells or independent cell colonies that do not contact other cells are identified as particles, and the particle count is normalized to consider the difference in cell number by total signal area.The increase of particle number indicates that individual cells move away from each other with dispersed behavior reaction.Compound efficacy is assessed by the statistical increase in the normalized particle count compared with independent HGF processing.The results are shown in Table 3.

[0572] Table 3. Cell scattering assay results for exemplary compounds.

[0573] Compound Effectiveness Compound Effectiveness 1a ++++ 2a + 3a - 4a + 5a ++++ 6a +++ 7a ++ 8a +++ 9 - 10 - 11 ++ 12 ++ 13 - 14 +++ 15 - 16 - 17 - 18 - 19 +++ 20 +++ 21 - 22 ++ 23 - 24 - 25 - 26 - 27 NT 28 - 29 NT 30 ++ 31 - 32 - 33 - 34 - 35 - 36 - 37 - 38 NT 39 - 40 NT 41 - 42 +++ 43 - 44 - 45 NT 46 - 47 NT 48 NT 49 ++++ 50 - 51 +++ 52 - 53 +++ 54 -

[0574] - The indicated compounds failed to significantly promote cell dispersal behavior

[0575] +Indicates maximum potency at or above 100 nM

[0576] ++ indicates maximum potency at or above 10 nM

[0577] +++ indicates maximum potency at or above 1 nM

[0578] ++++ indicates maximum potency at or above 0.1 nM

[0579] NT indicator compound not tested

[0580] Example B3. Solubility determination.

[0581] Aqueous solubility is a key drug property that helps predict bioavailability. In general, compounds with an aqueous solubility <100 μg / ml are poor drugs. To assess compound solubility, turbidimetric solubility assays were performed with exemplary compounds at concentrations ranging from 3 to 300 μM.

[0582] To assess the solubility of the compounds by turbidity, the test compound was first dissolved in an organic solvent (DMSO) at a concentration of 10 mM. This compound solution was then diluted in an aqueous solvent (PBS) in a 96-well assay plate in a dilution series from 3 to 300 μM. The solution was incubated at 37° C. for 2 hours.

[0583] In wells where the test compound exceeds its solubility limit, the compound will precipitate, effectively blocking light from passing through and thus increasing the absorbance signal of UV light at a wavelength of 620 nm. If turbidity increases the absorbance by more than 10% over the control reading, the compound is considered to be insoluble at the test concentration. The results are shown in Table 4.

[0584] Table 4. Solubility of exemplary compounds.

[0585]

[0586]

[0587] + indicates solubility at 10 μM

[0588] ++ indicates solubility at 30 μM

[0589] +++ indicates solubility at 100 μM

[0590] ++++ indicates solubility at 300 μM

[0591] Example B4. Permeability determination.

[0592] To be bioavailable, a drug must permeate the cell membranes lining the digestive tract. To estimate the permeation rate of exemplary compounds, an in vitro parallel artificial membrane permeability assay (PAMPA) was utilized.

[0593] Test compounds must have a standard curve in the final read plate to determine the partitioned concentration of each drug. A 6 point standard curve was prepared for each compound from 0 to 200 μM in phosphate buffered saline (PBS).

[0594] The test compound solution (300 μL in PBS) was added to the donor (bottom) wells of the PAMPA plate in 5 replicates, and PBS vehicle (200 μL) was added to the acceptor (top) wells of the appropriate wells to match the loading of the donor plate. The bottom and top of the PAMPA plate were then clamped together. The PAMPA plate was then incubated for 5 hours at room temperature. After incubation, 150 μL of the donor solution was added to the UV compatible plate containing the corresponding standard curve. 150 μL of the acceptor well solution was added near the corresponding standard curve of the compound and the donor well sample. The plate was then read using a UV plate reader.

[0595] The permeability and membrane retention were then calculated based on the following formula:

[0596] Permeability (cm / s): (Pe)(cm / s) = {-ln[1-CA(t) / Ceq]} / [A*(1 / VD+

[0597] 1 / VA)*t]

[0598] (Equation 1)

[0599] in:

[0600] A = filtration area (0.3 cm 2 );

[0601] VD = donor pore volume (0.3 mL);

[0602] VA = acceptor pore volume (0.2 mL);

[0603] t = incubation time (seconds);

[0604] CA(t) = concentration of compound in the receptor well at time t;

[0605] CD(t) = compound concentration in the donor well at time t; and Ceq = [CD(t)*VD+CA(t)*VA] / (VD+VA).

[0606] Membrane retention rate (R) = 1-[CD(t)*VD+CA(t)*VA] / (C0*VD)

[0607] (Equation 2)

[0608] in:

[0609] CD(t), VD, CA(t) and VA are defined as for Equation 1, and C0 = initial concentration in the donor well (200 uM).

[0610] The results are shown in Table 5.

[0611] Table 5. Permeability of exemplary compounds.

[0612]

[0613]

[0614] + Indicates above 1×10 -5 Permeability cm / s

[0615] ++ indicates higher than 2×10 -6 Permeability cm / s

[0616] +++ indicates less than 2×10 -6Permeability cm / s

[0617] NT indicator compound not tested

[0618] Example B5. Cytotoxicity assay.

[0619] This experiment was designed to obtain a preliminary assessment of cytotoxicity. Compounds were tested at high concentrations to determine if any cytotoxic effects were observed in hepatocyte (HepG2) cell cultures by measuring lactate dehydrogenase (LDH) release into the culture medium as a measure of lysed / dead cells.

[0620] HepG2 cells were plated in 96-well cell culture plates and incubated at 37°C, 5% CO 2 The cells were allowed to attach overnight in EMEM + 10% FBS. Treatments were performed in complete medium (EMEM + 10% FBS) and included a dilution series of test compounds ranging from 0.1 to 100 μM. The known cytotoxin cerivastatin was used as a positive assay control and was prepared at a final concentration of 0.5 μM.

[0621] The growth medium is replaced by treatment medium (EMEM + 10% FBS containing the test compound dissolved in DMSO) and the cells are incubated with the test compound for 48 hours. At the end of the incubation period, the supernatant medium from each well is transferred to a new plate and the LDH assay working solution is added. The LDH assay solution undergoes a colorimetric reaction proportional to the amount of lactate dehydrogenase (an intracellular protein found in the culture medium only in the presence of lysed cells) in the culture medium. The color reaction is quantified by measuring the absorbance at a wavelength of 490nm.

[0622] The signal range of the assay was determined by complete lysis of all cells in the negative control treatment without manipulation and lysis control samples. In this assay, compounds that increased the level of cytotoxicity by more than 20% over the negative control sample were considered cytotoxic. The results are shown in Table 6.

[0623] Table 6. Cytotoxicity of exemplary compounds.

[0624]

[0625]

[0626] + indicates no toxicity at 0.1 μM

[0627] ++ indicates no toxicity at 1 μM

[0628] +++ indicates no toxicity at 10 μM

[0629] ++++ indicates no toxicity at 100 μM

[0630] NT indicator compound not tested

[0631] Example B6. In vitro stability analysis.

[0632] Bioavailability can be estimated by compound stability when exposed to in vivo pathologies. As an initial assessment of stability properties for various pathologies present in animals, the stability of exemplary compounds was tested in a panel of simulated body compartments. The stability of the compounds was tested in the following solutions: simulated gastric fluid (SGF: 34.2 mM NaCl, pH 1.2), simulated gastric fluid with the digestive enzyme pepsin (SGF + enzyme: SGF with 3.2 mg / ml pepsin), simulated intestinal fluid with an enzyme mixture from porcine pancreatic enzymes (SIF + enzyme: 28.7 mM NaH 2 PO 4 , 105.7 mM NaCl, pH 6.8, 10 mg / ml pancreatin), rat plasma and human plasma.

[0633] The test compounds were incubated at 37°C in the above solutions at a final concentration of 5 μM, with samples removed at the following time points: 0, 1, 2, and 4 hours. The reaction was stopped and prepared for quantification by adding an excess quenching solution containing an internal standard (acetonitrile, 200 ng / mL bucetin). The test compound and internal standard in each sample were quantified by LC-MS / MS, and after internal normalization to bucetin, the test compound concentration was expressed as a percentage of the concentration at the 0 hour time point. The stability in the relevant test solution was then determined by the remaining percentage at the 4 hour time point. The results are shown in Table 7.

[0634] Table 7. In vitro stability of exemplary compounds.

[0635] Compound SGF SGF+Enz SIF Rat plasma Human plasma 1a ++++ ++++ ++++ ++ ++ 2a ++++ +++ ++++ ++ ++ 3a NT NT NT NT NT 4a NT NT NT NT NT 5a +++ + +++ ++ ++ 6a +++ + ++ +++ ++ 7a ++++ +++ ++ NT NT 8a ++++ +++ +++ ++++ ++ 9 NT NT NT NT NT 10 NT NT NT NT NT 11 +++ +++ ++++ ++++ +++ 12 +++ +++ ++ ++++ +++ 13 NT NT NT NT NT 14 ++ ++ +++ +++ +++ 15 NT NT NT NT NT 16 NT NT NT NT NT 17 +++ +++ +++ ++ +++ 18 NT NT NT NT NT 19 +++ ++ + +++ +++ 20 +++ +++ +++ ++ +++ 21 NT NT NT NT NT 22 +++ +++ +++ +++ +++

[0636] + indicates 20-39% compound remaining after 4 hours

[0637] ++ indicates 40-79% compound remaining after 4 hours

[0638] +++ indicates 80-99% compound remaining after 4 hours

[0639] ++++ indicates 100% compound remaining after 4 hours

[0640] NT indicator compound not tested

[0641] Example B7. In vivo pharmacokinetics.

[0642] Exemplary compounds are administered via selected routes, and then the compound in blood collection and plasma is quantitatively used to measure the pharmacokinetic (PK) profile of the compound. By dissolving the test compound in DMSO and then diluting the compound to an appropriate vehicle (saline or saline and polyethylene glycol), the compound is administered to at least 250 grams of mixed sex Sprague-Dawley rats. Administration is completed by tail vein puncture (IV) or oral gavage (PO), and the compound is administered to the animal according to its body weight with 1mL / kg. At the selected interval (10, 20, 40, 60, 120 and 360 minutes) after administration, blood is collected by bleeding from the tail vein. Whole blood is then centrifuged to produce plasma. The compound content in the quantitative plasma sample of LC-MS / MS is compared with internal standards and standard curves to accurately determine concentration.

[0643] Then the plasma concentration at each time point was averaged and plotted as a function of time. The area under the curve was calculated by integration of the curve, Cmax was the highest concentration reached in plasma, and Tmax was determined by the timing of Cmax. The results are shown in Table 8.

[0644] Table 8. Pharmacokinetic parameters of exemplary compounds.

[0645]

[0646] AUC: ++++ indicates a dose-corrected plasma AUC above 3000 ng*h / mL; +++ indicates a dose-corrected plasma AUC between 1000 and 2999 ng*h / mL; ++ indicates a dose-corrected plasma AUC between 100 and 999 ng*h / mL; + indicates a dose-corrected plasma AUC between 1 and 100 ng*h / mL.

[0647] Cmax: ++++ indicates a dose-corrected plasma Cmax above 3000 ng / mL; +++ indicates a dose-corrected plasma Cmax between 1000 and 2999 ng / mL; ++ indicates a dose-corrected plasma Cmax between 100 and 999 ng / mL; + indicates a dose-corrected plasma Cmax between 1 and 100 ng / mL.

[0648] Tmax: +++ indicates a Tmax of less than 30 minutes; ++ indicates a Tmax between 30 and 60 minutes; + indicates a Tmax of more than 60 minutes.

[0649] NT indicates that the compound was not tested.

[0650] Example B8. Oral availability calculation.

[0651] Oral bioavailability is crucial for developing small molecule therapies for oral administration. The calculation of oral bioavailability (%F) was completed by comparing the in vivo pharmacokinetic data (Example B7), using IV administration as the maximum possible exposure, and determining the exposure rate after PO administration. In these studies, the AUC from the dose correction of PO administration was divided by the AUC from the dose correction of IV administration and multiplied by 100 to produce %F. The results are shown in Table 9.

[0652] Table 9. Calculated oral availability of exemplary compounds.

[0653]

[0654]

[0655] ++++Indicates oral bioavailability greater than 50%

[0656] +++Indicates oral bioavailability between 25% and 50%

[0657] ++Indicates oral bioavailability between 1% and 25%

[0658] + Indication: Less than 1% oral bioavailability

[0659] NT indicator compound not tested

[0660] Example B9. Non-specific protein binding.

[0661] Plasma and tissue exposures of exemplary compounds were scaled by their nonspecific affinity for protein binding in target tissues or fluids to determine the fraction of compound available for interaction with the target.Nonspecific binding was determined in plasma and brain homogenates collected from mixed-sex Sprague-Dawley rats.

[0662] Test compounds at known concentrations were mixed with plasma or brain homogenate and incubated in the donor chamber of a rapid equilibrium dialysis (RED) device with empty PBS buffer in the receiving chamber. After 4 hours of incubation at 37°C in an orbital shaking incubator, the compounds in each chamber were quantified by LC-MS / MS. The unbound fraction (f u,tissue ):

[0663]

[0664] in:

[0665] f u，tissue is the unbound fraction in the tissue;

[0666] f u，homogenateis the ratio of the concentration in the buffer chamber to the concentration in the sample chamber; and

[0667] D is the dilution factor used to generate the sample.

[0668] The results are shown in Table 10.

[0669] Table 10. Non-specific protein binding of exemplary compounds.

[0670]

[0671] ++++ indicates an unbound fraction above 0.9

[0672] +++ indicates an unbound fraction between 0.5 and 0.9

[0673] ++ indicates an unbound fraction between 0.1 and 0.5

[0674] + indicates unbound fraction below 0.1

[0675] NT indicator compound not tested

[0676] Example B10. In vivo tissue distribution.

[0677] The distribution rate to the target tissue is an important feature of therapeutic molecules. The tissue distribution of exemplary compounds was performed in mixed sex Sprague-Dawley rats. Test compounds were delivered via tail vein injection (IV) and tissues were collected at Tmax (10 minutes after administration). Animals were deeply anesthetized with isoflurane and whole blood was collected from the right atrium and centrifuged to produce plasma. The animals were then fully perfused with PBS administered to the left ventricle to prevent blood contamination of the tissue.

[0678] Tissues were collected and homogenized, and the compound content in the target tissue was quantified by LC-MS / MS. The tissue distribution rate was determined by dividing the tissue concentration of the compound by the plasma concentration and multiplying by 100. The results are shown in Table 11.

[0679] Table 11. In vivo tissue distribution of exemplary compounds.

[0680]

[0681] ++++ indicates a distribution above 70%

[0682] +++ indicates a distribution between 40% and 69%

[0683] ++ indicates a distribution between 5% and 39%

[0684] + Indicates distribution between 0.05% and 5%

[0685] NT indicator compound not tested

[0686] Example B11. In vivo efficacy: Scopolamine-induced spatial memory deficits in the Morris Water Maze.

[0687] Exemplary compounds 2a and 6a were evaluated for their ability to reverse chemically induced spatial memory deficits in rats in the Morris water maze. The water maze consists of a large circular pool (2.1 m in diameter) filled with 26 to 28 ° C water at a depth of about 30 cm, and the water is made turbid with white paint. A circular platform (13 cm in diameter) is fixed so that it is located 2 to 3 cm below the water surface. High contrast visual cues are placed around the pool to help test the spatial orientation of the animal. The test consists of placing the animal in the water facing the pool wall at one of three arbitrarily specified starting positions and allowing the animal to swim and find a hidden platform for up to 120 seconds. The time consumed by locating the animal to the platform is recorded as escape latency. Animals are tested 5 times a day, with a 30-second rest period between trials. A total of 8 consecutive days complete the test.

[0688] Animals were divided into groups (N=8 / group) depending on the treatment. Control animals received only empty vehicle. The scopolamine group received 3 mg / kg scopolamine dissolved in sterile saline by intraperitoneal (IP) injection 30 minutes before the test. The test compound group received various concentrations of test compounds dissolved in 48% sterile saline, 50% polyethylene glycol (PEG-400) and 2% DMSO by oral gavage (PO) 40 minutes before the test. The escape latency of each animal tested 5 times a day was recorded for 8 consecutive days. The changes in the escape latency curve were statistically analyzed by two-way ANOVA with Bonferoni post-test. The results are shown in Table 12.

[0689] Exemplary compound 1a was evaluated for its ability to reverse chemically induced spatial memory deficits in rats in the Morris water maze. The water maze consists of a large circular pool (1.5 m in diameter) filled with 23 to 26 ° C water at a depth of about 30 cm, and the water is made turbid with white paint. The circular platform is fixed so that it is located 2 to 3 cm below the water surface. High contrast visual cues are placed around the pool to help test the spatial orientation of the animal. The test consists of placing the animal in the water facing the pool wall at one of three arbitrarily specified starting positions and allowing the animal to swim and find a hidden platform for up to 90 seconds. The time consumed by locating the animal to the platform is recorded as the escape latency. The animal is tested 5 times a day, with a 30-second rest period between trials. A total of 5 consecutive days to complete the test.

[0690] Animals were divided into groups (N=12 / group) depending on the treatment. Control animals received only empty vehicle. The scopolamine group received 2 mg / kg scopolamine dissolved in sterile saline by intraperitoneal (IP) injection 30 minutes before the test. The test compound group received various concentrations of test compounds dissolved in 78% sterile saline, 20% polyethylene glycol (PEG-400) and 2% DMSO by oral gavage (PO) 40 minutes before the test. The escape latency of each animal tested 5 times a day was recorded for 5 consecutive days. The changes in the escape latency curve were statistically analyzed by two-way ANOVA with Bonferroni post hoc test. The results are shown in Table 12.

[0691] Table 12. In vivo efficacy of exemplary compounds.

[0692]

[0693] +++ indicates a post hoc test p-value below 0.01

[0694] ++ indicates a post hoc test p-value between 0.05 and 0.01

[0695] + indicates a post hoc test p-value between 0.06 and 0.05

[0696] - indicates a post hoc test p-value above 0.06

[0697] Although the present invention has been described in some detail by means of illustration and example for purposes of clarity of understanding, the description and example should not be construed as limiting the scope of the invention. The disclosures of all patents and scientific literature cited herein are expressly incorporated herein by reference in their entirety.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: L is a direct bond, -C(=O)-, -(CR a R b ) m -C(=O)-, -C(=O)-(CR a R b ) m -or-(CR a R b ) m -; Each R a and R b are independently H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; R 1a and R 1b are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo or C6-C 10 Arylalkyl; R 2 is H, oxo or thioketo; R 3 is C2-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C 12 Cycloalkyl, C3-C6 cycloalkylalkyl, C6-C 10 arylalkyl, 5- to 10-membered heteroarylalkyl or 5- to 10-membered heterocyclylalkyl, wherein the 5- to 10-membered heteroarylalkyl or the 5- to 10-membered heterocyclylalkyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen; R 4 C6-C 10 aryl, 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclic group, wherein the 5- to 10-membered heteroaryl or the 5- to 10-membered heterocyclyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen; Each R 5 are independently C1-C6 alkyl, oxo or halo; R 6 is H, C1-C6 alkyl or oxo; R 7 is H or oxo; m is 1 or 2; and n is an integer from 0 to 3; Wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkyl, C6-C 10 Aryl, C6-C 10 Arylalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylalkyl, 5- to 10-membered heterocyclyl and 5- to 10-membered heterocyclylalkyl are optionally substituted with one to five substituents selected from the group consisting of hydroxy, halo, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, -(C=O)NH2, nitro, -SO2(C1-C6 alkyl) and -CO2H.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L is -C(=O)- or -(CR a R b ) m -.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein L is -C(=O)-.

4. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein L is -(CR a R b ) m -.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R a and R b Each is H, and m is 1.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 1a and R 1b each independently H; C1-C6 alkyl optionally substituted by 1 to 3 substituents selected from halo, -CO2H and -C(=O)NH2; C1-C6 alkoxy; halo; or C6-C6 alkyl optionally substituted by 1 to 3 substituents selected from halo and amino 10 Arylalkyl.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b Each is independently H, methyl, fluoro, 2-methylbutyl, -CH2F, methoxy, -CH2CO2H, -CH2C(=O)NH2, benzyl or 4-aminobenzyl.

8. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b Each is independently H or C1-C3 alkyl.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 1a is methyl and R 1b For H.

10. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b Each is H.

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