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WO2025069008A1 - Therapy for treating type 1 diabetes using rock2 and dyrk1 inhibitors - Google Patents

Therapy for treating type 1 diabetes using rock2 and dyrk1 inhibitors Download PDF

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Publication number
WO2025069008A1
WO2025069008A1 PCT/IB2024/059567 IB2024059567W WO2025069008A1 WO 2025069008 A1 WO2025069008 A1 WO 2025069008A1 IB 2024059567 W IB2024059567 W IB 2024059567W WO 2025069008 A1 WO2025069008 A1 WO 2025069008A1
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alkyl
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alkenyl
alkynyl
cycloalkyl
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Samuel D. Waksal
Maria Vilenchik
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Graviton Bioscience BV
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Graviton Bioscience BV
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present disclosure relates to therapies for preventing and/or treating type 1 diabetes.
  • the present disclosure provides combination therapies for treating type 1 diabetes using a Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor and a dual specificity tyrosine-phosphorylation-regulated kinase 1 (DYRK1) inhibitor.
  • ROCK2 Rho-associated coiled-coil containing protein kinase 2
  • DYRK1 dual specificity tyrosine-phosphorylation-regulated kinase 1
  • methods for using the combination of a ROCK2 and a DYRK1 inhibitor and kits using the same Also provided are methods of preventing the progression or development of type 1 diabetes by administering a ROCK2 inhibitor.
  • Type 1 diabetes is a chronic condition in which the pancreas makes little or no insulin.
  • the underlying mechanism causing type 1 diabetes involves an autoimmune destruction of the insulin-producing beta cells in the pancreas.
  • the cause of type 1 diabetes is unknown, but it is believed to involve a combination of genetic and environmental factors.
  • Type 1 diabetes makes up an estimated 5–10% of all diabetes cases, or 11–22 million cases worldwide. Although the exact number of people affected globally is unknown, it is estimated that about 80,000 children develop the disease each year. Symptoms can begin at any age, but onset is most common in children from about 5 years old through puberty.
  • type 1 diabetes The destruction of the ⁇ -cells in type 1 diabetes results in progressive insulin deficiency, as there are no other cells in the body that produce insulin. Accordingly, the most pressing complication of type 1 diabetes is the constant risks attendant to poor blood sugar control, including severe hypoglycemia and diabetic ketoacidosis. In addition to the acute complications from type 1 diabetes, long-term hyperglycemia results in damage to small blood vessels throughout the body. This damage manifests particularly in the eyes, nerves and kidneys, causing diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy, respectively. Moreover, patients with type 1 diabetes have increased risk of cardiovascular disease, which is estimated to shorten the life of the average type 1 diabetic by 8–13 years.
  • the method comprises administering to the subject (i) a therapeutically effective amount of a Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor, and (ii) a therapeutically effective amount of a dual specificity tyrosine- phosphorylation-regulated kinase 1 (DYRK1) inhibitor.
  • a ROCK2 inhibitor is a ribonucleic acid (RNA).
  • the ROCK2 inhibitor is antisense RNA against ROCK2 transcription.
  • the ROCK2 inhibitor is small interfering RNA (siRNA) or micro RNA (miRNA).
  • the ROCK2 inhibitor is a compound according to one or more of the formulae (A-I), (B-I), (C-I), (D-I), (E-I), (F-I), (G-I), (H-I), (J-I), (K-I), (L-I) and their subordinates, and exemplary compounds thereof.
  • the DYRK1 inhibitor is a ribonucleic acid (RNA).
  • the DYRK1 inhibitor is antisense RNA against ROCK2 transcription.
  • the DYRK1 inhibitor is small interfering RNA (siRNA) or micro RNA (miRNA).
  • the DYRK1 inhibitor is a compounds according to one or more of the formulae (M-I), (N-I), (O-I), (P-I), (Q-I), (R-I), (S-I), (T-I), (U-I), (V-I), (W-I), (X-I), (Y-I), (Z-I) and their subordinates, and exemplary compounds thereof.
  • the ROCK2 inhibitor may be selected from Compound A, Compound B, Compound C, Compound D, belumosudil (KD025), Zelasudil, Y-27632, fasudil, GSK429286A, RKI-1447, TC-S 7001, TC-S 7004, hydroxyfasudil, GSK269962A, ripasudil, AT13148, RX007, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof.
  • the ROCK2 inhibitor is belumosudil (2-(3-(4-((1H-indazol-5- yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide), or a pharmaceutically acceptable salt thereof.
  • the ROCK2 inhibitor is Zelasudil or a pharmaceutically acceptable salt thereof.
  • the ROCK2 inhibitor is selected from Compound A, Compound B, Compound C, and Compound D, or a pharmaceutically acceptable salt thereof.
  • the ROCK2 inhibitor is (6-(4-((4-(1H-pyrazol-4- yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-1H-indol-2-yl)(3,3-difluoroazetidin-1- yl)methanone (Compound A), or a pharmaceutically acceptable salt thereof.
  • Figure 1 shows results of a glucose tolerance test in mice at time course 5 days after treatment.
  • the treatment groups were treated with: DYRK1 inhibitor compounds (FX7742, FX8474), and FX8474 in combination with a ROCK2 inhibitor compound (Compound A) in comparison to control groups of (i) a no treatment group without diabetes, and (ii) a no treatment group having diabetes.
  • Figure 2 shows levels of the fasted glucose in blood of the mice 5 days after treatment.
  • the treatment groups were treated with: DYRK1 inhibitor compounds (FX7742, FX8474), respectively, and FX8474 in combination with ROCK2 inhibitor compound (Compound A) in comparison to control groups of (i) a no treatment group without diabetes, and (ii) a no treatment group having diabetes.
  • combination therapies comprising a Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor and a dual specificity tyrosine- phosphorylation-regulated kinase 1 (DYRK1) inhibitor, methods of using the combination therapy in the treatment of type 1 diabetes, and kits comprising a dosage form of a ROCK2 inhibitor and a dosage form of the DYRK1 inhibitor.
  • the combination therapy may be used in the treatment of type I diabetes in a subject.
  • the combination therapy disclosed herein comprises a therapeutically effective amount of a ROCK2 inhibitor and a therapeutically effective amount of a DYRK1 inhibitor, which promotes the re-growth of beta cells while also promoting the maintenance of the beta cells by inhibiting further autoimmune destruction of the patient’s beta cells.
  • the combination therapy may restore the population and function of the patient’s beta cells, thereby allowing the patient’s own population of beta cells to control blood sugar levels, and reducing or eliminating the patient’s reliance on exogenous insulin for the control of blood sugar.
  • ROCK2 Inhibitors include use of ROCK2 inhibitors, and in particular ROCK2 selective inhibitors.
  • Rho-associated coiled-coil containing protein kinase is a serine/threonine kinase from the AGC (PKA, PKG, and PKC) kinase family and comprises two isoforms, ROCK1 and ROCK2.
  • the two isoforms are expressed and regulated differently in specific tissues.
  • ROCK1 is ubiquitously expressed at a relatively high level
  • ROCK2 is preferentially expressed in certain tissues including heart, brain and skeletal muscle.
  • ROCK2 inhibitors has been shown efficacious effects in inflammatory disease models.
  • the compounds for use in the methods and compositions disclosed herein are ROCK inhibitors, and in particular ROCK2 selective inhibitors.
  • the compounds provide excellent inhibitory activity of ROCK2, and preferably have good selectivity (higher selectivity towards ROCK2 as compared with ROCK1).
  • the compounds may additionally provide one or more of good physicochemical properties (e.g., solubility, physical and/or chemical stability), good pharmacokinetic properties (e.g., improved bioavailability, proper half-life and duration of action), and acceptable safety (low toxicity and/or less side effects, wide therapeutic window).
  • ROCK2 inhibitors are disclosed in, for example, WO2019/000682, WO 2019/000683, WO2019/001572, WO2020/094111, WO2020/177587, WO2020/259528, WO2022/042711, WO2022/042712, WO2006/105081, WO2019/145729, WO2007/007737, WO90/05723, WO2011/130740, WO2005/037197, WO2008/110846, WO2005/082890, WO2005/037197; US Pat.
  • the ROCK2 inhibitor has the structure of Formula (A-I): or a pharmaceutically acceptable salt thereof, wherein: R A1 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 7 cycloalkyl, halo, -CN, C 1 -C 3 perfluoro alkyl, -OR A11 , -O-(C 1 -C 6 alkyl)-OR A11 , -(C 1 -C 6 alkyl)-OR A11 , -NR A11 R A12 , -O-(C 1 -C 6 alkyl)-NR A11 R A12 , -(C 1 -C 6 alkyl)-NR A11 R A12 , - NR A11 -(C 1 -C 6 alkyl)-NR A11 R A12 , -NR A11 -(C 1 -C 6
  • the ROCK2 inhibitor has the structure of Formula (A-II): or a pharmaceutically acceptable salt thereof, wherein: R A1 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 7 cycloalkyl, halo, -CN, C 1 -C 3 perfluoro alkyl, -OR A11 , -O-(C 1 -C 6 alkyl)-OR A11 , -(C 1 -C 6 alkyl)-OR A11 , -NR A11 R A12 , -O-(C 1 -C 6 alkyl)-NR A11 R A12 , -(C 1 -C 6 alkyl)-NR A11 R A12 , - NR A11 -(C 1 -C 6 alkyl)-NR A11 R A12 , -NR A11 -(C 1 -C
  • the ROCK2 inhibitor has the structure of Formula (A-III): (A-III) or a pharmaceutically acceptable salt thereof.
  • R A1 , R A2 , R A3 , R A4 , R A5 , R A7 , X 4 and n1 are as described above.
  • the ROCK2 inhibitor has the structure of Formula (A-IIIa): (A-IIIa) or a pharmaceutically acceptable salt thereof, wherein: R A1 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 7 cycloalkyl, halo, -CN, C 1 -C 3 perfluoro alkyl, -OR A11 , -O-(C 1 -C 6 alkyl)-OR A11 , -(C 1 -C 6 alkyl)-OR A11 , -NR A11 R A12 , -O-(C 1 -C 6 alkyl)-NR A11 R A12 , -(C 1 -C 6 alkyl)-NR A11 R A12 , - NR A11 -(C 1 -C 6 alkyl)-NR A11 R A12 , - NR A11
  • the ROCK2 inhibitor has the structure of Formula (A-IIIb): or a pharmaceutically acceptable salt thereof, wherein: R A1 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 7 cycloalkyl, halo, -CN, C 1 -C 3 perfluoro alkyl, -OR A11 , -O-(C 1 -C 6 alkyl)-OR A11 , -(C 1 -C 6 alkyl)-OR A11 , -NR A11 R A12 , -O-(C 1 -C 6 alkyl)-NR A11 R A12 , -(C 1 -C 6 alkyl)-NR A11 R A12 , - NR A11 -(C 1 -C 6 alkyl)-NR A11 R A12 , -NR A11 -(C 1 -C
  • R A5 is hydrogen, or n1 is 0.
  • the ROCK2 inhibitor has the structure: , or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula (A-I) and its subordinates, as well as other disclosed ROCK2 inhibitors, may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, WO2019/000682, WO 2019/000683, WO2019/001572, WO2020/094111, WO2020/177587, WO2020/259528, WO2022/042711, WO2022/042712 and US Pat.
  • the ROCK2 inhibitor has the structure of Formula (B-I): or a pharmaceutically acceptable salt thereof, wherein: X B1 is N or CH; X B2 is N or CH; X B3 is N or CR B3 ; X B4 is N or CR B4 ; X B5 is selected from the group consisting of C, CH and N; a1 is selected from 1 or 2; the dotted lines represent optional double bonds; each R B1 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, halo, oxo, -CN, C 1 -C 3 perfluoro alkyl, -OR B11
  • the ROCK2 inhibitor has the structure of Formula (B-II): or a pharmaceutically acceptable salt thereof, wherein: X B1 is N or CH; X B2 is N or CH; X B3 is N or CR B3 ; X B4 is N or CR B4 ; X B5 is selected from the group consisting of C, CH and N; the dotted lines represent optional double bonds; each R B1 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, halo, oxo, -CN, C 1 -C 3 perfluoro alkyl, -OR B11 , and -NR B11 R B12 ; or alternatively, two R B1 attached to the same carbon or to adjacent carbons are taken together to form a 3- to 6-membered ring, which may optionally contain
  • the ROCK2 inhibitor has the structure of Formula (B-III): or a pharmaceutically acceptable salt thereof, wherein: X B2 is N or CH; X B3 is N or CR B3 ; X B5 is selected from the group consisting of C, CH and N; the dotted lines represent optional double bonds; each R B1 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, halo, oxo, -CN, C 1 -C 3 perfluoro alkyl, -OR B11 , and -NR B11 R B12 ; or alternatively, two R B1 attached to the same carbon or to adjacent carbons are taken together to form a 3- to 6-membered ring, which may optionally contain 0 to 2 ring heteroatoms selected from O, S and N, and which may be unsubstituted
  • the ROCK2 inhibitor has the structure of Formula (B-IV): or a pharmaceutically acceptable salt thereof, wherein: R B3 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 7 cycloalkyl, halo, -CN, C 1 -C 3 perfluoro alkyl, -OR B11 , -O-(C 1 -C 6 alkyl)-OR B11 , -(C 1 -C 6 alkyl)-OR B11 , -NR B11 R B12 , -O-(C 1 -C 6 alkyl)-NR B11 R B12 , -(C 1 -C 6 alkyl)-NR B11 R B12 , - NR B11 -(C 1 -C 6 alkyl)-NR B11 R B12 , -NR B11 -(C 1 -C 6
  • the ROCK2 inhibitor has the structure of Formula (B-V): or a pharmaceutically acceptable salt thereof, wherein: R B3 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 7 cycloalkyl, halo, -CN, C 1 -C 3 perfluoro alkyl, -OR B11 , -O-(C 1 -C 6 alkyl)-OR B11 , -(C 1 -C 6 alkyl)-OR B11 , -NR B11 R B12 , -O-(C 1 -C 6 alkyl)-NR B11 R B12 , -(C 1 -C 6 alkyl)-NR B11 R B12 , - NR B11 -(C 1 -C 6 alkyl)-NR B11 R B12 , -NR B11 -(C 1 -C 6
  • the ROCK2 inhibitor has the structure of: or a pharmaceutically acceptable salt thereof.
  • Synthesis and biological assays of Formula (B-I) and its subordinates are described in WO2024/110851, the entire disclosure of which is incorporated herein by reference.
  • each R C4 and R C5 is independently H or unsubstituted C 1 -C 6 alkyl. In some embodiments, R C4 and R C5 are H.
  • the ROCK2 inhibitor has the structure of Formula (C-II): or a pharmaceutically acceptable salt thereof.
  • R C1 , R C2 , R C3 , n3 and m3 are as for the compound of the formula I.
  • each R C13 and R C14 is independently H or unsubstituted C 1 -C 6 alkyl. In some embodiments, each R C13 and R C14 is independently unsubstituted C 1 -C 6 alkyl. In some embodiments, each R C13 and R C14 is independently methyl or ethyl. In some embodiments, R C13 and R C14 are methyl.
  • the ROCK2 inhibitor has the structure of (Compound E), or a pharmaceutically acceptable salt thereof.
  • Compound E has the chemical name 2-(3-(4- ((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N,N-dimethylacetamide and is also known as KD025 or belumosudil.
  • the compounds of Formula (C-I) and its subordinates, including compound E, may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, U.S. Pat. Nos.8,357,693, 9,815,820, 10,183,931, 10,696,660, and 11,311,541, the entire contents of which are incorporated herein by reference.
  • the ROCK2 inhibitor has the structure of Formula (D-I): or pharmaceutically acceptable salts thereof, wherein: R D1 is L-R D2 , wherein L is a bond or -L D1 -L D2 -, wherein L D1 is selected from the group consisting of a bond, -(CR A R B ) 1-3 -, -O(CR A R B ) 1-3 -, - (CR A R B ) 0-3 O-, and -NR C (CR A R B ) 1-3 -; and L D2 is selected from the group consisting of a bond, -(CR A R B ) 1-3 -, -O-, -NR D -, -C(O)NR D -, - NR D C(O)-, -C(O)O-, -OC(O)-, -C(O)-, -S(O) 2 NR D -, -NR D S(O)
  • the ROCK2 inhibitor has the structure of Formula (D-II): or pharmaceutically acceptable salts thereof.
  • R D1 is -L D1 -L D2 -R D2 .
  • L D1 is a bond and L D2 is -NR D -, -C(O)NR D -, -NR D C(O)-, -C(O)O-.
  • R D1 is .
  • R D2 is C 1 -C 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, or t-butyl), or C 1 -C 6 haloalkyl (e.g., mono, di, or per- fluoro C 1 -C 6 alkyl).
  • R D4 is hydrogen, or C 1-4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, or t-butyl). In some embodiments, R D4 is methyl.
  • R D5 is hydrogen, halo, C 1-4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, or t-butyl), C 1-6 haloalkyl (e.g., mono, di, or per- fluoro C 1 -C 6 alkyl), or C 3-8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl, cyclohexyl).
  • R D5 is cyclopropyl.
  • the exemplary ROCK2 inhibitor has the structure of , or a pharmaceutically acceptable salt thereof.
  • This compound has the chemical name 4-(5- ((4-cyclopropyl-1H-indazol-5-yl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2- difluoroethyl)-benzamide and is also known as Zelasudil.
  • the ROCK2 inhibitor has the structure of Formula (D-IIIa) or D-IIIb): or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula (D-I) and its subordinates may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, U.S. Pat. No.11,497,751, the entire content of which is incorporated herein by reference.
  • the ROCK2 inhibitor has the structure of Formula (E-Ia) or (E-Ib): or pharmaceutically acceptable salts thereof, wherein: each R E1 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, halogen, -CN, -OR E11 , or -NR E11 R E12 ; n5 is an integer of 0 to 3; each R E2 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, halogen, -CN, -OR E21 , or -NR E21 R E22 ; m5 is an integer of 0 to 10; and each R E11 , R E12 , R E21 , and R E22 is independently H and C 1 -C 6 alkyl,
  • the ROCK2 inhibitor has the structure of Formula (E-IIa) or (E-IIb): or pharmaceutically acceptable salts thereof.
  • R E1 and R E2 are as described above.
  • R E1 is hydrogen or unsubstituted C 1 -C 3 alkyl (e.g., methyl, ethyl, or propyl).
  • R E2 is hydrogen, halogen (e.g., F, Cl, or Br) or unsubstituted C 1 -C 3 alkyl (e.g., methyl, ethyl, or propyl).
  • R E1 and R E2 are hydrogen.
  • R E1 is -F, and R E2 is methyl. In some embodiments, R E1 is methyl, and R E2 is methyl.
  • the ROCK2 inhibitor has the structure of pharmaceutically acceptable salt thereof.
  • the compounds of Formula (E-I) and its subordinates may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, WO2007/007737 and U.S. Pat. No.8,193,193, the entire contents of which are incorporated herein by reference.
  • the ROCK2 inhibitor has the structure of Formula (F-II): or an isomer or a pharmaceutically acceptable salt thereof.
  • R F1 , R F2 , R F3 , R F5 and n6 are described above.
  • each R F1 , R F2 , R F3 , and R F5 is independently hydrogen or in some embodiments, n6 is 0 or 1.
  • the ROCK2 inhibitor has the structure of [0062]
  • These compounds of Formula (F-I) and its subordinates may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, WO90/05723 and U.S. Pat. No.4,997,834, the entire contents of which are incorporated herein by reference.
  • the ROCK2 inhibitor has the structure of (G-I), or a pharmaceutically acceptable salt thereof, wherein: n7 is 1, 2, or 3; each R G1 and R G2 is independently hydrogen, alkyl, or acetyl; R G3 is cycloalkyl or aryl, wherein the cycloalkyl or aryl is optionally substituted with one or more of -OH, -CO 2 CH 3 , -C(O)NH 2 , -C(O)CH 3 , -NO 2 , -NH 2 , -NR 6 R 7 , carbonyl, alkyl, alkoxy, alkylalkoxy, alkoxylalkoxy, cycloalkyl, aryl, -OCX G 3, -OCHX G 2, -OCH 2 X G , - OSO 2 CH 3 , -tosyl, or halogen; R 6 and R 7 are, independently of one another, H, alkyl
  • the ROCK2 inhibitor has the structure of Formula (G-II): or a pharmaceutically acceptable salt thereof, wherein: R G4 is -OH, -CO 2 CH 3 , -C(O)NH 2 , -NO 2 , -NH 2 , -NR G5 R G6 , alkoxy, alkylalkoxy, alkyl, - OSO 2 CH 3 , tosyl, or halogen; each R G5 and R G6 is independently hydrogen, or alkyl ; m7 is an integer of 0 to 6; and R G1 , R G2 , and n7 are described above.
  • R G4 is attached to the meta position on the phenyl ring.
  • m7 is 0 or 1.
  • R G4 is -OH.
  • the ROCK2 inhibitor has the structure of , or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula (G-I) and its subordinates may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, WO2011/130740 and U.S. Pat. No.9,221,808, the entire contents of which are incorporated herein by reference.
  • the ROCK2 inhibitor has the structure of Formula (H-I): or a pharmaceutically acceptable salt thereof, wherein: R H1 is halogen, cyano, methyl, ethyl, hydroxyethyl, methoxyethyl or cyclopropyl; R H2 is hydrogen or halogen; R H3 is hydrogen, halogen, trifluoromethyl or pentafluoroethyl; and R H4 is hydrogen or halogen. [0069] In some embodiments, R H1 is hydrogen, or C 1 -C 3 alkyl (e.g., methyl, ethyl, or propyl).
  • R H2 is halogen (e.g., F, Cl, or Br).
  • R H3 is halogen (e.g., F, Cl, or Br).
  • R H4 is halogen (e.g., F, Cl, or Br).
  • the ROCK2 inhibitor has the structure of pharmaceutically acceptable salt thereof.
  • the ROCK2 inhibitor has the structure of Formula (J-I): or a pharmaceutically acceptable salt thereof, wherein: R J1 is an aryl or heteroaryl group; each R J2 and R J3 is independently selected from hydrogen, or C 1 -C 4 alkyl; each R J4 , R J5 and R J6 is independently selected from hydrogen, halogen, or C 1 -C 4 alkyl; R J7 is hydrogen, halogen, OH, -CO 2 CH 3 , -C(O)NH 2 , -NO 2 , or C 1 -C 4 alkyl; n8 is an integer of 0 to 3; and m8 is an integer of 0 to 8.
  • R J1 is an aryl or heteroaryl group
  • each R J2 and R J3 is independently selected from hydrogen, or C 1 -C 4 alkyl
  • each R J4 , R J5 and R J6 is independently selected from hydrogen, halogen, or C 1 -C 4 alkyl
  • R J7
  • the ROCK2 inhibitor has the structure of Formula (J-II), or a pharmaceutically acceptable salt thereof, wherein: R J8 is hydrogen, halogen, OH, -CO 2 CH 3 , -C(O)NH 2 , -NO 2 , or C 1 -C 4 alkyl; and [0075] In some embodiments, the ROCK2 inhibitor has the structure of , or a pharmaceutically acceptable salt thereof. [0076] These compounds of Formula (J-I) and its subordinates may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, WO2008/110846 and U.S. Pat. No.8,497,294, entire contents of which are incorporated herein by reference.
  • the ROCK2 inhibitor has the structure of Formula (K-I) or a pharmaceutically acceptable salt thereof, wherein: each R K1 and R K2 is independently selected from the group consisting of hydrogen and C 1 - C 6 alkyl; R K3 is phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of F, Cl, trifluoromethyl, and phenyl; naphthyl; and quinolinyl; R K4 is selected from the group consisting of hydrogen and methyl; R K5 is C 1 -C 3 alkyl; R K6 is hydrogen or hydrogen; and each R K7 and R K8 is independently selected from the group consisting of hydrogen, halogen, and C 1 -C 3 alkyl.
  • R K-I Formula (K-I) or a pharmaceutically acceptable salt thereof, wherein: each R K1 and R K2 is independently selected from the group consisting of hydrogen and C 1 - C 6 alkyl; R K3 is phenyl optionally substituted with 1 to 3 substitu
  • the ROCK2 inhibitor has the structure of Formula (K-II), or a pharmaceutically acceptable salt thereof, wherein: R K3 is optionally substituted aryl or heteroaryl; R K4 is hydrogen or optionally substituted C 1 -C 2 alkyl; R K5 is optionally substituted C 1 -C 2 alkyl; R K6 is hydrogen or halogen; and each R K7 and R K8 is hydrogen, halogen, and optionally substituted C 1 -C 3 alkyl. [0079] In some embodiments, R K3 is substituted phenyl. In some embodiments, R K4 , R K7 and R K8 are hydrogen.
  • R K4 is substituted C 1 -C 2 alkyl (e.g., methyl or ethyl).
  • R K6 is halogen (e.g., F, Cl, or Br).
  • the ROCK2 inhibitor has the structure of , or a pharmaceutically acceptable salt thereof. [0081] These compounds of Formula (K-I) and its subordinates may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, WO2005/082890 and U.S. Pat. No.7,592,357, the entire contents of which are incorporated herein by reference.
  • the ROCK2 inhibitor has the structure of Formula (L-I) or a pharmaceutically acceptable salt thereof, wherein: X L is a bond, C 1 -C 6 alkylene, NH, O, S, SO or S(O) 2 ; R L1 is hydrogen or C 1 -C 6 alkyl; R L2 is C 1 -C 6 alkyl, or phenyl optionally substituted; R L3 is hydrogen, C 1 -C 6 alkyl, and C 3-7 cycloalkyl or R L3 and R L4 together form a ring; and each R L4 and R 5 is independently hydrogen, or C 1 -C 6 alkyl. [0083] In some embodiments, the ROCK2 inhibitor has the structure of Formula (L-II),
  • the ROCK2 inhibitor has the structure of , or a pharmaceutically acceptable salt thereof.
  • the ROCK2 inhibitor of Formula (L-II) includes a hydrochloride salt.
  • These compounds of Formula (L-I) and its subordinates may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, WO2005/037197 and U.S. Pat. No.7,547,779, the entire contents of which are incorporated herein by reference.
  • the ROCK2 antagonist is a ribonucleic acid (RNA), such as an antisense RNA.
  • Antisense RNA also referred to as antisense transcript or antisense oligonucleotide, is a single stranded RNA that is complementary to a protein coding messenger RNA (mRNA) with which it hybridizes, and thereby blocks the mRNA’s translation into protein.
  • mRNA protein coding messenger RNA
  • Antisense RNA can be classified into short (less than 200 nucleotides) and long (200 or more nucleotides) non-coding RNAs (ncRNAs).
  • ncRNAs non-coding RNAs
  • the primary function of asRNA is regulating gene expression. asRNA molecules can be designed and produced synthetically and have found widespread use as research tools for gene knockdown. They also have therapeutic applications.
  • the antisense RNA targeting ROCK2 comprises one or more unnatural nucleic acids.
  • the antisense RNA is administered via injection or inhalation. In some embodiments, the antisense RNA targeting ROCK2 is selective for the ROCK2 mRNA. In some embodiments, the antisense RNA targeting ROCK2 does not bind the ROCK1 mRNA. The design and use of selective antisense RNA molecules is routine in the art.
  • the ROCK2 antagonist is RNA interference (RNAi), small inhibiting RNA (siRNA), or micro-RNA (miRNA).
  • RNAi RNA interference
  • siRNA small inhibiting RNA
  • miRNA micro-RNA
  • RNAi examples include without limitation small inhibitory RNAs (siRNAs), micro RNAs (miRNAs), and small hairpin RNAs (shRNAs).
  • RNA interference has been shown to be a useful tool for gene silencing in determination of gene function and may be used as a therapeutic agent to suppress genes associated with the development of a number of diseases.
  • Gene regulation by RNAi can occur through small RNAs known as micro RNAs (miRNAs).
  • miRNAs micro RNAs
  • Micro RNAs can be regulators of diverse cellular processes.
  • the siRNA or miRNA may allow the use of the endogenous cellular RNAi machinery to direct the degradation of a target gene product (e.g., gene encoding ROCK2 and genes associated with the production or regulation of ROCK2) with the use of artificial siRNA or miRNAs.
  • a target gene product e.g., gene encoding ROCK2 and genes associated with the production or regulation of ROCK2
  • the siRNA or miRNA selectively degrades a ROCK2 mRNA.
  • the siRNA or miRNA does not degrade a ROCK1 mRNA.
  • the design and use of selective siRNA and miRNA molecules are routine in the art.
  • a small inhibitory or interfering RNA may be a double-stranded RNA molecule, such as, for example, RNA having 19-25 (e.g., 19-23) base pairs in length, that induces RNA interference in a cell.
  • a small hairpin RNA may be an RNA molecule, such as, for example, RNA having approximately 19-25 (e.g., 19-23) base pairs of double stranded RNA linked by a short loop (e.g., about 4-11 nucleotides) that induces RNA interference in a cell.
  • a microRNA can be an RNA molecule that induces RNA interference in a cell having a short (e.g., 19-25 base pairs) sequence of double-stranded RNA linked by a loop and containing one or more additional sequences of double-stranded RNA comprising one or more bulges (e.g., mis-paired or unpaired base pairs).
  • the term “miRNA” encompasses endogenous miRNAs as well as exogenous or heterologous miRNAs.
  • “miRNA” may refer to a pri-miRNA or a pre-miRNA. During miRNA processing, a pri-miRNA transcript is produced.
  • the pri-miRNA is processed by Drosha-DGCR8 to produce a pre-miRNA by excising one or more sequences to leave a pre- miRNA with a 5’-flanking region, a guide strand, a loop region, a non-guide strand, and a 3’- flanking region; or a 5’-flanking region, a non-guide strand, a loop region, a guide strand, and a 3’-flanking region.
  • the pre-miRNA is then exported to the cytoplasm and processed by Dicer to yield a siRNA with a guide strand and a non-guide (or passenger) strand.
  • the guide strand is then used by the RISC complex to catalyze gene silencing, e.g., by recognizing a target RNA sequence complementary to the guide strand.
  • additional compounds shown to have ROCK2 inhibition activities can be used.
  • Methods of determining kinase inhibition are disclosed herein. For example, kinase activity of an enzyme and the inhibitory capacity of a test compound can be determined by measuring enzyme specific phosphorylation of a substrate. Commercial assays and kits can be employed. For example, kinase inhibition can be determined using an IMAP® assay (Molecula Devices).
  • This assay method involves the use of a fluorescently tagged peptide substrate. Phosphorylation of the tagged peptide by a kinase of interest promotes binding of the peptide to a trivalent metal-based nanoparticle via the specific, high affinity interaction between the phosphor group and the trivalent metal. Proximity to the nanoparticle results in increased fluorescence polarization. Inhibition of the kinase by a kinase inhibitor prevents phosphorylation of the substrate and thereby limits binding of the fluorescently tagged substrate to the nanoparticle.
  • Such an assay can be compatible with a microwell assay format, allowing simultaneous determination of IC 50 of multiple compounds.
  • Rho proteins are members of the small GTP-binding protein family and operate via their downstream mediators, two isoforms: Rho-associated coiled coil containing protein kinase 1 (ROCK1) and Rho-associated coiled coil containing protein kinase 2 (ROCK2). These kinases can display various cellular functions, including cell motility, proliferation, adhesion, migration, and apoptosis.
  • Various nonspecific ROCK inhibitors have been developed, such as fasudil (approved for cerebral vasospasm treatment in 1995), and ripasudil (approved for glaucoma treatment in 2014). Lack of isoform selectivity may induce hypotension as a dose-limiting side effect due to ROCK1 inhibition.
  • ROCK2 selective inhibitors may display little or no hypotensive effects. In addition, inhibiting ROCK1 may not produce immunity enhancement due to the distribution of ROCK1 in organs and tissues.
  • the ROCK2 selective inhibitors disclosed herein may be used in the therapy for type 1 diabetes provided herein, while causing little or no adverse health risks. Inhibitors that specifically target ROCK2 over ROCK1 are desirable for the therapies for treatment of type 1 diabetes disclosed herein.
  • DYRK1 Inhibitors [0094]
  • the combination therapy also includes use of DYRK1 inhibitors, and in particular DYRK1 selective inhibitors.
  • the DYRK1 inhibitor may be a selected inhibitor of DYRK1A, and/or selectively inhibit DYRK1A and DYRK1B.
  • Dual-specificity tyrosine-regulated kinases encompass four subtypes, 1 (e.g., 1A, 1B), 2, 3 and 4. These CMCG family protein kinases self-activate by auto- phosphorylation of a conserved tyrosine residue and subsequently phosphorylate serine and threonine residues of their respective substrates.
  • DYRK1A and DYRK1B share 85% identity at the amino acid level, although expression and functional characteristics may differ.
  • DYRK1A While DYRK1A is ubiquitously expressed, DYRK1B was found in a limited number of tissues and organs such as testis and skeletal muscle. DYRK1A participates in biochemical pathways involved in cell proliferation, neural differentiation, brain development and function, neurodegenerative diseases, tumorigenesis, and apoptosis. Additionally, DYRK1A may be involved in multiple pathways relevant to pancreatic ⁇ -cell proliferation. [0096] The DYRK1 inhibitors provide inhibitory activity of DYRK1 (i.e., DYRK1A and DYRK1B), and good selectivity, e.g., higher selectivity towards DYRK1 as compared with other isoformer (e.g., DYRK2/3/4).
  • inhibitors of DYRK1 are disclosed in, for example, WO2018/119039, WO2021/064141, WO 2010/010797, WO2005/007672, WO2009/050352, WO2011/041655, WO2011037962, WO2012099066, WO2012098070, WO2012098065, WO2010/150211, GB2447791, U.S. Pat.
  • the DYRK1 inhibitor may be selected from FX7742 or FX8474.
  • These compounds of Formula (M-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, U.S. Pat. No. 10,577,365, the entire content of which is incorporated herein by reference.
  • the DYRK1 inhibitor is FX-1610, FX-9847, FX-8553 and FX-5372 or other compounds disclosed in U.S. Patent No.9,446,044, incorporated herein in its entirety; or the DYRK1 inhibitor is FX-7742, FX-8474 or other compound disclosed in U.S.
  • the DYRK1 inhibitor has the structure of Formula (N-II): or a pharmaceutically acceptable salt thereof.
  • R N2 , R N3 , R N4 , R N5 and n14 are as described above.
  • each R N2 is independently hydrogen or C 1 ⁇ C 4 alkyl.
  • R N4 is hydrogen or C 1 ⁇ C 4 alkyl.
  • R N4 is NR N6 R N6 , or heterocyclyl, which may be optionally substituted with halogen or C 1 -C 6 alkyl.
  • the DYRK1 inhibitor has the structure of Formula (N-III): or a pharmaceutically acceptable salt thereof.
  • the DYRK1 inhibitor has the structure of pharmaceutically acceptable salt thereof.
  • These compounds in Formula (N-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, WO2021/064141, the entire content of which is incorporated herein by reference.
  • the DYRK1 inhibitor has the structure of Formula (O-I): or a pharmaceutically acceptable salt thereof, wherein: R O1 is hydrogen, C 1 -C 3 alkyl, NH 2 , -OH, or C 3 -C 7 cycloalkyl; R O2 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, -CN, C 1 -C 3 perfluoro alkyl, -OR O11 , -O-(C 1 -C 6 alkyl)-OR O11 , -(C 1 -C 6 alkyl)-OR O11 , -NR O11 R O12 , - O-(C 1 -C 6 alkyl)-NR O11 R O12 , -(C 1 -C 6 alkyl)-NR O11 R O12 , -NR O11
  • the DYRK1 inhibitor has the structure of Formula (O-II): or a pharmaceutically acceptable salt thereof.
  • R O1 and R O2 are as described above.
  • R O1 is hydrogen or C 1 -C 6 alkyl.
  • R O11 is hydrogen, or C 1 -C 6 alkyl (e.g., methyl or ethyl).
  • the DYRK1 inhibitor has the structure of acceptable salt thereof.
  • the DYRK1 inhibitor has the structure of Formula (P-I): or a pharmaceutically acceptable salt thereof, wherein: R P1 is aryl or heteroaryl.
  • R P2 is alkyl, aryl, -SO 2 R P11 , or COR P11 ;
  • R P3 is alkyl, aryl, or heteroaryl; and
  • R P11 is hydrogen or C 1 -C 4 alkyl.
  • the DYRK1 inhibitor has the structure of Formula (P-II): or a pharmaceutically acceptable salt thereof, wherein: R P4 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, -CN, C 1 -C 3 perfluoro alkyl, -OR P11 , -O-(C 1 -C 6 alkyl)-OR P11 , -(C 1 -C 6 alkyl)-OR P11 , -NR P11 R P12 , - O-(C 1 -C 6 alkyl)-NR P11 R P12 , - -
  • the DYRK1 inhibitor has the structure of Formula (P-III): or a pharmaceutically acceptable salt thereof, wherein: R P6 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, -CN, C 1 -C 3 perfluoro alkyl, -OR P11 , -O-(C 1 -C 6 alkyl)-OR P11 , -(C 1 -C 6 alkyl)-OR P11 , -NR P11 R P12 , - O-(C 1 -C 6 alkyl)-NR P11 R P12 , -(C 1 -C 6 alkyl)-NR P11 R P12 , -NR P11 -(C 1 -C 6 alkyl)-NR P11 R P12 , -NR P11 -(C 1 -C 6 alkyl)-NR P11 R P
  • the DYRK1 inhibitor has the structure of pharmaceutically acceptable salt thereof.
  • These compounds of Formula (P-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, Eur. Neuropsychopharmacol. (2015) 25(11):2170-2182, the entire content of which is incorporated herein by reference.
  • the DYRK1 inhibitor has the structure of Formula (Q-I): or a pharmaceutically acceptable salt thereof, wherein: X Q1 is C or N; each Ring A and Ring B is independently substituted or unsubstituted 5 to 6 membered carbocyclic, substituted or unsubstituted 5 to 6 membered heterocyclic, substituted or unsubstituted 5 to 6 membered heteroaryl, or substituted or unsubstituted phenyl; each R Q1 is independently a hydrogen, halogen, a substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 2 to 5 membered heterocycloalkyl, aryl, alkylaryl, heterocyclic, alkylheterocyclic, -NR Q4 R Q5 , -OR Q4 , or -CR Q4 R Q5 ; R Q2 is -R Q4 , -NR Q4 R Q5 ;
  • the DYRK1 inhibitor has the structure of Formula (Q-II): or a pharmaceutically acceptable salt thereof.
  • R Q1 , R Q2 , R Q3 , n17 and m17 are as described above.
  • the DYRK1 inhibitor has the structure of Formula (Q-III): III), or a pharmaceutically acceptable salt thereof.
  • R Q1 , R Q2 , R Q3 , n17 and m17 are as described above.
  • the DYRK1 inhibitor has the structure of Formula (Q-IV): or a pharmaceutically acceptable salt thereof.
  • R Q1 , R Q2 , and R Q3 are as described above.
  • the DYRK1 inhibitor has the structure of Formula (Q-V): or a pharmaceutically acceptable salt thereof.
  • R Q1 , R Q2 , R Q3 , n17 and m17 are as described above.
  • the DYRK1 inhibitor has the structure of Formula (Q-VI): or a pharmaceutically acceptable salt thereof.
  • R Q1 , R Q2 , and R Q3 are as described above.
  • the DYRK1 inhibitor has the structure of Formula (Q-VII): or a pharmaceutically acceptable salt thereof.
  • R Q1 , R Q2 , and R Q3 are as described above.
  • R Q1 is hydrogen, halogen, unsubstituted C 1 -C 4 alkyl, or - OR Q4 and R Q4 is independently hydrogen, or unsubstituted C 1 -C 4 alkyl.
  • R Q2 is hydrogen or methyl.
  • R Q3 is hydrogen, unsubstituted C 1 -C 4 alkyl, -NR Q4 R Q5 , -OR Q4 , or -C(O)OR Q4 and R Q4 is independently hydrogen, or unsubstituted C 1 -C 4 alkyl.
  • the DYRK1 inhibitor has the structure of: , [00125]
  • These compounds of Formula (Q-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, GB2447791, WO2005/007672, U.S. Pub.2011/0021776, and Biochem J (2007) 408 (3): 297–315, the entire contents of which are incorporated herein by reference.
  • the DYRK1 inhibitor has the structure of Formula (R-I): or a pharmaceutically acceptable salt thereof, wherein: X R1 and X R2 are each independently selected from C and N, provided that at least one of X R1 and X R2 is N; R R1 is hydrogen, C 1-4 alkyl, or substituted or unsubstituted C 1-4 alkyl, OR R6 , NR R6 R R7 , substituted or unsubstituted heterocyclic; R R2 is halogen, OR R6 , or NR R6 R R7 ; R R3 is hydrogen, halogen, or unsubstituted C 1-4 alky; R R4 is hydrogen or halogen; R R5 is hydrogen or substituted or unsubstituted C 1-4 alkyl; and each R R6 and R R7 is independently hydrogen, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted heterocyclic, and substituted or
  • the DYRK1 inhibitor has the structure of Formula (R-II): or a pharmaceutically acceptable salt thereof.
  • R R1 , R R2 , R R3 , and R R5 are as described above.
  • the DYRK1 inhibitor has the structure of Formula (R-III): or a pharmaceutically acceptable salt thereof.
  • R R1 , R R2 , R R3 , and R R5 are as described above.
  • R R3 is halogen (e.g., F, Cl, or Br).
  • R R1 is -OR R6 and R R6 is hydrogen or methyl.
  • the DYRK1 inhibitor has the structure of: pharmaceutically acceptable salt thereof.
  • These compounds of Formula (R-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, U.S. Pat. Pub. 2012/0184562 and Molecular Cancer Therapeutics 10: 2104-2114, the entire contents of which are incorporated herein by reference.
  • the DYRK1 inhibitor has the structure of Formula (S-II): pharmaceutically acce S1 S2 ptable salt thereof.
  • R , R , R S3 , R S4 , R S7 , and R S8 are as described above.
  • a S1 is NH and B S1 is a OR S5 or NR S5 R S6 .
  • a S1 is NH and B S1 is a OCH 3 .
  • a S1 is O and B S1 is NH 2 .
  • the DYRK1 inhibitor has the structure of Formula (S-III): or a pharmaceutically acceptable salt thereof, wherein: each R S9 is independently hydrogen, halogen, OR S5 , NR S5 R S6 , cyano, or substituted or unsubstituted C 1 -C 5 alkyl; and n19 is an integer of 0 to 5.
  • R S5 , R S7 , and R S8 are as described above.
  • n19 is 1 or 2.
  • R S9 is hydrogen, halogen, OR S5 , or NR S5 R S6 .
  • the DYRK1 inhibitor has the structure of Formula (S-IV): or a pharmaceutically acceptable salt thereof.
  • R S5 , R S7 , R S8 and R S9 are as described above.
  • the DYRK1 inhibitor has the structure of: pharmaceutically acceptable salt thereof.
  • These compounds of Formula (S-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, U.S. Pat. No. 9,446,044, the entire content of which is incorporated herein by reference.
  • the DYRK1 inhibitor has the structure of Formula (T-I): or a pharmaceutically acceptable salt thereof, wherein: R T1 is a hydrogen, halogen, amino, cyano or a substituted or unsubstituted C 1 -C 6 alkyl; Each R T2 and R T3 is independently hydrogen, halogen, OR S5 , NR S5 R S6 , cyano, or substituted or unsubstituted C 1 -C 5 alkyl; R T4 is hydrogen, halogen, OR S5 , NR S5 R S6 , cyano, NO 2 , or substituted or unsubstituted C 1 -C 5 alkyl; R S5 and R S6 are independently chosen from a hydrogen atom and a substituted or unsubstituted C 1 -C 8 alkyl; n20 is an integer of 0 to 5; and m20 is an integer of 0 to 4.
  • R T1 is a hydrogen, halogen, amino,
  • R T4 is a -NO 2 .
  • the DYRK1 inhibitor has the structure of Formula (T-II): pharmaceutically acceptabl T2 T3 e salt thereof. R and R are as described above.
  • the DYRK1 inhibitor has the structure of: pharmaceutically acceptable salt thereof.
  • the DYRK1 inhibitor has the structure of Formula (U-I) or a pharmaceutically acceptable salt thereof, wherein: R U1 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 carbocyclic, substituted or unsubstituted 5 to 6 membered heterocyclic, substituted or unsubstituted 5 to 6 membered heteroaryl, or substituted or unsubstituted phenyl; R U2 is a hydrogen, halogen, OR U3 , NR U3 R U4 , cyano, NO 2 , or substituted or unsubstituted C 1 - C 4 alkyl; each R U3 and R U4 is independently a hydrogen and substituted or unsubstituted C 1 -C 4 alkyl; L U1 is -C(O)NH- or
  • the DYRK1 inhibitor has the structure of Formula (U-II) or a pharmaceutically acceptable salt thereof.
  • L U2 , R U1 and R U2 are as described above.
  • the DYRK1 inhibitor has the structure of Formula (U-III) or a pharmaceutically acceptable salt thereof.
  • L U2 , R U1 and R U2 are as described above.
  • the DYRK1 inhibitor has the structure of: pharmaceutically acceptable salt thereof.
  • the DYRK1 inhibitor has the structure of Formula (V-I): or a pharmaceutically acceptable salt thereof, wherein: R V1 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 carbocyclic, substituted or unsubstituted 5 to 6 membered heterocyclic, substituted or unsubstituted 5 to 6 membered heteroaryl, or substituted or unsubstituted phenyl.
  • the DYRK1 inhibitor has the structure of: pharmaceutically acceptable salt thereof.
  • the DYRK1 inhibitor has the structure of Formula (W-I): or a pharmaceutically acceptable salt thereof, wherein: R W1 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 carbocyclic, substituted or unsubstituted 5 to 6 membered heterocyclic, substituted or unsubstituted 5 to 6 membered heteroaryl, or substituted or unsubstituted phenyl; each R W2 and R W3 is independently a hydrogen, or substituted or unsubstituted C 1 -C 4 alkyl; R W4 is independently a hydrogen, halogen, or substituted or unsubstituted C 1 -C 4 alkyl; and n23 is an integer of 0 to 3.
  • R W1 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl,
  • the DYRK1 inhibitor has the structure of Formula (W-II): phar W1 maceutically acceptable salt thereof. R is as described above. [00155] In some embodiments, the DYRK1 inhibitor has the structure of: [00156] These compounds of Formula (W-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, WO2011/041655, BMCL, (2009) 19, 6700 and BMCL, (2011) 21, 3152, the entire contents of which are incorporated herein by reference.
  • the DYRK1 inhibitor has the structure of Formula (X-I): or a pharmaceutically acceptable salt thereof, wherein: each R X1 and R X2 is a hydrogen, halogen, OR X3 , NR X3 R X4 , cyano, or substituted or unsubstituted C 1 -C 4 alkyl; each R X3 and R X4 is independently a hydrogen and substituted or unsubstituted C1-C4 alkyl; n24 is an integer of 0 to 5; and m24 is an integer of 0 to 5. [00158] In some embodiments, the DYRK1 inhibitor has the structure of Formula (X-II): pharmaceutically acceptable salt thereof.
  • the DYRK1 inhibitor has the structure of: pharmaceutically acceptable salt thereof.
  • These compounds of Formula (X-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, BMCL, (2006) 16, 3772 and BMCL, (2009) 19, 2324, the entire contents of which are incorporated herein by reference.
  • the DYRK1 inhibitor has the structure of Formula (Y-I): or a pharmaceutically acceptable salt thereof, wherein: X Y1 is S or O; each R Y1 and R Y2 is a hydrogen, halogen, OR Y3 , NR Y3 R Y4 , cyano, or substituted or unsubstituted C 1 -C 4 alkyl; each R Y3 and R Y4 is independently a hydrogen and substituted or unsubstituted C 1 -C 4 alkyl; n25 is an integer of 0 to 5; and m25 is an integer of 0 to 5.
  • Formula (Y-I) or a pharmaceutically acceptable salt thereof, wherein: X Y1 is S or O; each R Y1 and R Y2 is a hydrogen, halogen, OR Y3 , NR Y3 R Y4 , cyano, or substituted or unsubstituted C 1 -C 4 alkyl; each R Y3
  • the DYRK1 inhibitor has the structure of Formula (Y-II): , or a pharmaceutically acceptable salt thereof.
  • R Y1 and R Y2 are as described above.
  • the DYRK1 inhibitor has the structure of pharmaceutically acceptable salt thereof.
  • These compounds of Formula (Y-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, WO2011/037962, the entire content of which is incorporated herein by reference.
  • the DYRK1 inhibitor has the structure of Formula (Z-I): or a pharmaceutically acceptable salt thereof, wherein: Z 1 is CR Z5 or N; Z 2 is C or N; R Z1 is substituted or unsubstituted 5 to 6 membered heteroaryl, or substituted or unsubstituted phenyl; each R Z2 is a hydrogen, halogen, OR Z3 , NR Z3 R Z4 , cyano, or substituted or unsubstituted C 1 -C 4 alkyl; each R Z3 and R Z4 is independently a hydrogen and substituted or unsubstituted C 1 -C 4 alkyl; R Z5 is a hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; n26 is an integer of 0 to 5; and m26 is an integer of 0 to 4.
  • Z 1 is CR Z5 or N
  • Z 1 is CR Z5 .
  • the DYRK1 inhibitor has the structure of Formula (Z-II): pharmaceutically acceptable salt thereof.
  • R Z1 , R Z2 , R Z3 , R Z5 , and n26 are described above.
  • the DYRK1 inhibitor has the structure of Formula (Z-III): pharmaceutically acceptable salt thereof.
  • R Z1 , R Z2 , R Z3 , R Z5 , and n26 are described above.
  • the DYRK1 inhibitor has the structure of Formula (Z-IV): pharmaceutically acceptable salt thereof.
  • the DYRK1 inhibitor has the structure of: pharmaceutically acceptable salts thereof.
  • These compounds of Formula (Z-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, WO2012/099066, WO2012/098070, and WO2012/098065, the entire contents of which are incorporated herein by reference.
  • the DYRK1 inhibitor has the following structure: pharmaceutically acceptable salts thereof, wherein: Ring X and Z are independently substituted or unsubstituted heteroaryl containing one or more nitrogens, or substituted or unsubstituted phenyl; Ring Y is a heteroaryl containing one or more nitrogens; and L is a linker or a bond. [00173] In some embodiments, L is a bond. In some embodiments, L is substituted or unsubstituted C 1 -C 4 alkylene or alkenylene. [00174] In some embodiments, the DYRK1 inhibitor has the following structure: acceptable salts thereof.
  • the DYRK1 inhibitor has the following structure: pharmaceutically acceptable salts thereof, wherein: Ring X’ is substituted or unsubstituted heteroaryl containing one or more nitrogens, or substituted or unsubstituted phenyl; and Ring Y’ is a heteroaryl containing nitrogen or sulfur; Ring Z’ is substituted or unsubstituted heteroaryl containing nitrogen or sulfur; and L’ is a linker or a bond.
  • the DYRK1 inhibitor has the following structure: , , or a pharmaceutically acceptable salt thereof.
  • DYRK1 inhibitors include Haspin-inhibitors having the following structures: , , or a pharmaceutically acceptable salt thereof.
  • These compounds may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, Eur J Med Chem.2022 Jun 5;236:114369, the entire content of which is incorporated herein by reference.
  • the DYRK1 inhibitor has the following structure: pharmaceutically acceptable salt thereof. [00181] These compounds may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, Biochem J (2008) 415 (3): 353–365, the entire content of which is incorporated herein by reference. [00182] In one aspect, the DYRK1 inhibitor has the following structure: , , or pharmaceutically acceptable salts thereof. [00183] These compounds may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, Biochem J (2003) 371 (1): 199–204, the entire content of which is incorporated herein by reference.
  • the DYRK1 inhibitor is a macrocyclic compound, for example, having the following structure, but examples of the DYRK1 inhibitor macrocyclic compounds are not limited thereto.
  • These compounds may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, ACS Med Chem Lett.2022 Mar 8;13(4):577-585, the entire content of which is incorporated herein by reference.
  • additional compounds shown to have DYRK1 inhibition activities can be used without limitation in the combinations described herein.
  • the DYRK1 inhibitor is an RNA, such as an antisense RNA.
  • Antisense RNA also referred to as antisense transcript or antisense oligonucleotide, is a single stranded RNA that is complementary to a protein coding messenger RNA (mRNA) with which it hybridizes, and thereby blocks the mRNA’s translation into protein.
  • the antisense RNA can be short (less than 200 nucleotides) or long (200 or more nucleotides) non-coding RNAs (ncRNAs).
  • the DYRK1 inhibitor is RNA interference (RNAi), small inhibiting RNA (siRNA), or micro-RNA (miRNA).
  • RNAi RNA interference
  • small inhibitory or interfering RNA may be a double-stranded RNA molecule, such as, for example, RNA having 19-25 (e.g., 19-23) base pairs in length, that induces RNA interference in a cell.
  • a small hairpin RNA may be an RNA molecule, such as, for example, RNA having approximately 19-25 (e.g., 19-23) base pairs of double stranded RNA linked by a short loop (e.g., about 4-11 nucleotides) that induces RNA interference in a cell.
  • a microRNA can be an RNA molecule that induces RNA interference in a cell having a short (e.g., 19-25 base pairs) sequence of double-stranded RNA linked by a loop and containing one or more additional sequences of double-stranded RNA comprising one or more bulges (e.g., mis-paired or unpaired base pairs).
  • miRNA encompasses endogenous miRNAs as well as exogenous or heterologous miRNAs.
  • the inhibition of DYRK1 may be evaluated using an enzyme assay for inhibitory activity. Definition [00190]
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen.
  • Preferred heteroatoms are nitrogen (N), oxygen (O), and sulfur (S).
  • halogen or "halo” designates -F, -Cl, -Br or –I. Preferred halo genes are -F, -Cl and -Br.
  • hydroxyl means -OH.
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups and branched-chain alkyl groups.
  • C 1 -C 6 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, and the like.
  • cycloalkyl refers to saturated, carbocyclic groups having from 3 to 7 carbons in the ring. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • alkenyl refers to a linear or branched hydrocarbyl having a double bond and 2-6 carbon atoms (“C 2 -C 6 alkenyl”).
  • the alkenyl includes vinyl, 1-propenyl, 2- propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.
  • the compound of the present disclosure contains an alkenyl group, the compound may exist as the E-form, the Z-form, or any mixture thereof.
  • alkynyl refers to a linear or branched hydrocarbyl having a triple bond and 2-6 carbon atoms (“C 2 -C 6 alkynyl).
  • the alkynyl includes ethynyl, propynyl, and the like.
  • aryl as used herein includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • aryl heterocycles “heteroaromatics” or "heteroaryl”.
  • aryl also includes 7- to 14-membered polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic (including heteroaryl), e.g., the other cyclic rings can be fused cycloalkyls, cycloalkenyls, aryls, heteroaryl and/or heterocyclic groups.
  • Single-ring heteroaryl groups may have from 1 to 3 ring heteroatoms and fused polycyclic heteroaryl groups may have from 1 to 5 ring heteroatoms, wherein the ring heteroatoms are selected from N, O and S.
  • heterocyclyl refers to 3- to 10-membered ring structures, more preferably 5- or 6-membered rings, whose ring structures include one to four heteroatoms.
  • Heterocycles can also be polycycles.
  • Heterocyclic groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, ox
  • alkylaryl refers to a C 1 -C 6 alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • aryl group e.g., an aromatic or heteroaromatic group.
  • substitution includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds disclosed herein and inorganic and organic basic addition salts of the compounds disclosed herein.
  • ROCK2 inhibitor or to a DYRK1 inhibitor includes the neutral compound and any pharmaceutically acceptable salt for of the ROCK2 inhibitor or the DYRK1 inhibitor.
  • the pharmaceutically acceptable salt forms which may be selected on the basis of a chosen route of administration and according to standard pharmaceutical practice.
  • certain embodiments of the ROCK2 and/or DYRK1 inhibitors may contain a basic functional group, such as amino, and are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids.
  • salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
  • the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non- toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic,
  • the compounds provided in this disclosure may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra).
  • Certain compounds provided in this disclosure may exist in particular geometric or stereoisomeric forms. The disclosure contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included in this invention.
  • the term “inhibition”, “inhibit”, “inhibiting” and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In embodiments inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments inhibition refers to reduction of a disease or symptoms of disease. In embodiments, inhibition refers to a reduction in the activity of a particular protein target.
  • inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein.
  • inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g., an inhibitor binds to the target protein).
  • inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation).
  • inhibitor may include synthetic or biological molecule (e.g., small molecule, nucleic acid, peptide or antibody) inhibiting or negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor.
  • Preferred inhibitor is a small molecule.
  • the inhibitor can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the inhibitor or antagonist. In certain instances, activity is 1.5-fold, 2-fold, 3- fold, 4-fold, 5 -fold, 10-fold or lower than the expression or activity in the absence of the inhibitor.
  • the combination therapy comprising a ROCK2 inhibitor and a DYRK1 inhibitor may be used in the treatment of type I diabetes in a subject.
  • the combination therapy may restore the population of the patient’s beta cells, thereby allowing the patient’s own population of beta cells to control blood sugar levels, and reducing or eliminating the patient’s reliance on exogenous insulin for the control of blood sugar.
  • the present disclosure provides a method for the treatment of type 1 diabetes in a subject, the method comprising administering to the subject a combination therapy providing a therapeutically effective amount of an inhibitor of ROCK2 and a therapeutically effective amount of an inhibitor of DYRK1.
  • the ROCK2 inhibitor(s) may include one or more compounds having the formulae (A-I), (B-I), (C-I), (D-I), (E-I), (F-I), (G-I), (H-I), (J-I), (K- I), (L-I) and their subordinates, exemplary compounds thereof, or derivatives thereof which may be obtained or known by one of ordinary skill in the art.
  • the DYRK1 inhibitor(s) may include one or compounds having the formulae (M-I), (N-I), (O-I), (P-I), (Q-I), (R-I), (S-I), (T-I), (U-I), (V-I), (W-I), (X-I), (Y-I), (Z-I) and their subordinates, exemplary compounds thereof, or derivatives thereof which may be obtained or known by one of ordinary skill in the art.
  • the present disclosure provides a method of restoring a population of pancreatic beta-cells in a subject suffering from type 1 diabetes, the method comprising administering to the subject a therapeutically effective amount of a ROCK2 inhibitor and a therapeutically effective amount of a DYRK1 inhibitor.
  • the combination therapy disclosed herein comprises a therapeutically effective amount of a ROCK2 inhibitor and a therapeutically effective amount of a DYRK1 inhibitor to promote the re-growth of beta cells and also promotes the maintenance of the beta cells by inhibiting further autoimmune destruction of the patient’s beta cells.
  • the present disclosure provides a method of promoting regrowth of pancreatic beta cells in a subject suffering from type 1 diabetes, the method comprising administering to the subject a therapeutically effective amount of a ROCK2 inhibitor and a therapeutically effective amount of a DYRK1 inhibitor.
  • the ROCK2 and DYRK1 inhibitors for treating type 1 diabetes in the subject may be co-administered.
  • the “co-administration” is meant to include simultaneous or sequential administration of the ROCK2 inhibitor and the DYRK1 inhibitor.
  • the ROCK2 inhibitor and the DYRK1 inhibitor may be administered to the patient as separate dosage forms, i.e., the combination therapy comprises the administration of a dosage form comprising the ROCK2 inhibitor and a dosage form comprising the DYRK1 inhibitor.
  • the ROCK2 inhibitor and the DYRK1 inhibitor may be administered to the patient in a combination formulation, e.g., the dosage form comprises both the ROCK2 inhibitor and the DYRK1 inhibitor.
  • the ROCK2 inhibitor and DYRK1 inhibitor may be administered at the same time, or at separate times.
  • the ROCK2 inhibitor and the DYRK1 inhibitor are co- administered.
  • the phrase “co-administration” refers to any form of administration of the therapeutic formulations of the ROCK2 inhibitor and the DYRK1 inhibitor such that one of the formulations is administered while the other therapeutic formulation is still effective in the body. Accordingly, the ROCK2 inhibitor and the DYRK1 inhibitor are simultaneously effective in the patient, which may include synergistic effects of the two agents. Thus, the patient who receives such treatment can benefit from a combined effect or synergetic effect of the ROCK2 inhibitor and the DYRK1 inhibitor. Particularly, the combination treatment may result in improved outcomes, such as reduction of severity, delay or elimination of recurrence, or reduced side effects of a primary agent with pre-treatment with the secondary agent.
  • the efficacy or therapeutic effects of the DYRK1 inhibitors may be improved by at least about 10 %, 20%, 25%, 30%, 40%, 50%, 60 %, 70%, 80%, 90%, or greater in the combination treatment with the ROCK2 inhibitors when compared to the same treatment with the DYKR1 inhibitors as a single agent, as determined, for example, in glucose tolerance or by measuring blood glucose.
  • the production of pancreatic insulin producing cells may be increased by at least about 10 %, 20%, 25%, 30%, 40%, 50%, 60 %, 70%, 80%, 90%, or greater in the combination treatment with the ROCK2 inhibitor when compared to the same treatment with the DYKR1 inhibitor as a single agent, as determined, for example, in glucose tolerance or by measuring blood glucose.
  • the production of pancreatic insulin producing cells may be increased by at least about 10 %, 20%, 25%, 30%, 40%, 50%, 60 %, 70%, 80%, 90%, or greater in the combination treatment with the ROCK2 inhibitor when compared to the same treatment with the DYKR1 inhibitor as a single agent, as determined, for example, by pancreatic ⁇ -cell proliferation in the patient.
  • the combination therapies using the ROCK2 inhibitor and the DYRK1 inhibitor and methods of co-administrating may also allow reduction in doses and/or frequency of administration of the primary therapeutic agents (i.e. DYRK1) to achieve the same therapeutic effects and/or improvements in comparison to using a single primary agent (i.e. DYRK1) or other existing single treatment.
  • the administration routes and regimen of the disclosed combination may well vary depending on the condition prior to or after the treatment, extent of progression in insulin production, age and physical condition of the subject, exact combination selected, and other factors. Administration regimen may include multiple doses per period of time, the treatments administered simultaneously or sequentially.
  • a first therapeutic agent may be administered 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours before administering a second therapeutic agent.
  • the combination therapy includes administering the ROCK2 inhibitor (e.g., suppressing autoimmune using the ROCK2 inhibitors) prior to administering the DYRK1 inhibitor (e.g., promoting pancreatic beta cells using the DYRK1 inhibitors).
  • the therapeutic agent including the ROCK2 inhibitor for autoimmune suppression may be administered 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, or 96 hours before administering the DYRK1 inhibitor.
  • the therapeutic agent including the ROCK2 inhibitor may be administered at the same time (simultaneously) as the therapeutic agent including the DYRK1 inhibitor.
  • the therapeutic agent including the ROCK2 inhibitor may be additionally administered 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours after administering the therapeutic agent including the DYRK1 inhibitor.
  • the ROCK2 inhibitor described herein may preferably include a compound having a structure of formular (A-I), (B-I), (C-I), (D-I), (E-I), (F-I), (G-I), (H-I), (J-I), (K-I), (L-I), their subordinates, or exemplary compounds thereof.
  • the ROCK2 inhibitor may be selected from Compound A, Compound B, Compound C, Compound D, belumosudil (KD025), Zelasudil, Y-27632, fasudil, GSK429286A, RKI-1447, TC-S 7001, TC-S 7004, hydroxyfasudil, GSK269962A, ripasudil, AT13148, RX007, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof, but the examples of the ROCK2 inhibitors are not limited thereto.
  • the DYRK1 inhibitor described herein may preferably include a compound having a structure of formular (M-I), (N-I), (O-I), (P-I), (Q-I), (R-I), (S-I), (T-I), (U-I), (V-I), (W-I), (X-I), (Y-I), (Z-I) and their subordinates, or exemplary compounds thereof.
  • the DYRK1 inhibitor may be selected from is FX-1610, FX-9847, FX-8553, FX-5372, AZ191, paprotrain, harmine, GNF4877, GNF2133, INDY, FINDY, EHT1610, EHT 5372, AZ-Dyrk1B-33, KH- CB20, ARN25068, haspin, JH-XVII-10, leucettine L41, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof, but the examples of the DYRK1 inhibitors are not limited thereto. [00221] In some embodiments, the ROCK2 inhibitor and the DYRK1 inhibitor are formulated in a single composition.
  • ROCK2 inhibitor and the DYRK1 inhibitor are prepared separately and/or formulated in separate compositions.
  • ROCK2 Inhibitor for the prevention of type 1 diabetes [00222] Also provided are methods of preventing the progression of type 1 diabetes in a subject, comprising administering to the subject a therapeutically effective amount of a ROCK2 inhibitor. This method prevents or delays the progression to clinical type 1 diabetes before irremediable beta cell destruction and insulin deficiency occur in the patient.
  • this disclosure provides a method of preventing or delaying the onset of type 1 diabetes in a patient that has been diagnosed to have a high risk of developing type 1 diabetes, and/or that is diagnosed to be experiencing the symptoms of the onset, or progression towards, type 1 diabetes, wherein the method comprises administering a therapeutically effective amount of a ROCK 2 inhibitor.
  • Changes in beta cell function may precede the clinical diagnosis of type 1 diabetes in individuals who are identified as at-risk for the disease based on the presence, for example, of islet autoantibodies. Patient may experience an ongoing and/or intermittently progressive decline in beta cell function, that may begin years before clinical diagnosis of type 1 diabetes, and at a time when glucose tolerance is still normal.
  • patients with two or more islet autoantibodies may be classified in stages disease progression towards type 1 diabetes, with further specification according to the level of metabolic dysfunction: stage 1 prior to glucose abnormalities, stage 2 with dysglycemia during an oral glucose tolerance test (OGTT), and stage 3 at clinical presentation with hyperglycemia.
  • an inhibitor of ROCK2 may be administered to the patient, thereby inhibiting further autoimmune destruction of the patient’s beta cells, and preventing or delaying the progression to type 1 diabetes.
  • a DYRK1 inhibitor may be administered for a period of time in addition to the ROCK 2 inhibitor to restore the population and function of the patient’s beta cells.
  • the patient may be one that has been recognized or diagnosed to have a high risk of developing type 1 diabetes, and/or that is recognized or diagnosed to be experiencing the symptoms of the onset, or progression towards, type 1 diabetes (i.e., prediabetes).
  • the patient may have one or more of the following: a relative with type 1 diabetes, blood tests suggesting the patient may develop type 1 diabetes, and/or one or more symptoms associated with the development of type 1 diabetes.
  • Blood tests may include assays for the patient’s blood sugar level, such as a glycated hemoglobin (A1C) test, a random blood sugar test, or a fasted blood sugar test.
  • A1C glycated hemoglobin
  • An A1C between about 5.7 and 6.4% may indicate pre-diabetes.
  • a blood sample is taken at a random time, with a random blood sugar level of about 200 mg/dL (11.1 mmol/L) or higher suggesting the onset of diabetes.
  • a fasting blood sugar level from about 100 to 125 mg/dL (5.6 to 6.9 mmol/L) may indicate pre- diabetes, and a fasting blood sugar level of about 126 mg/dL (7 mmol/L) or higher on two separate tests may indicate more advanced disease progression or diabetes.
  • the blood test(s) may include assays for one or more antibodies that are associated with the development of type 1 diabetes.
  • the antibodies may include one or more of islet cell cytoplasmic autoantibodies (ICA), glutamic acid decarboxylase autoantibodies (GADA), insulinoma-associated-2 autoantibodies (IA-2A), and insulin autoantibodies (IAA).
  • ICA islet cell cytoplasmic autoantibodies
  • GADA glutamic acid decarboxylase autoantibodies
  • IA-2A insulinoma-associated-2 autoantibodies
  • IAA insulin autoantibodies
  • the present disclosure provides a method for preventing or delaying the onset of type 1 diabetes in a subject, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of ROCK2.
  • the ROCK2 inhibitor(s) may include one or more compounds having the formulae (A-I), (B-I), (C-I), (D-I), (E-I), (F-I), (G-I), (H-I), (J-I), (K-I), (L-I) and their subordinates, exemplary compounds thereof, or derivatives thereof which may be obtained or known by one of ordinary skill in the art.
  • the ROCK2 inhibitor may be selected from Compound A, Compound B, Compound C, Compound D, belumosudil (KD025), Zelasudil, Y-27632, fasudil, GSK429286A, RKI-1447, TC-S 7001, TC-S 7004, hydroxyfasudil, GSK269962A, ripasudil, AT13148, RX007, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof.
  • compositions for use in the treatment of type 1 diabetes which comprise a therapeutically effective amount of a ROCK2 inhibitor and a therapeutically effective amount of a DYRK1 inhibitor, each formulated with one or more pharmaceutically acceptable carriers.
  • compositions of the present disclosure may be formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginal or intrarectal administration, for example, as a suppository, pessary, cream or foam; (5) sublingual administration; (6) ocular administration; (7) transdermal administration; or (8) nasal administration.
  • oral administration for example, drenches (aqueous or non-aqueous
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals with toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), solvent, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • solvent or solvent encapsulating material
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • the compounds of this disclosure may be formulated with conventional carriers and excipients, which can be selected in accord with ordinary practice.
  • Tablets can contain excipients, glidants, fillers, binders and the like.
  • Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally can be isotonic. All formulations can optionally contain excipients such as those set forth in the “Handbook of Pharmaceutical Excipients” (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • compositions may include compositions wherein the active ingredient (e.g. compounds or combinations described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose.
  • compositions When administered in methods to treat a disease (e.g., type 1 diabetes), such compositions may contain an amount of active ingredient effective to achieve the desired result, e.g., modulating the activity of a target molecule, and/or reducing, eliminating, or slowing the progression of disease symptoms (e.g., increased insulin secretion in pancreas or regrowth of insulin producing cells).
  • active ingredient effective to achieve the desired result, e.g., modulating the activity of a target molecule, and/or reducing, eliminating, or slowing the progression of disease symptoms (e.g., increased insulin secretion in pancreas or regrowth of insulin producing cells).
  • the formulations include those suitable for the administration routes provided herein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.).
  • Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
  • the active ingredients When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. [00239] If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • a polyhydric alcohol i.e., an alcohol having two or more hydroxyl groups
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas.
  • Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
  • the oily phase of the emulsions of this disclosure may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer.
  • Emulsifying agents and emulsion stabilizers suitable for use in the formulation of the disclosure include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
  • emulsifying agents and emulsion stabilizers suitable for use in the formulation of the disclosure include Tween® 80.
  • Tween® 80 The choice of suitable oils or fats for the formulation is based on achieving the desired properties.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
  • compositions according to the present disclosure comprise a combination according to the disclosure together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • Pharmaceutical formulations containing an active ingredient may be in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing an active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsules where an active ingredient is mixed with an inert solid diluent, for example starch, mannitol, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the disclosure contain an active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally-occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
  • a suspending agent such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone,
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules of the disclosure suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above.
  • compositions of the disclosure may also be in the form of oil- in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally-occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • compositions of the disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution isotonic sodium chloride solution, and hypertonic sodium chloride solution.
  • a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35 etc., which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • Suitable formulations include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds.
  • Formulations suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • the disclosure further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
  • controlled release formulations in which the release of the active ingredient are controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as horse, cattle, swine and sheep; and poultry and pets in general, such as cats and dogs.
  • the present disclosure also provides a kit that includes a pharmaceutical composition of formulation including the combination described herein.
  • the kit may include a product instruction for administration of the combination, for example, that a first pharmaceutical composition including the ROCK2 inhibitor and a second pharmaceutical composition including the DYRK1 inhibitor are administered (co- administered) simultaneously or subsequently.
  • the kit may instruct administration of the ROCK2 inhibitor formulation administered to a subject prior to administration of DYRK1 inhibitor formulation.
  • ADP-Glo kinase assay (Promega).
  • the ADP-GloTM Kinase Assay is a luminescent ADP detection assay that allows measurement of kinase activity based on the amount of ADP produced during a kinase reaction.
  • the kinase reaction is performed in the presence of ATP, S6K substrate (KRRRLASLR) and the ROCK kinase in the appropriate Kinase Reaction Buffer (1x).
  • ATP ATP
  • S6K substrate KRRRLASLR
  • ROCK ROCK kinase
  • ADP-GloTM Reagent agent that binds ADP to ATP
  • Kinase Detection Reagent is added to convert ADP to ATP and allow the newly synthesized ATP to be measured using a luciferase/luciferin reaction.
  • the luminescence is proportional to the produced ADP and consequently to the kinase activity.
  • the ADP-GloTM Kinase Assay was performed in a 384 well plate format as follows.
  • Kinase Detection Reagent Preparation The Kinase Detection Buffer was thawed at room temperature (RT). If a precipitate was present, the buffer was incubated at 37 °C with constant swirling for 15 minutes to dissolve the precipitate or the precipitate was removed from the buffer by carefully pipetting the supernatant from the bottle. After equilibrating both the Kinase Detection Buffer and Kinase Detection Substrate to room temperature, the entire volume of Kinase Detection Buffer was transferred into the bottle containing Kinase Detection Substrate to reconstitute the lyophilized substrate, followed by stricte mixing to obtain a homogeneous solution.
  • RT room temperature
  • Kinase Reaction Buffer Preparation Kinase reaction buffer was prepared freshly before each experiment. The formulation of this buffer is provided in Table 1 below: Table 1. Formulation of kinase reaction buffer (1x) for ADP-Glo kinase assay. Reagent: Final concentration Stock concentration Tris, pH 7.5 40 mM 500 mM in H 2 O DTT 0.05 mM 100 mM in H 2 O MgCl2 20 mM 500 mM in H 2 O BSA 0.1 mg/mL 5.0 mg/mL [00264] ADP-Glo Reagents Preparation.
  • Test and reference compounds were diluted in 100% DMSO to obtain 10 mM stock solutions. Each compound was tested in 8-serial dilutions in duplicate. The final concentration of DMSO in the reaction was 1% (up to 50 nL). [00270] 5 ⁇ l/well Kinase Reaction Buffer (1x) was dispensed to blank control wells.
  • 2 ⁇ l/well Kinase Reaction Buffer (1x) was dispensed to control without protein (low control) and without substrate (autophosphorylation) wells. The plate was sealed with adhesive film followed by a short spin (1 min, 1000 rpm).
  • 2 ⁇ l/well kinase (2.5x) solution was dispensed into relevant wells of the assay plate. The plate was sealed with adhesive film followed by a short spin (1 min, 1000 rpm).
  • 2 ⁇ l/well S6K substrate (2.5x) solution was dispensed into relevant wells of the assay plate. The plate was sealed with adhesive film followed by a short spin (1 min, 1000 rpm).
  • ADP-GloTM Reagent 5 ⁇ l was dispensed to stop the kinase reaction and deplete the unconsumed ATP.
  • the plate was sealed with adhesive film followed by a short spin (1 min, 1000 rpm), and was incubated at 25 ⁇ C for 40 minutes with 450 rpm shaking speed.
  • 10 ⁇ l of Kinase Detection Reagent was dispensed to convert ADP to ATP and introduce luciferase and luciferin to detect ATP.
  • the plate was sealed with adhesive film followed by a short spin (1 min, 1000 rpm), and was incubated at 25 ⁇ C for 60 minutes with 450 rpm shaking speed.
  • the treatment groups were treated with: DYRK1 inhibitor compounds (FX7742, FX8474), and FX8474 in combination with a ROCK2 inhibitor compound (Compound A) in comparison to control groups of (i) a no treatment group without diabetes, and (ii) a no treatment group having diabetes.
  • Figure 2 shows levels of the fasted glucose in blood of the mice 5 days after treatment.
  • the treatment groups were treated with: DYRK1 inhibitor compounds (FX7742, FX8474), respectively, and FX8474 in combination with ROCK2 inhibitor compound (Compound A) in comparison to control groups of (i) a no treatment group without diabetes, and (ii) a no treatment group having diabetes.

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Abstract

The present disclosure relates to therapies for preventing and/or treating type 1 diabetes. The present disclosure provides combination therapies for treating type 1 diabetes using a Rho-associated coiled coil containing protein kinase 2 (ROCK2) inhibitor and a dual specificity tyrosine-phosphorylation-regulated kinase 1 (DYRK1) inhibitor. Also, provided are methods for using the combination of a ROCK2 and a DYRK1 inhibitor and kits using the same. Also provided are methods of preventing the progression or development of type 1 diabetes by administering a ROCK2 inhibitor.

Description

322930.47476 THERAPY FOR TREATING TYPE 1 DIABETES USING ROCK2 AND DYRK1 INHIBITORS FIELD [0001] The present disclosure relates to therapies for preventing and/or treating type 1 diabetes. The present disclosure provides combination therapies for treating type 1 diabetes using a Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor and a dual specificity tyrosine-phosphorylation-regulated kinase 1 (DYRK1) inhibitor. Also, provided are methods for using the combination of a ROCK2 and a DYRK1 inhibitor and kits using the same. Also provided are methods of preventing the progression or development of type 1 diabetes by administering a ROCK2 inhibitor. BACKGROUND [0002] Type 1 diabetes is a chronic condition in which the pancreas makes little or no insulin. The underlying mechanism causing type 1 diabetes involves an autoimmune destruction of the insulin-producing beta cells in the pancreas. The cause of type 1 diabetes is unknown, but it is believed to involve a combination of genetic and environmental factors. [0003] Type 1 diabetes makes up an estimated 5–10% of all diabetes cases, or 11–22 million cases worldwide. Although the exact number of people affected globally is unknown, it is estimated that about 80,000 children develop the disease each year. Symptoms can begin at any age, but onset is most common in children from about 5 years old through puberty. [0004] The destruction of the β-cells in type 1 diabetes results in progressive insulin deficiency, as there are no other cells in the body that produce insulin. Accordingly, the most pressing complication of type 1 diabetes is the constant risks attendant to poor blood sugar control, including severe hypoglycemia and diabetic ketoacidosis. In addition to the acute complications from type 1 diabetes, long-term hyperglycemia results in damage to small blood vessels throughout the body. This damage manifests particularly in the eyes, nerves and kidneys, causing diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy, respectively. Moreover, patients with type 1 diabetes have increased risk of cardiovascular disease, which is estimated to shorten the life of the average type 1 diabetic by 8–13 years. [0005] There has been no generally accepted means to prevent type 1 diabetes nor to cure the disease in those suffering from type 1 diabetes. The disease may be managed by the administration of exogenous insulin to the patient. Treatment with insulin is required for the patient’s survival and must continue throughout the patient’s life. The monitoring of blood sugar levels and the self-administration of insulin present a substantial life-long burden on patients. [0006] There is a clear need for improved therapies for patients with type 1 diabetes. A therapy that could restore the population and function of the patient’s beta cells would relieve the life-long burden on patient’s due to insulin therapy and could greatly improve patient life quality, health and lifespan. SUMMARY [0007] Described herein are methods for treating type 1 diabetes in a subject in need thereof. In some embodiments, the method comprises administering to the subject (i) a therapeutically effective amount of a Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor, and (ii) a therapeutically effective amount of a dual specificity tyrosine- phosphorylation-regulated kinase 1 (DYRK1) inhibitor. [0008] Also described are methods of preventing the progression of type 1 diabetes in a subject, comprising administering to the subject a therapeutically effective amount of a ROCK2 inhibitor. [0009] In some embodiments, the ROCK2 inhibitor is a ribonucleic acid (RNA). In some embodiments, the ROCK2 inhibitor is antisense RNA against ROCK2 transcription. In some embodiments, the ROCK2 inhibitor is small interfering RNA (siRNA) or micro RNA (miRNA). In some embodiments, the ROCK2 inhibitor is a compound according to one or more of the formulae (A-I), (B-I), (C-I), (D-I), (E-I), (F-I), (G-I), (H-I), (J-I), (K-I), (L-I) and their subordinates, and exemplary compounds thereof. [0010] In some embodiments, the DYRK1 inhibitor is a ribonucleic acid (RNA). In some embodiments, the DYRK1 inhibitor is antisense RNA against ROCK2 transcription. In some embodiments, the DYRK1 inhibitor is small interfering RNA (siRNA) or micro RNA (miRNA). In some embodiments, the DYRK1 inhibitor is a compounds according to one or more of the formulae (M-I), (N-I), (O-I), (P-I), (Q-I), (R-I), (S-I), (T-I), (U-I), (V-I), (W-I), (X-I), (Y-I), (Z-I) and their subordinates, and exemplary compounds thereof. [0011] The ROCK2 inhibitor may be selected from Compound A, Compound B, Compound C, Compound D, belumosudil (KD025), Zelasudil, Y-27632, fasudil, GSK429286A, RKI-1447, TC-S 7001, TC-S 7004, hydroxyfasudil, GSK269962A, ripasudil, AT13148, RX007, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof. In some embodiments, the ROCK2 inhibitor is belumosudil (2-(3-(4-((1H-indazol-5- yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide), or a pharmaceutically acceptable salt thereof. In other embodiments the ROCK2 inhibitor is Zelasudil or a pharmaceutically acceptable salt thereof. In other embodiments, the ROCK2 inhibitor is selected from Compound A, Compound B, Compound C, and Compound D, or a pharmaceutically acceptable salt thereof. In an embodiment, the ROCK2 inhibitor is (6-(4-((4-(1H-pyrazol-4- yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-1H-indol-2-yl)(3,3-difluoroazetidin-1- yl)methanone (Compound A), or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE FIGURES [0012] Figure 1 shows results of a glucose tolerance test in mice at time course 5 days after treatment. The treatment groups were treated with: DYRK1 inhibitor compounds (FX7742, FX8474), and FX8474 in combination with a ROCK2 inhibitor compound (Compound A) in comparison to control groups of (i) a no treatment group without diabetes, and (ii) a no treatment group having diabetes. [0013] Figure 2 shows levels of the fasted glucose in blood of the mice 5 days after treatment. The treatment groups were treated with: DYRK1 inhibitor compounds (FX7742, FX8474), respectively, and FX8474 in combination with ROCK2 inhibitor compound (Compound A) in comparison to control groups of (i) a no treatment group without diabetes, and (ii) a no treatment group having diabetes. DETAILED DESCRIPTION [0014] The present invention will now be further described. In the following passages, different aspects of the invention are provided. Each aspect presented may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous. [0015] Provided herein, inter alia, are combination therapies comprising a Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor and a dual specificity tyrosine- phosphorylation-regulated kinase 1 (DYRK1) inhibitor, methods of using the combination therapy in the treatment of type 1 diabetes, and kits comprising a dosage form of a ROCK2 inhibitor and a dosage form of the DYRK1 inhibitor. [0016] The combination therapy may be used in the treatment of type I diabetes in a subject. The combination therapy disclosed herein comprises a therapeutically effective amount of a ROCK2 inhibitor and a therapeutically effective amount of a DYRK1 inhibitor, which promotes the re-growth of beta cells while also promoting the maintenance of the beta cells by inhibiting further autoimmune destruction of the patient’s beta cells. The combination therapy may restore the population and function of the patient’s beta cells, thereby allowing the patient’s own population of beta cells to control blood sugar levels, and reducing or eliminating the patient’s reliance on exogenous insulin for the control of blood sugar. [0017] Also provided are methods of preventing the progression of type 1 diabetes in a subject, comprising administering to the subject a therapeutically effective amount of a ROCK2 inhibitor. ROCK2 Inhibitors [0018] In the present disclosure, the combination therapy includes use of ROCK2 inhibitors, and in particular ROCK2 selective inhibitors. [0019] Rho-associated coiled-coil containing protein kinase (ROCK) is a serine/threonine kinase from the AGC (PKA, PKG, and PKC) kinase family and comprises two isoforms, ROCK1 and ROCK2. The two isoforms are expressed and regulated differently in specific tissues. For example, ROCK1 is ubiquitously expressed at a relatively high level, while ROCK2 is preferentially expressed in certain tissues including heart, brain and skeletal muscle. ROCK2 inhibitors has been shown efficacious effects in inflammatory disease models. [0020] The compounds for use in the methods and compositions disclosed herein are ROCK inhibitors, and in particular ROCK2 selective inhibitors. The compounds provide excellent inhibitory activity of ROCK2, and preferably have good selectivity (higher selectivity towards ROCK2 as compared with ROCK1). The compounds may additionally provide one or more of good physicochemical properties (e.g., solubility, physical and/or chemical stability), good pharmacokinetic properties (e.g., improved bioavailability, proper half-life and duration of action), and acceptable safety (low toxicity and/or less side effects, wide therapeutic window). [0021] ROCK2 inhibitors are disclosed in, for example, WO2019/000682, WO 2019/000683, WO2019/001572, WO2020/094111, WO2020/177587, WO2020/259528, WO2022/042711, WO2022/042712, WO2006/105081, WO2019/145729, WO2007/007737, WO90/05723, WO2011/130740, WO2005/037197, WO2008/110846, WO2005/082890, WO2005/037197; US Pat. Nos.10,323,023, 10,329,282, 11,390,609, 8,357,693, 9,815,820, 10,183,931, 10,696,660, 11,311,541, 11,497,751, 8,193,193, 4,997,834, 9,221,808, 7,547,779, 8,497,294, 7,592,357, 7,547,779; WO2023/209692 and WO2024/110851. [0022] In one aspect, the ROCK2 inhibitor has the structure of Formula (A-I): or a pharmaceutically acceptable salt thereof, wherein: RA1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1- C(=O)RA11, -O-(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)
Figure imgf000007_0001
C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; RA2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1- C(=O)RA11, -O-(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)
Figure imgf000007_0002
C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; alternatively, RA1 and RA2 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O- (C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, C1-C3 perfluoro alkyl, -NRA11-(C1-C6 alkyl)NRA11RA12, and - NRA11-(C1-C6 alkyl)-ORA11; RA3 and RA4 are each independently selected from the group consisting of H, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1-C(=O)NRA11RA12; alternatively RA3 and RA4 are taken together with the nitrogen to which they are attached to provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10-membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, oxo, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1- C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1-C(=O)RA11, - (C1-C6 alkyl)x1- C(=O)
Figure imgf000008_0001
(C1-C6 alkyl)x1- C(=O)ORA11; the dotted lines represent optional double bonds; each RA5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1-C6 alkyl)x1-C -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)
Figure imgf000008_0002
n1 is 0 to 3; XA1 is CRA6 or N; XA2 is CHRA6, NRA7, O or S; XA3 is C, CH or N; XA4 is N or CH; XA5 is N or CH; each RA6 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O- (C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, - (C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1-C6 alkyl)x1-C -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)
Figure imgf000008_0003
each RA7 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)- alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)
Figure imgf000009_0001
each x1 is independently selected from 0 and 1; and each RA11 and RA12 are independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, RA11 and RA12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, - NH2, C1-C3 perfluoro alkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. [0023] In embodiments, the ROCK2 inhibitor has the structure of Formula (A-II):
Figure imgf000009_0002
or a pharmaceutically acceptable salt thereof, wherein: RA1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x- C(=O)RA11, -O-(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)
Figure imgf000009_0003
C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; RA2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1- C(=O)RA11, -O-(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, - 6 alkyl)x1-C(=O)RA11, and alternatively, RA1 and RA2 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O- (C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, C1-C3 perfluoro alkyl, -NRA11-(C1-C6 alkyl)NRA11RA12, and - NRA11-(C1-C6 alkyl)-ORA11; RA3 and RA4 are each independently selected from the group consisting of H, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)- x1-C(=O)RA11, -(C1-C6 alkyl)
Figure imgf000010_0001
alkyl)x1- alternatively
Figure imgf000010_0002
are taken together with the nitrogen to which they are attached to provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring to heteroatoms selected from N, O and S, or (ii) a 5- to 10-membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, oxo, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1- C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1-C(=O)RA11, - (C1-C6 alkyl)x1- alkyl)x1- C(=O)
Figure imgf000010_0003
(C1-C6 alkyl)x1- C(=O)ORA11; the dotted lines represent optional double bonds; each RA5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; n1 is 0 to 3; RA7 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1- C(=O)NRA11RA12; each x1 is independently selected from 0 and 1; and each RA11 and RA12 are independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, RA11 and RA12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, - NH2, C1-C3 perfluoro alkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. [0024] In some embodiments, the ROCK2 inhibitor has the structure of Formula (A-III):
Figure imgf000011_0001
(A-III) or a pharmaceutically acceptable salt thereof. RA1, RA2, RA3, RA4, RA5, RA7, X4 and n1 are as described above. [0025] In some embodiments, the ROCK2 inhibitor has the structure of Formula (A-IIIa):
Figure imgf000011_0002
(A-IIIa) or a pharmaceutically acceptable salt thereof, wherein: RA1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)- alkyl)-ORA11, -(C1-C6 alkyl)x- C(=O)RA11, -O-(C1-C6 alkyl) C6 alkyl)x1-C(=O) C(=O)ORA11, -(C1-C6 alkyl) -NRA11-(C1-C6 alkyl)
Figure imgf000012_0002
-NRA11-(C1-C6 alkyl)x1-C(=O)
Figure imgf000012_0001
RA2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1- C(=O)RA11, -O-(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)
Figure imgf000012_0003
C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; alternatively, RA1 and RA2 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O- (C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, C1-C3 perfluoro alkyl, -NRA11-(C1-C6 alkyl)NRA11RA12, and - NRA11-(C1-C6 alkyl)-ORA11; RA3 and RA4 are each independently selected from the group consisting of H, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)- x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1- alternatively
Figure imgf000012_0004
are taken together with the nitrogen to which they are attached to provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring to heteroatoms selected from N, O and S, or (ii) a 5- to 10-membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, oxo, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1- C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1-C(=O)RA11, - (C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1-C6 alkyl)x1- C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1- C(=O)ORA11; the dotted lines represent optional double bonds; each RA5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; n1 is 0 to 3; RA7 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1- C
Figure imgf000013_0001
each x1 is independently selected from 0 and 1; and each RA11 and RA12 are independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, RA11 and RA12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, - NH2, C1-C3 perfluoro alkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. [0026] In some embodiments, the ROCK2 inhibitor has the structure of Formula (A-IIIb): or a pharmaceutically acceptable salt thereof, wherein: RA1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x- C(=O)RA11, -O-(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, - C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; RA2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1- C(=O)RA11, -O-(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)
Figure imgf000014_0001
C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; alternatively, RA1 and RA2 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O- (C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, C1-C3 perfluoro alkyl, -NRA11-(C1-C6 alkyl)NRA11RA12, and - NRA11-(C1-C6 alkyl)-ORA11; RA3 and RA4 are each independently selected from the group consisting of H, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1-C(=O)NRA11RA12; alternatively RA3 and RA4 are taken together with the nitrogen to which they are attached to provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring to heteroatoms selected from N, O and S, or (ii) a 5- to 10-membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1- C6 alkyl)- alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1- (C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1-C(=O)RA11, - (C1-C6 -C(=O)-RA11, -C(=O)ORA11, -(C1-C6 alkyl)x1- C(=O) A11 A11
Figure imgf000015_0001
C6 alkyl)x1-C(=O)R , and -NR -(C1-C6 alkyl)x1- C(=O)ORA11; the dotted lines represent optional double bonds; each RA5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; n1 is 0 to 3; RA7 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1-
Figure imgf000015_0002
each x1 is independently selected from 0 and 1; and each RA11 and RA12 are independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, RA11 and RA12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, - NH2, C1-C3 perfluoro alkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. [0027] In some embodiments, RA5 is hydrogen, or n1 is 0. [0028] In some embodiments, the ROCK2 inhibitor has the structure:
Figure imgf000016_0001
, or a pharmaceutically acceptable salt thereof. [0029] The compounds of Formula (A-I) and its subordinates, as well as other disclosed ROCK2 inhibitors, may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, WO2019/000682, WO 2019/000683, WO2019/001572, WO2020/094111, WO2020/177587, WO2020/259528, WO2022/042711, WO2022/042712 and US Pat. No.10,323,023, 10,329,282 and 11,390,609, and WO2023/209692, the entire contents of which are each incorporated herein by reference. [0030] In another aspect, the ROCK2 inhibitor has the structure of Formula (B-I): or a pharmaceutically acceptable salt thereof, wherein: XB1 is N or CH; XB2 is N or CH; XB3 is N or CRB3; XB4 is N or CRB4; XB5 is selected from the group consisting of C, CH and N; a1 is selected from 1 or 2; the dotted lines represent optional double bonds; each RB1 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, oxo, -CN, C1-C3 perfluoro alkyl, -ORB11, and -NRB11RB12; or alternatively, two RB1 attached to the same carbon or to adjacent carbons are taken together to form a 3- to 6-membered ring, which may optionally contain 0 to 2 ring heteroatoms selected from O, S and N, and which may be unsubstituted or optionally substituted by 1 to 3 substituents selected from halo, C1-C3 alkyl, NH2, OH, and O-C1-C3 alkyl; b1 is selected from 0, 1, and 2; RB2 is selected from H, halo, C1-C3 alkyl, NH2, OH, and O-C1-C3 alkyl; RB3 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2- C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)-RB11, - C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and - NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; RB4 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2- C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)-RB11, - C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and - NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; alternatively, RB3 and RB4 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O- (C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, -O- (C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, and - NRB11-(C1-C6 alkyl)-ORB11; each RB5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11,
Figure imgf000018_0001
n2 is 0 to 3; RB6 and RB7 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O- (C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -O- (C1-C6 alkyl)-C(=O)NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)- C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, - C(=O)-RB11, -C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2- C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; alternatively, RB6 and RB7 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C10 aryl, C5-C10 heteroaryl, 3- to 10-membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C10 aryl), -C1-C6 alkyl- (C5-C10 heteroaryl), -C1-C6 alkyl-(3- to 10-membered heterocyclyl), halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), - NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, and -C(=O)-N(RB8)(RB9), and wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; RB8 and RB9 are each independently selected from the group consisting of H, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, and -(C1-C6 alkyl)x2-C(=O)NRB11RB12, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; alternatively RB8 and RB9 are taken together with the nitrogen to which they are attached provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10-membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoro alkyl, -ORB11, oxo, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)-RB11, -C(=O)ORB11, -(C1-C6 alkyl)x2- C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2- C(=O)ORB11; each x2 is independently selected from 0 and 1; and each RB11 and RB12 are independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, RB11 and RB12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, - NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. [0031] In some embodiments, the ROCK2 inhibitor has the structure of Formula (B-II):
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof, wherein: XB1 is N or CH; XB2 is N or CH; XB3 is N or CRB3; XB4 is N or CRB4; XB5 is selected from the group consisting of C, CH and N; the dotted lines represent optional double bonds; each RB1 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, oxo, -CN, C1-C3 perfluoro alkyl, -ORB11, and -NRB11RB12; or alternatively, two RB1 attached to the same carbon or to adjacent carbons are taken together to form a 3- to 6-membered ring, which may optionally contain 0 to 2 ring heteroatoms selected from O, S and N, and which may be unsubstituted or optionally substituted by 1 to 3 substituents selected from halo, C1-C3 alkyl, NH2, OH, and O-C1-C3 alkyl; b1 is selected from 0, 1, and 2; RB3 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2- C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)-RB11, - C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and - NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; RB4 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2- C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x22-C(=O)ORB11, -C(=O)-RB11, - C(=O)ORB11, -(C1-C6 alkyl)x22-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11-(C1-C6 alkyl)x22-C(=O)ORB11; alternatively, RB3 and RB4 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O- (C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, -O- (C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, and - NRB11-(C1-C6 alkyl)-ORB11; each RB5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)-RB11, -C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2- C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; n2 is 0 to 3; X6 is selected from the group consisting of NRB10, O and S; X7 is selected from the group consisting of CH and N; RB8 and RB9 are each independently selected from the group consisting of H, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)- 6 alkyl)x2-C(=O)ORB11, and -(C1-C6 alkyl)x2-C(=O)NRB11RB12, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; alternatively RB8 and RB9 are taken together with the nitrogen to which they are attached provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10-membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoro alkyl, -ORB11, oxo, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)-RB11, -C(=O)ORB11, -(C1-C6 alkyl)x2- C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2- C(=O)ORB11; RB10 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C10 aryl, C5-C10 heteroaryl, 3- to 10-membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C10 aryl), -C1-C6 alkyl-(C5-C10 heteroaryl), - C1-C6 alkyl-(3- to 10-membered heterocyclyl), -(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)NRB11RB12, -(C1-C6 alkyl)-ORB11, and -C(=O)-N(RB11)(RB12), and wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; each x2 is independently selected from 0 and 1; and each RB11 and RB12 are independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, RB11 and RB12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, - NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. [0032] In some embodiments, the ROCK2 inhibitor has the structure of Formula (B-III):
Figure imgf000023_0001
or a pharmaceutically acceptable salt thereof, wherein: XB2 is N or CH; XB3 is N or CRB3; XB5 is selected from the group consisting of C, CH and N; the dotted lines represent optional double bonds; each RB1 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, oxo, -CN, C1-C3 perfluoro alkyl, -ORB11, and -NRB11RB12; or alternatively, two RB1 attached to the same carbon or to adjacent carbons are taken together to form a 3- to 6-membered ring, which may optionally contain 0 to 2 ring heteroatoms selected from O, S and N, and which may be unsubstituted or optionally substituted by 1 to 3 substituents selected from halo, C1-C3 alkyl, NH2, OH, and O-C1-C3 alkyl; b1 is selected from 0, 1, and 2; RB3 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2- C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)-RB11, - C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and - NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; RB4 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2- C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)-RB11, - C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and - NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; alternatively, RB3 and RB4 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O- (C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, -O- (C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, and - NRB11-(C1-C6 alkyl)-ORB11; each RB5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)-RB11, -C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2- C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; n2 is 0 to 3; XB6 is selected from the group consisting of NRB10, O and S; XB7 is selected from the group consisting of CH and N; RB8 and RB9 are each independently selected from the group consisting of H, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)x-C(=O)RB11, -(C1-C6 alkyl)x-C(=O)ORB11, and -(C1-C6 alkyl)x- C(=O)NRB11RB12, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; alternatively RB8 and RB9 are taken together with the nitrogen to which they are attached provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10-membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoro alkyl, -ORB11, oxo, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)-RB11, -C(=O)ORB11, -(C1-C6 alkyl)x2- C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2- C(=O)ORB11; RB10 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C10 aryl, C5-C10 heteroaryl, 3- to 10-membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C10 aryl), -C1-C6 alkyl-(C5-C10 heteroaryl), - C1-C6 alkyl-(3- to 10-membered heterocyclyl), -(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)NRB11RB12, -(C1-C6 alkyl)-ORB11, and -C(=O)-N(RB11)(RB12), and wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; each x2 is independently selected from 0 and 1; and each RB11 and RB12 are independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, RB11 and RB12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, - NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. [0033] In some embodiments, the ROCK2 inhibitor has the structure of Formula (B-IV): or a pharmaceutically acceptable salt thereof, wherein: RB3 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2- C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)-RB11, - C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and - NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; RB4 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2- C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)-RB11, - C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and - NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; alternatively, RB3 and RB4 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O- (C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, -O- (C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, and - NRB11-(C1-C6 alkyl)-ORB11; XB6 is selected from the group consisting of NRB10, O and S; XB7 is selected from the group consisting of CH and N; RB8 and RB9 are each independently selected from the group consisting of H, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, and -(C1-C6 alkyl)x2-C(=O)NRB11RB12, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; alternatively RB8 and RB9 are taken together with the nitrogen to which they are attached provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10-membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoro alkyl, -ORB11, oxo, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)-RB11, -C(=O)ORB11, -(C1-C6 alkyl)x2- C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2- C(=O)ORB11; RB10 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C10 aryl, C5-C10 heteroaryl, 3- to 10-membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C10 aryl), -C1-C6 alkyl-(C5-C10 heteroaryl), - C1-C6 alkyl-(3- to 10-membered heterocyclyl), -(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)NRB11RB12, -(C1-C6 alkyl)-ORB11, and -C(=O)-N(RB11)(RB12), and wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; each x2 is independently selected from 0 and 1; and each RB11 and RB12 are independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, RB11 and RB12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, - NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. [0034] In some embodiments, the ROCK2 inhibitor has the structure of Formula (B-V):
Figure imgf000028_0001
or a pharmaceutically acceptable salt thereof, wherein: RB3 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2- C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)-RB11, - C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and - NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; RB4 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2- C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)-RB11, - C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and - NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; alternatively, RB3 and RB4 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O- (C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, -O- (C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, and - NRB11-(C1-C6 alkyl)-ORB11; RB8 and RB9 are each independently selected from the group consisting of H, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, and -(C1-C6 alkyl)x2-C(=O)NRB11RB12, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; alternatively RB8 and RB9 are taken together with the nitrogen to which they are attached provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10-membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoro alkyl, -ORB11, oxo, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)-RB11, -C(=O)ORB11, -(C1-C6 alkyl)x2- C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2- C(=O)ORB11; RB10 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C10 aryl, C5-C10 heteroaryl, 3- to 10-membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C10 aryl), -C1-C6 alkyl-(C5-C10 heteroaryl), - C1-C6 alkyl-(3- to 10-membered heterocyclyl), -(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)NRB11RB12, -(C1-C6 alkyl)-ORB11, and -C(=O)-N(RB11)(RB12), and wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; each x2 is independently selected from 0 and 1; and each RB11 and RB12 are independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, RB11 and RB12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, - NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. [0035] In some embodiments, the ROCK2 inhibitor has the structure of:
Figure imgf000030_0001
or a pharmaceutically acceptable salt thereof. [0036] Synthesis and biological assays of Formula (B-I) and its subordinates are described in WO2024/110851, the entire disclosure of which is incorporated herein by reference. [0037] In one aspect, the ROCK2 inhibitor has the structure of Formula (C-I):
Figure imgf000030_0002
or a pharmaceutically acceptable salt thereof, wherein: RC1 is selected from the group consisting of -O-
Figure imgf000030_0003
-O-(CH2)y3- C(=O)NRC13RC14, -O-(CH2)y3-heteroaryl, -O-(CH2)y3-cycloalkyl, -O-C(=O)-(CH2)y3- NRC13RC14, -O-(CH2)z3-NRC13RC14, -NH-C(=O)-(CH2 -NRC13RC14, -NH-C(=O)-X3-RC15, -NH-(CH2)y3-NRC13RC14; RC12 is selected from the group consisting of C1-C6 alkyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1- C6 alkyl)-NRC16RC17, -(C1-C6 alkyl)-
Figure imgf000030_0004
alkyl)-O- (C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; RC13 and RC14 are independently selected from the group consisting of H, C1-C8 alkyl, C2- C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-NRC16RC17, -
Figure imgf000031_0001
aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or RC13 and RC14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3- C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; X3 is selected from a covalent bond, O, NH, and C1-C6 alkyl; RC15 is selected from the group consisting of heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1- C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl, or RC15 is selected from -(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-NRC16RC17, -CO2RC18, - O-(CH2)x3-CO2RC18, and -C(=O)NRC16RC17; RC16 and RC17 are independently selected from the group consisting of H, C1-C8 alkyl, C2- C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3- C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or RC16 and RC17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; RC18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, -(C1- C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-NRC16RC17, -(C1-C6 alkyl)-O-(C1-C6 alkyl)-O- (C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1- C3 perfluoroalkyl; x3 is selected from 0 to 6; y3 is selected from 0 to 6; each RC2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each RC3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; RC4 is selected from H, -(CH2)a3-NRC43RC44, -Y-RC42, -O-(CH2)a3-CO2RC42, -O-(CH2)a3- C(=O)NRC43RC44,-O-(CH2)a3-heteroaryl, -O-(CH2)a3-cycloalkyl, -O-C(=O)-(CH2)a3- NRC43RC44, -O-(CH2)c3-NRC43RC44, -NH-C(=O)-(CH2)a-NRC43RC44, -NH-C(=O)-Y-RC45,
Figure imgf000032_0001
RC42 is selected from the group consisting of C1-C6 alkyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1- C6 alkyl)-NRC46RC47, -(C1-C6 alkyl)-
Figure imgf000032_0002
alkyl)-O- (C1-C6 alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; RC43 and RC44 are independently selected from the group consisting of H, C1-C8 alkyl, C2- C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-NRC46RC47, - (C1-C6 alkyl)-C(=O)NRC46RC47, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or RC43 and RC44 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; Y is selected from a covalent bond, O, NH, and C1-C6 alkyl; RC45 is selected from the group consisting of H, aryl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-NRC46RC47, -CO2RC48, -O-(CH2)b3-CO2RC48, and -C(=O)NRC46RC47, RC46 and RC47 independently selected from the group consisting of H, C1-C8 alkyl, C2- C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3- C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or RC46 and RC47 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; RC48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, -(C1- C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-NRC46RC47, -(C1-C6 alkyl)-O-(C1-C6 alkyl)-O- (C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1- C3 perfluoroalkyl; a3 is selected from 0 to 6; b3 is selected from 0 to 6; c3 is selected from 2 to 6; RC5 is selected from the group consisting of H, C1-C6 alkyl, -(CH2)d3-C(=O)-NRC53RC54, -
Figure imgf000033_0001
RC53 and RC54 are independently selected from the group consisting of H, C1-C8 alkyl, C2- C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-NRC56RC57, - (C1-C6 alkyl)-C(=O)NRC56RC57, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or RC53 and RC54 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3- C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; RC55 is selected from the group consisting of H, aryl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1- C6 alkyl)-NRC56RC57, -CO2RC58, -O-(CH2)e3-CO2RC58, and -C(=O)NRC56RC57, RC56 and RC57 independently selected from the group consisting of H, C1-C8 alkyl, C2- C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3- C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or RC56 and RC57 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; RC58 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, -(C1- C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-NRC56RC57, -(C1-C6 alkyl)-O-(C1-C6 alkyl)-O- (C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1- C3 perfluoroalkyl; d3 is selected from 0 to 6; e3 is selected from 0 to 6; RC6 is selected from the group consisting of H, C1-C6 alkyl, -(CH2)r3-C(=O)-NRC63RC64, -
Figure imgf000034_0001
RC63 and RC64 are independently selected from the group consisting of H, C1-C8 alkyl, C2- C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-NRC66RC67, - (C1-C6 alkyl)-C(=O)NRC66RC67, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or RC63 and RC64 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3- C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; RC65 is selected from the group consisting of H, aryl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1- C6 alkyl)-NRC66RC67, -CO2RC68, -O-(CH2)s3-CO2RC68, and -C(=O)NRC66RC67, RC66 and RC67 independently selected from the group consisting of H, C1-C8 alkyl, C2- C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3- C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or RC66 and RC67 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; RC68 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, -(C1- C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-NRC66RC67, -(C1-C6 alkyl)-O-(C1-C6 alkyl)-O- (C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1- C3 perfluoroalkyl; r3 is selected from 0 to 6; s3 is selected from 0 to 6; n3 is selected from 0 to 4; m3 is selected from 0 to 3; and p3 is selected from 0 and 1. [0038] In some embodiments, in Formula (C-I), each RC4 and RC5 is independently H or unsubstituted C1-C6 alkyl. In some embodiments, RC4 and RC5 are H. [0039] In some embodiments, the ROCK2 inhibitor has the structure of Formula (C-II):
Figure imgf000035_0001
or a pharmaceutically acceptable salt thereof. RC1, RC2, RC3, n3 and m3 are as for the compound of the formula I. [0040] In some embodiments, the ROCK2 inhibitor has the structure of Formula (C-III): or a pharmaceutically acceptable salt thereof, wherein: RC13 and RC14 are independently selected from the group consisting of H, C1-C8 alkyl, C2- C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NRC16RC17, —(C1-C6 alkyl)-C(=O)NRC16RC17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or RC13 and RC14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3- C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; RC16 and RC17 are independently selected from the group consisting of H, C1-C8 alkyl, C2- C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3- C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or RC16 and RC17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; each RC2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each RC3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; n3 is selected from 0 to 4; and m3 is selected from 0 to 3. [0041] In some embodiments, in Formula (C-III), each RC13 and RC14 is independently H or unsubstituted C1-C6 alkyl. In some embodiments, each RC13 and RC14 is independently unsubstituted C1-C6 alkyl. In some embodiments, each RC13 and RC14 is independently methyl or ethyl. In some embodiments, RC13 and RC14 are methyl. [0042] In some embodiments, the ROCK2 inhibitor has the structure of
Figure imgf000037_0001
(Compound E), or a pharmaceutically acceptable salt thereof. Compound E has the chemical name 2-(3-(4- ((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N,N-dimethylacetamide and is also known as KD025 or belumosudil. [0043] The compounds of Formula (C-I) and its subordinates, including compound E, may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, U.S. Pat. Nos.8,357,693, 9,815,820, 10,183,931, 10,696,660, and 11,311,541, the entire contents of which are incorporated herein by reference. [0044] In one aspect, the ROCK2 inhibitor has the structure of Formula (D-I):
Figure imgf000037_0002
or pharmaceutically acceptable salts thereof, wherein: RD1 is L-RD2, wherein L is a bond or -LD1-LD2-, wherein LD1 is selected from the group consisting of a bond, -(CRARB)1-3-, -O(CRARB)1-3-, - (CRARB)0-3O-, and -NRC(CRARB)1-3-; and LD2 is selected from the group consisting of a bond, -(CRARB)1-3-, -O-, -NRD-, -C(O)NRD-, - NRDC(O)-, -C(O)O-, -OC(O)-, -C(O)-, -S(O)2NRD-, -NRDS(O)2-, -S(O)2-, -S(O)(NRD)-, -NRDC(O)NRE-, -OC(O)NRD-, and -C(O)NRDS(O)2-; and RD2 is selected from the group consisting of H, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted with -ORF, C1-C6 alkyl substituted with -NRFRG, C1-4 haloalkyl substituted with -ORF, C3-8 cycloalkyl substituted with OH, C1-4 alkyl substituted with 3 to 8 membered heterocycloalkyl, C1-4 alkyl substituted with 6 membered heteroaryl, -
Figure imgf000038_0001
10 carbocyclic ring system, and 3 to 10 membered heterocyclic ring system, wherein the carbocyclic ring or heterocyclic ring system is substituted or unsubstituted with: =O, - NRFRG, -C(O)RF, halo, -CN, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkyl substituted with -ORF; RD3 is independently selected at each occurrence from the group consisting of halo, C1-4 alkyl, C1-C6 haloalkyl, -CN, -ORJ, =O, C1-4 alkyl substituted with -ORJ, -NRJRK, C1-4 alkyl substituted with -NRJRK, C3-8 cycloalkyl, C1-4 alkyl substituted with C3-8 cycloalkyl, 3 to 8 membered heterocycloalkyl and C1-4 alkyl substituted with 3 to 8 membered heterocycloalkyl; or two RD3 are optionally joined to form a phenyl or heteroaryl group may be substituted with halo or C1-4 alkyl; RD4 is selected from the group consisting of H, C1-4 alkyl, C1-4 alkyl substituted with -ORL, C1- 4 alkyl substituted with -NRLRL, C3-8 cycloalkyl, substituted or unsubstituted phenyl, 3 to 8 membered heterocycloalkyl, C1-4 alkyl substituted with C3-8 cycloalkyl, C1-4 alkyl substituted with 3 to 8 membered heterocycloalkyl and substituted or unsubstituted 5 or 6 membered heteroaryl, wherein the phenyl or heteroaryl group may be substituted with halo or C1-4 alkyl; RD5 is selected from the group consisting of H, halo, —ORJ, C1-4 alkyl, C1-6 haloalkyl, C1- 4 alkenyl, —CN, and C3-8 cycloalkyl; RD6 is selected from the group consisting of H, halo, C1-4 alkyl, C1-6 haloalkyl, —CN, and C3- 8 cycloalkyl; n4 is 0, 1, or 2; RA and RB are selected from the group consisting of H, C1-4 alkyl, or C1-4 haloalkyl or RA and RB together with the atom to which they are attached form a 3 to 6 membered cycloalkyl or a 3 to 6 membered heterocycloalkyl; RC, RD, RE, RF and RG are each independently selected from the group consisting of H, C1- 4 alkyl and C1-4 haloalkyl; RH and RI are each H except one pair of RH and RI on the same carbon atom, together with that carbon atom, form a 3 to 6 membered cycloalkyl or a 3 to 6 membered heterocycloalkyl; and RJ, RK, RL, RM, RN and RO are each independently at each occurrence selected from the group consisting of H or C1-4 alkyl. [0045] In some embodiments, the ROCK2 inhibitor has the structure of Formula (D-II):
Figure imgf000039_0001
or pharmaceutically acceptable salts thereof. [0046] In some embodiments, in Formula (D-II), RD1 is -LD1-LD2-RD2. In some embodiments, LD1 is a bond and LD2 is -NRD-, -C(O)NRD-, -NRDC(O)-, -C(O)O-. In some embodiments, RD1 is
Figure imgf000039_0002
. In some embodiments, RD2 is C1-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, or t-butyl), or C1-C6 haloalkyl (e.g., mono, di, or per- fluoro C1-C6 alkyl). [0047] In some embodiments, in Formula (D-II), RD4 is hydrogen, or C1-4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, or t-butyl). In some embodiments, RD4 is methyl. [0048] In some embodiments, in Formula (D-II), RD5 is hydrogen, halo, C1-4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, or t-butyl), C1-6 haloalkyl (e.g., mono, di, or per- fluoro C1-C6 alkyl), or C3-8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl, cyclohexyl). In some embodiments, RD5 is cyclopropyl. [0049] In some embodiments, the exemplary ROCK2 inhibitor has the structure of
Figure imgf000039_0003
, or a pharmaceutically acceptable salt thereof. This compound has the chemical name 4-(5- ((4-cyclopropyl-1H-indazol-5-yl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2- difluoroethyl)-benzamide and is also known as Zelasudil. [0050] In some embodiments, the ROCK2 inhibitor has the structure of Formula (D-IIIa) or D-IIIb):
Figure imgf000040_0001
or a pharmaceutically acceptable salt thereof. [0051] The compounds of Formula (D-I) and its subordinates, including for example Zelasudil, may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, U.S. Pat. No.11,497,751, the entire content of which is incorporated herein by reference. [0052] In one aspect, the ROCK2 inhibitor has the structure of Formula (E-Ia) or (E-Ib):
Figure imgf000041_0001
or pharmaceutically acceptable salts thereof, wherein: each RE1 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halogen, -CN, -ORE11, or -NRE11RE12; n5 is an integer of 0 to 3; each RE2 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halogen, -CN, -ORE21, or -NRE21RE22; m5 is an integer of 0 to 10; and each RE11, RE12, RE21, and RE22 is independently H and C1-C6 alkyl. [0053] In some embodiments, the ROCK2 inhibitor has the structure of Formula (E-IIa) or (E-IIb):
Figure imgf000041_0002
or pharmaceutically acceptable salts thereof. RE1 and RE2 are as described above. [0054] In some embodiments, RE1 is hydrogen or unsubstituted C1-C3 alkyl (e.g., methyl, ethyl, or propyl). In some embodiments, RE2 is hydrogen, halogen (e.g., F, Cl, or Br) or unsubstituted C1-C3 alkyl (e.g., methyl, ethyl, or propyl). In some embodiments, RE1 and RE2 are hydrogen. In some embodiments, RE1 is -F, and RE2 is methyl. In some embodiments, RE1 is methyl, and RE2 is methyl. [0055] In some embodiments, the ROCK2 inhibitor has the structure of
Figure imgf000042_0001
pharmaceutically acceptable salt thereof. [0056] The compounds of Formula (E-I) and its subordinates may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, WO2007/007737 and U.S. Pat. No.8,193,193, the entire contents of which are incorporated herein by reference. [0057] In one aspect, the ROCK2 inhibitor has the structure of Formula (F-I):
Figure imgf000042_0002
or an isomer thereof; or a pharmaceutically acceptable salt thereof, wherein: RF1 and RF2 are the same or different and each is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl, aralkyl, piperidyl or pyrrolidinyl, any of which may have a substituent on the ring, or -CR’=NR”, wherein R’ is hydrogen, alkyl, amine, heterocycloalkyl, heteroaryl, or cycloalkyl, R’ and R” are optionally joined to form a heterocycloalkyl or heteroaryl RF1 and RF2 form, together with the nitrogen atom, a heterocyclic ring which may have, in the ring, an oxygen atom, sulfur atom or optionally substituted nitrogen atom; each RF3 and RF4 is independently hydrogen or alkyl; RF5 is hydrogen, halogen, alkyl, alkoxy, aralkyl, or haloalkyl; A is a single bond or alkylene optionally substituted with C1-C3 alkyl; X is =CH- or =N-; and n6 is an integer of 0 or 8. [0058] In some embodiments, the ROCK2 inhibitor has the structure of Formula (F-II):
Figure imgf000043_0001
or an isomer or a pharmaceutically acceptable salt thereof. RF1, RF2, RF3, RF5 and n6 are described above. [0059] In some embodiments, X is =N-. [0060] In some embodiments, each RF1, RF2, RF3, and RF5 is independently hydrogen or in some embodiments, n6 is 0 or 1. [0061] In some embodiments, the ROCK2 inhibitor has the structure of
Figure imgf000043_0002
[0062] These compounds of Formula (F-I) and its subordinates may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, WO90/05723 and U.S. Pat. No.4,997,834, the entire contents of which are incorporated herein by reference. [0063] In one aspect, the ROCK2 inhibitor has the structure of (G-I),
Figure imgf000043_0003
or a pharmaceutically acceptable salt thereof, wherein: n7 is 1, 2, or 3; each RG1 and RG2 is independently hydrogen, alkyl, or acetyl; RG3 is cycloalkyl or aryl, wherein the cycloalkyl or aryl is optionally substituted with one or more of -OH, -CO2CH3, -C(O)NH2, -C(O)CH3, -NO2, -NH2, -NR6R7, carbonyl, alkyl, alkoxy, alkylalkoxy, alkoxylalkoxy, cycloalkyl, aryl, -OCXG 3, -OCHXG 2, -OCH2XG, - OSO2CH3, -tosyl, or halogen; R6 and R7 are, independently of one another, H, alkyl, -SO2CH3, -C(O)CH3, or -C(O)NH2; and XG is halogen. [0064] In some embodiments, the ROCK2 inhibitor has the structure of Formula (G-II):
Figure imgf000044_0001
or a pharmaceutically acceptable salt thereof, wherein: RG4 is -OH, -CO2CH3, -C(O)NH2, -NO2, -NH2, -NRG5RG6, alkoxy, alkylalkoxy, alkyl, - OSO2CH3, tosyl, or halogen; each RG5 and RG6 is independently hydrogen, or alkyl ; m7 is an integer of 0 to 6; and RG1, RG2, and n7 are described above. [0065] In some embodiments, RG4 is attached to the meta position on the phenyl ring. In some embodiments, m7 is 0 or 1. In some embodiments, RG4 is -OH. [0066] In some embodiments, the ROCK2 inhibitor has the structure of
Figure imgf000044_0002
, or a pharmaceutically acceptable salt thereof. [0067] The compounds of Formula (G-I) and its subordinates may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, WO2011/130740 and U.S. Pat. No.9,221,808, the entire contents of which are incorporated herein by reference. [0068] In one aspect, the ROCK2 inhibitor has the structure of Formula (H-I):
Figure imgf000044_0003
or a pharmaceutically acceptable salt thereof, wherein: RH1 is halogen, cyano, methyl, ethyl, hydroxyethyl, methoxyethyl or cyclopropyl; RH2 is hydrogen or halogen; RH3 is hydrogen, halogen, trifluoromethyl or pentafluoroethyl; and RH4 is hydrogen or halogen. [0069] In some embodiments, RH1 is hydrogen, or C1-C3 alkyl (e.g., methyl, ethyl, or propyl). In some embodiments, RH2 is halogen (e.g., F, Cl, or Br). In some embodiments, RH3 is halogen (e.g., F, Cl, or Br). In some embodiments, RH4 is halogen (e.g., F, Cl, or Br). [0070] In some embodiments, the ROCK2 inhibitor has the structure of
Figure imgf000045_0001
pharmaceutically acceptable salt thereof. [0071] These compounds of Formula (H-I) and its subordinates may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, WO2005/037197A2 and U.S. Pat. No.7,547,779, entire contents of which are incorporated herein by reference. [0072] In one aspect, the ROCK2 inhibitor has the structure of Formula (J-I):
Figure imgf000045_0002
or a pharmaceutically acceptable salt thereof, wherein: RJ1 is an aryl or heteroaryl group; each RJ2 and RJ3 is independently selected from hydrogen, or C1-C4 alkyl; each RJ4, RJ5 and RJ6 is independently selected from hydrogen, halogen, or C1-C4 alkyl; RJ7 is hydrogen, halogen, OH, -CO2CH3, -C(O)NH2, -NO2, or C1-C4 alkyl; n8 is an integer of 0 to 3; and m8 is an integer of 0 to 8. [0073] In some embodiments, the ROCK2 inhibitor has the structure of Formula (J-II), or a pharmaceutically acceptable salt thereof, wherein: RJ8 is hydrogen, halogen, OH, -CO2CH3, -C(O)NH2, -NO2, or C1-C4 alkyl; and
Figure imgf000046_0002
[0075] In some embodiments, the ROCK2 inhibitor has the structure of
Figure imgf000046_0001
, or a pharmaceutically acceptable salt thereof. [0076] These compounds of Formula (J-I) and its subordinates may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, WO2008/110846 and U.S. Pat. No.8,497,294, entire contents of which are incorporated herein by reference. [0077] In one aspect, the ROCK2 inhibitor has the structure of Formula (K-I) or a pharmaceutically acceptable salt thereof, wherein: each RK1 and RK2 is independently selected from the group consisting of hydrogen and C1- C6 alkyl; RK3 is phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of F, Cl, trifluoromethyl, and phenyl; naphthyl; and quinolinyl; RK4 is selected from the group consisting of hydrogen and methyl; RK5 is C1-C3 alkyl; RK6 is hydrogen or hydrogen; and each RK7 and RK8 is independently selected from the group consisting of hydrogen, halogen, and C1-C3 alkyl. [0078] In some embodiments, the ROCK2 inhibitor has the structure of Formula (K-II),
Figure imgf000047_0001
or a pharmaceutically acceptable salt thereof, wherein: RK3 is optionally substituted aryl or heteroaryl; RK4 is hydrogen or optionally substituted C1-C2 alkyl; RK5 is optionally substituted C1-C2 alkyl; RK6 is hydrogen or halogen; and each RK7 and RK8 is hydrogen, halogen, and optionally substituted C1-C3 alkyl. [0079] In some embodiments, RK3 is substituted phenyl. In some embodiments, RK4, RK7 and RK8 are hydrogen. In some embodiments, RK4 is substituted C1-C2 alkyl (e.g., methyl or ethyl). In some embodiments, RK6 is halogen (e.g., F, Cl, or Br). [0080] In some embodiments, the ROCK2 inhibitor has the structure of , or a pharmaceutically acceptable salt thereof. [0081] These compounds of Formula (K-I) and its subordinates may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, WO2005/082890 and U.S. Pat. No.7,592,357, the entire contents of which are incorporated herein by reference. [0082] In one aspect, the ROCK2 inhibitor has the structure of Formula (L-I)
Figure imgf000048_0001
or a pharmaceutically acceptable salt thereof, wherein: XL is a bond, C1-C6 alkylene, NH, O, S, SO or S(O)2; RL1 is hydrogen or C1-C6 alkyl; RL2 is C1-C6 alkyl, or phenyl optionally substituted; RL3 is hydrogen, C1-C6 alkyl, and C3-7 cycloalkyl or RL3 and RL4 together form a ring; and each RL4 and R5 is independently hydrogen, or C1-C6 alkyl. [0083] In some embodiments, the ROCK2 inhibitor has the structure of Formula (L-II),
pharmaceutically acceptable salt thereof. RL1 is described above. [0084] In some embodiments, the ROCK2 inhibitor has the structure of
Figure imgf000049_0001
, or a pharmaceutically acceptable salt thereof. In some embodiments, the ROCK2 inhibitor of Formula (L-II) includes a hydrochloride salt. [0085] These compounds of Formula (L-I) and its subordinates may be synthesized and assayed for ROCK2 inhibition activity in vitro as described in, for example, WO2005/037197 and U.S. Pat. No.7,547,779, the entire contents of which are incorporated herein by reference. [0086] In some embodiments, the ROCK2 antagonist is a ribonucleic acid (RNA), such as an antisense RNA. Antisense RNA (asRNA), also referred to as antisense transcript or antisense oligonucleotide, is a single stranded RNA that is complementary to a protein coding messenger RNA (mRNA) with which it hybridizes, and thereby blocks the mRNA’s translation into protein. Antisense RNA can be classified into short (less than 200 nucleotides) and long (200 or more nucleotides) non-coding RNAs (ncRNAs). The primary function of asRNA is regulating gene expression. asRNA molecules can be designed and produced synthetically and have found widespread use as research tools for gene knockdown. They also have therapeutic applications. In some embodiments, the antisense RNA targeting ROCK2 comprises one or more unnatural nucleic acids. In some embodiments, the antisense RNA is administered via injection or inhalation. In some embodiments, the antisense RNA targeting ROCK2 is selective for the ROCK2 mRNA. In some embodiments, the antisense RNA targeting ROCK2 does not bind the ROCK1 mRNA. The design and use of selective antisense RNA molecules is routine in the art. [0087] In some embodiments, the ROCK2 antagonist is RNA interference (RNAi), small inhibiting RNA (siRNA), or micro-RNA (miRNA). As used herein, an “RNAi” generally refers to any RNA molecule that induces RNA interference in a cell. Examples of RNAi include without limitation small inhibitory RNAs (siRNAs), micro RNAs (miRNAs), and small hairpin RNAs (shRNAs). RNA interference (RNAi) has been shown to be a useful tool for gene silencing in determination of gene function and may be used as a therapeutic agent to suppress genes associated with the development of a number of diseases. Gene regulation by RNAi can occur through small RNAs known as micro RNAs (miRNAs). Micro RNAs can be regulators of diverse cellular processes. The siRNA or miRNA may allow the use of the endogenous cellular RNAi machinery to direct the degradation of a target gene product (e.g., gene encoding ROCK2 and genes associated with the production or regulation of ROCK2) with the use of artificial siRNA or miRNAs. In some embodiments, the siRNA or miRNA selectively degrades a ROCK2 mRNA. In some embodiments, the siRNA or miRNA does not degrade a ROCK1 mRNA. The design and use of selective siRNA and miRNA molecules are routine in the art. [0088] A small inhibitory or interfering RNA (siRNA) may be a double-stranded RNA molecule, such as, for example, RNA having 19-25 (e.g., 19-23) base pairs in length, that induces RNA interference in a cell. A small hairpin RNA (shRNA) may be an RNA molecule, such as, for example, RNA having approximately 19-25 (e.g., 19-23) base pairs of double stranded RNA linked by a short loop (e.g., about 4-11 nucleotides) that induces RNA interference in a cell. [0089] A microRNA (miRNA) can be an RNA molecule that induces RNA interference in a cell having a short (e.g., 19-25 base pairs) sequence of double-stranded RNA linked by a loop and containing one or more additional sequences of double-stranded RNA comprising one or more bulges (e.g., mis-paired or unpaired base pairs). As used herein, the term “miRNA” encompasses endogenous miRNAs as well as exogenous or heterologous miRNAs. In some embodiments, “miRNA” may refer to a pri-miRNA or a pre-miRNA. During miRNA processing, a pri-miRNA transcript is produced. The pri-miRNA is processed by Drosha-DGCR8 to produce a pre-miRNA by excising one or more sequences to leave a pre- miRNA with a 5’-flanking region, a guide strand, a loop region, a non-guide strand, and a 3’- flanking region; or a 5’-flanking region, a non-guide strand, a loop region, a guide strand, and a 3’-flanking region. The pre-miRNA is then exported to the cytoplasm and processed by Dicer to yield a siRNA with a guide strand and a non-guide (or passenger) strand. The guide strand is then used by the RISC complex to catalyze gene silencing, e.g., by recognizing a target RNA sequence complementary to the guide strand. [0090] While the exemplary compounds of ROCK2 inhibitors which have been known to the present time are disclosed above, additional compounds shown to have ROCK2 inhibition activities can be used. [0091] Methods of determining kinase inhibition are disclosed herein. For example, kinase activity of an enzyme and the inhibitory capacity of a test compound can be determined by measuring enzyme specific phosphorylation of a substrate. Commercial assays and kits can be employed. For example, kinase inhibition can be determined using an IMAP® assay (Molecula Devices). This assay method involves the use of a fluorescently tagged peptide substrate. Phosphorylation of the tagged peptide by a kinase of interest promotes binding of the peptide to a trivalent metal-based nanoparticle via the specific, high affinity interaction between the phosphor group and the trivalent metal. Proximity to the nanoparticle results in increased fluorescence polarization. Inhibition of the kinase by a kinase inhibitor prevents phosphorylation of the substrate and thereby limits binding of the fluorescently tagged substrate to the nanoparticle. Such an assay can be compatible with a microwell assay format, allowing simultaneous determination of IC50 of multiple compounds. [0092] As disclosed above, Rho proteins are members of the small GTP-binding protein family and operate via their downstream mediators, two isoforms: Rho-associated coiled coil containing protein kinase 1 (ROCK1) and Rho-associated coiled coil containing protein kinase 2 (ROCK2). These kinases can display various cellular functions, including cell motility, proliferation, adhesion, migration, and apoptosis. Various nonspecific ROCK inhibitors have been developed, such as fasudil (approved for cerebral vasospasm treatment in 1995), and ripasudil (approved for glaucoma treatment in 2014). Lack of isoform selectivity may induce hypotension as a dose-limiting side effect due to ROCK1 inhibition. ROCK2 selective inhibitors, however, may display little or no hypotensive effects. In addition, inhibiting ROCK1 may not produce immunity enhancement due to the distribution of ROCK1 in organs and tissues. [0093] Thus, the ROCK2 selective inhibitors disclosed herein may be used in the therapy for type 1 diabetes provided herein, while causing little or no adverse health risks. Inhibitors that specifically target ROCK2 over ROCK1 are desirable for the therapies for treatment of type 1 diabetes disclosed herein. DYRK1 Inhibitors [0094] In the present disclosure, the combination therapy also includes use of DYRK1 inhibitors, and in particular DYRK1 selective inhibitors. Specifically, the DYRK1 inhibitor may be a selected inhibitor of DYRK1A, and/or selectively inhibit DYRK1A and DYRK1B. [0095] Dual-specificity tyrosine-regulated kinases (DYRKs) encompass four subtypes, 1 (e.g., 1A, 1B), 2, 3 and 4. These CMCG family protein kinases self-activate by auto- phosphorylation of a conserved tyrosine residue and subsequently phosphorylate serine and threonine residues of their respective substrates. DYRK1A and DYRK1B share 85% identity at the amino acid level, although expression and functional characteristics may differ. While DYRK1A is ubiquitously expressed, DYRK1B was found in a limited number of tissues and organs such as testis and skeletal muscle. DYRK1A participates in biochemical pathways involved in cell proliferation, neural differentiation, brain development and function, neurodegenerative diseases, tumorigenesis, and apoptosis. Additionally, DYRK1A may be involved in multiple pathways relevant to pancreatic β-cell proliferation. [0096] The DYRK1 inhibitors provide inhibitory activity of DYRK1 (i.e., DYRK1A and DYRK1B), and good selectivity, e.g., higher selectivity towards DYRK1 as compared with other isoformer (e.g., DYRK2/3/4). These compounds may also provide one or more of good physicochemical properties (e.g., solubility, physical and/or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, proper half-life and duration of action), and improved safety (low toxicity and/or less side effects, wide therapeutic window). [0097] For example, inhibitors of DYRK1 are disclosed in, for example, WO2018/119039, WO2021/064141, WO 2010/010797, WO2005/007672, WO2009/050352, WO2011/041655, WO2011037962, WO2012099066, WO2012098070, WO2012098065, WO2010/150211, GB2447791, U.S. Pat. Nos.10,577,365, 9,446,044, U.S. Pub. 2011/0021776; and U.S. Pat. Pub.2012/0184562. [0098] In one aspect, the DYRK1 inhibitor has the structure of Formula (M-I) or a tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein: each RM1, RM3, and RM4 is independently selected from the group consisting of (i) H, halogen, CN, NO2, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl; wherein each substitutable carbon atom in the aforementioned moieties is independently substituted or unsubstituted with one or more, same or different substituents RM7; (ii) C(=O)RM5, C(=O)ORM6, C(=O)SRM6, C(=O)N(RM6a)(RM6b), ORM6, S(=O)n13RM6, S(=O)n13N(RM6a)(RM6b), S(=O)n13ORM6, N(RM6a)(RM6b), N(RM6)C(=O)RM5, N(RM6)C(=O)ORM6, N(RM6)C(=O)N(RM6a)(RM6b), N(RM6)S(=O)n13RM6, N(RM6)S(=O)n13N(RM6a)(RM6b), N(RM6)S(=O)n13ORM6; (iii) a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic or bicyclic moieties is independently substituted or unsubstituted with one or more, same or different substituents R8; RM2 is selected from the group consisting of H, halogen, CN, NO2, C1-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy and C1-C6-haloalkoxy;
Figure imgf000053_0001
RM6a, RM6b are independently selected from the group consisting of H, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkylcarbonyl, wherein each substitutable carbon atom in the aforementioned moieties is independently substituted or unsubstituted with one or more, same or different substituents RM9; and a 3- to 9- membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic moieties is independently substituted or unsubstituted with one or more, same or different substituents RM10; RM7 is selected from the group consisting of halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C(=O)RM5, C(=O)ORM6, C(=O)SRM6, C(=O)N(RM6a)(RM6b), ORM6, S(=O)n13RM6, S(=O)n13N(RM6a)(RM6b), S(=O)n13ORM6, N(RM6a)(RM6b), N(RM6)C(=O)RM5, N(RM6)C(=O)ORM6, N(RM6)C(=O)N(RM6a)(RM6b), N(RM6)S(=O)n13(RM6), N(RM6)S(=O)n13N(RM6a)(RM6b), N(RM6)S(=O)n13ORM6; and a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non- oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned cyclic or bicyclic moieties is substituted or unsubstituted with one or more, same or different substituents RM8; RM8 is selected from the group consisting of halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6- alkylcarbonyl, N(RM6a)(RM6b), ORM6 and S(=O)n13RM6; RM9 is selected from the group consisting of halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6- alkylcarbonyl, N(RM11a)(RM11b), ORM11 and S(=O)n13RM11; and a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic moieties is substituted or unsubstituted with one or more, same or different substituents RM10; RM10 is selected from halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6- haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6-alkylcarbonyl, N(RM11a)(RM11b), ORM11 and S(=O)n13RM11; RM11, RM11a, RM11b are independently selected from the group consisting of H, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl; and n13 is 0, 1 or 2. [0100] In some embodiments, the DYRK1 inhibitor may be selected from FX7742 or FX8474. [0099] These compounds of Formula (M-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, U.S. Pat. No. 10,577,365, the entire content of which is incorporated herein by reference. In embodiments, the DYRK1 inhibitor is FX-1610, FX-9847, FX-8553 and FX-5372 or other compounds disclosed in U.S. Patent No.9,446,044, incorporated herein in its entirety; or the DYRK1 inhibitor is FX-7742, FX-8474 or other compound disclosed in U.S. Patent No.10,577,365, incorporated herein in its entirety. [00100] In one aspect, the DYRK1 inhibitor has the structure of Formula (N-I):
Figure imgf000055_0001
or a pharmaceutically acceptable salt thereof, wherein: XN1 is–N=, –CH= or –CF=; XN2 is–N=, –CH=, or –C(RN1)=; XN3 is –N=, or –CH=; each RN1, RN2 and RN5 is independently hydrogen or C1‒C6 alkyl which is optionally substituted with one or more halogen, -ORN6, -NRN6RN6, ‒halogen, ‒CN, ‒NO2, oxo, ‒ C(O)RN6, ‒COORN6, ‒C(O)NRN6RN6, ‒N(RN6)‒C(O)RN6, ‒N(RN6)‒C(O)‒ORN6, ‒ O‒C(O)RN6, ‒O‒C(O)‒NRN6RN6, ‒ SR N6, ‒S(O)R*, ‒S(O)2R N6, and ‒S(O)2‒NR*R*, heterocyclyl which is optionally substituted with halogen or C1-6alkyl, carbocyclyl which is optionally substituted with halogen or C1-6alkyl; RN4 is hydrogen, or C1‒C4 alkyl, C3-C6 carbocyclyl or heterocyclyl, which may be optionally substituted with halogen or C1-C6 alkyl; RN6 is independently selected from H and C1‒6 alkyl which is optionally substituted with halogen or any two RN6 are optionally joined form a heterocyclyl which is optionally substituted with halogen or C1-6alkyl; and n14 is an integer of 0 to 4. [00101] In some embodiments, the DYRK1 inhibitor has the structure of Formula (N-II):
Figure imgf000056_0001
or a pharmaceutically acceptable salt thereof. RN2, RN3, RN4, RN5 and n14 are as described above. [00102] In some embodiments, each RN2 is independently hydrogen or C1‒C4 alkyl. In some embodiments, RN4 is hydrogen or C1‒C4 alkyl. In some embodiments, RN4 is NRN6RN6, or heterocyclyl, which may be optionally substituted with halogen or C1-C6 alkyl. [00103] In some embodiments, the DYRK1 inhibitor has the structure of Formula (N-III):
Figure imgf000056_0002
or a pharmaceutically acceptable salt thereof. RN4 and RN5 are as described above. [00104] In some embodiments, the DYRK1 inhibitor has the structure of
Figure imgf000056_0003
pharmaceutically acceptable salt thereof. [00105] These compounds in Formula (N-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, WO2021/064141, the entire content of which is incorporated herein by reference. [00106] In one aspect, the DYRK1 inhibitor has the structure of Formula (O-I):
Figure imgf000057_0001
or a pharmaceutically acceptable salt thereof, wherein: RO1 is hydrogen, C1-C3 alkyl, NH2, -OH, or C3-C7 cycloalkyl; RO2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C3 perfluoro alkyl, -ORO11, -O-(C1-C6 alkyl)-ORO11, -(C1-C6 alkyl)-ORO11, -NRO11RO12, - O-(C1-C6 alkyl)-NRO11RO12, -(C1-C6 alkyl)-NRO11RO12, -NRO11-(C1-C6 alkyl)- NRO11RO12, -NRO11-(C1-C6 alkyl)-ORO11, -(C1-C6 alkyl)x15-C(=O)RO11, -O-(C1-C6 alkyl)x15-C(=O)RO11, -(C1-C6 alkyl)x15-C(=O)ORO11, -C(=O)-RO11, -C(=O)ORO11, -(C1- C6 alkyl)x15-C(=O)NRO11RO12, -NRO11-(C1-C6 alkyl)
Figure imgf000057_0002
alkyl)x15-C(=O)ORO11; each RO11 and RO12 are independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, RO11 and RO12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, - NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH; n15 is an integer of 0 to 4; and x15 is an integer of 0 to 10. [00107] In some embodiments, the DYRK1 inhibitor has the structure of Formula (O-II):
Figure imgf000057_0003
or a pharmaceutically acceptable salt thereof. RO1 and RO2 are as described above. [00108] In some embodiments, RO1 is hydrogen or C1-C6 alkyl. In some embodiments, RO2 is -OH, -ORO11, -C(=O)-RO11, or -C(=O)ORO11, and RO11 is hydrogen, or C1-C6 alkyl (e.g., methyl or ethyl). [00109] In some embodiments, the DYRK1 inhibitor has the structure of
Figure imgf000058_0001
acceptable salt thereof. [00110] These compounds of Fomrula (O-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, WO 2010/010797 and Nat. Commun., (2010) 1:861, and Nat. Commun. (2016) 7:11391, the entire contents of which are incorporated herein by reference. [00111] In one aspect, the DYRK1 inhibitor has the structure of Formula (P-I):
Figure imgf000058_0002
or a pharmaceutically acceptable salt thereof, wherein: RP1 is aryl or heteroaryl. RP2 is alkyl, aryl, -SO2RP11, or CORP11; RP3 is alkyl, aryl, or heteroaryl; and RP11 is hydrogen or C1-C4 alkyl. [00112] In some embodiments, the DYRK1 inhibitor has the structure of Formula (P-II):
Figure imgf000058_0003
or a pharmaceutically acceptable salt thereof, wherein: RP4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C3 perfluoro alkyl, -ORP11, -O-(C1-C6 alkyl)-ORP11, -(C1-C6 alkyl)-ORP11, -NRP11RP12, - O-(C1-C6 alkyl)-NRP11RP12, -(C1-C6 alkyl)-NRP11RP12, -NRP11-(C1-C6 alkyl)- NRP11RP12, -NRP11-(C1-C6 alkyl)-ORP11, -(C1-C6 alkyl)x16-C(=O)RP11, -O-(C1-C6 alkyl)x16-C(=O)RP11, -(C1-C6 alkyl)x16-C(=O)ORP11, -C(=O)-RP11, -C(=O)ORP11, -(C1- C6 alkyl)x16-C(=O)NRP11RP12, -NRP11-(C1-C6 alkyl)x16-C(=O)RB11, and -NRB11-(C1-C6 alkyl)x16-C(=O)ORO11; RP5 is hydrogen, halogen, C1-C3 alkyl, -NH2, -OH, or C3-C7 cycloalkyl; each RP11 and RP12 are independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, RP11 and RP12 are optionally joined together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl), and -(C1- C6 alkyl)-OH; n16 is an integer of 0 to 3; and x16 is an integer of 0 to 10. RP2 is as described above [00113] In some embodiments, the DYRK1 inhibitor has the structure of Formula (P-III):
Figure imgf000059_0001
or a pharmaceutically acceptable salt thereof, wherein: RP6 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C3 perfluoro alkyl, -ORP11, -O-(C1-C6 alkyl)-ORP11, -(C1-C6 alkyl)-ORP11, -NRP11RP12, - O-(C1-C6 alkyl)-NRP11RP12, -(C1-C6 alkyl)-NRP11RP12, -NRP11-(C1-C6 alkyl)- NRP11RP12, -NRP11-(C1-C6 alkyl)-ORP11, -(C1-C6 alkyl)x16-C(=O)RP11, -O-(C1-C6 alkyl)x16-C(=O)RP11, -(C1-C6 alkyl)x16-C(=O)ORP11, -C(=O)-RP11, -C(=O)ORP11, -(C1- C6 alkyl)x16-C(=O)NRP11RP12, -NRP11-(C1-C6 alkyl)x16-C(=O)RB11, and -NRB11-(C1-C6
Figure imgf000059_0002
m16 is an n16, x16 and m16 are as described above. [00114] In some embodiments, the DYRK1 inhibitor has the structure of
Figure imgf000059_0003
pharmaceutically acceptable salt thereof. [00115] These compounds of Formula (P-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, Eur. Neuropsychopharmacol. (2015) 25(11):2170-2182, the entire content of which is incorporated herein by reference. [00116] In one aspect, the DYRK1 inhibitor has the structure of Formula (Q-I):
Figure imgf000060_0001
or a pharmaceutically acceptable salt thereof, wherein: XQ1 is C or N; each Ring A and Ring B is independently substituted or unsubstituted 5 to 6 membered carbocyclic, substituted or unsubstituted 5 to 6 membered heterocyclic, substituted or unsubstituted 5 to 6 membered heteroaryl, or substituted or unsubstituted phenyl; each RQ1 is independently a hydrogen, halogen, a substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 5 membered heterocycloalkyl, aryl, alkylaryl, heterocyclic, alkylheterocyclic, -NRQ4RQ5, -ORQ4, or -CRQ4RQ5; RQ2 is -RQ4, -NRQ4RQ5, -ORQ4, -CRQ4RQ5, or -RQ4-C(O)NH2; each RQ3 is independently hydrogen, -NRQ4RQ5, -ORQ4, -C(O)ORQ4, -NHC(O)RQ4, -CRQ4RQ5, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 5 membered heterocycloalkyl, aryl, alkylaryl, heterocyclic, or alkylheterocyclic; or two of RQ3 are optionally joined to form a substituted or unsubstituted 5 to 6 membered carbocyclic, substituted or unsubstituted 5 to 6 membered heterocyclic, substituted or unsubstituted 5 to 6 membered heteroaryl, or substituted or unsubstituted phenyl; each RQ4 and RQ5 is independently hydrogen, or substituted or unsubstituted C1-C4 alkyl; and n17 is an integer of 0 to 4; and m17 is an integer of 0 to 4. [00117] In some embodiments, the DYRK1 inhibitor has the structure of Formula (Q-II):
Figure imgf000060_0002
or a pharmaceutically acceptable salt thereof. RQ1, RQ2, RQ3, n17 and m17 are as described above. [00118] In some embodiments, the DYRK1 inhibitor has the structure of Formula (Q-III):
Figure imgf000061_0001
III), or a pharmaceutically acceptable salt thereof. RQ1, RQ2, RQ3, n17 and m17 are as described above. [00119] In some embodiments, the DYRK1 inhibitor has the structure of Formula (Q-IV):
Figure imgf000061_0002
or a pharmaceutically acceptable salt thereof. RQ1, RQ2, and RQ3 are as described above. [00120] In some embodiments, the DYRK1 inhibitor has the structure of Formula (Q-V):
Figure imgf000061_0003
or a pharmaceutically acceptable salt thereof. RQ1, RQ2, RQ3, n17 and m17 are as described above. [00121] In some embodiments, the DYRK1 inhibitor has the structure of Formula (Q-VI):
Figure imgf000061_0004
or a pharmaceutically acceptable salt thereof. RQ1, RQ2, and RQ3 are as described above. [00122] In some embodiments, the DYRK1 inhibitor has the structure of Formula (Q-VII): or a pharmaceutically acceptable salt thereof. RQ1, RQ2, and RQ3 are as described above. [00123] In some embodiments, RQ1 is hydrogen, halogen, unsubstituted C1-C4 alkyl, or - ORQ4 and RQ4 is independently hydrogen, or unsubstituted C1-C4 alkyl. In some embodiments, RQ2 is hydrogen or methyl. In some embodiments, RQ3 is hydrogen, unsubstituted C1-C4 alkyl, -NRQ4RQ5, -ORQ4, or -C(O)ORQ4 and RQ4 is independently hydrogen, or unsubstituted C1-C4 alkyl. [00124] In some embodiments, the DYRK1 inhibitor has the structure of: ,
Figure imgf000062_0001
[00125] These compounds of Formula (Q-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, GB2447791, WO2005/007672, U.S. Pub.2011/0021776, and Biochem J (2007) 408 (3): 297–315, the entire contents of which are incorporated herein by reference. [00126] In one aspect, the DYRK1 inhibitor has the structure of Formula (R-I): or a pharmaceutically acceptable salt thereof, wherein: XR1 and XR2 are each independently selected from C and N, provided that at least one of XR1 and XR2 is N; RR1 is hydrogen, C1-4 alkyl, or substituted or unsubstituted C1-4 alkyl, ORR6, NRR6RR7, substituted or unsubstituted heterocyclic; RR2 is halogen, ORR6, or NRR6RR7; RR3 is hydrogen, halogen, or unsubstituted C1-4 alky; RR4 is hydrogen or halogen; RR5 is hydrogen or substituted or unsubstituted C1-4 alkyl; and each RR6 and RR7 is independently hydrogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted heterocyclic, and substituted or unsubstituted cycloalkyl. [00127] In some embodiments, the DYRK1 inhibitor has the structure of Formula (R-II):
Figure imgf000063_0001
or a pharmaceutically acceptable salt thereof. RR1, RR2, RR3, and RR5 are as described above. [00128] In some embodiments, the DYRK1 inhibitor has the structure of Formula (R-III):
Figure imgf000063_0002
or a pharmaceutically acceptable salt thereof. RR1, RR2, RR3, and RR5 are as described above. [00129] In some embodiments, RR3 is halogen (e.g., F, Cl, or Br). In some embodiments, RR1 is -ORR6 and RR6 is hydrogen or methyl. [00130] In some embodiments, the DYRK1 inhibitor has the structure of:
Figure imgf000064_0001
pharmaceutically acceptable salt thereof. [00131] These compounds of Formula (R-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, U.S. Pat. Pub. 2012/0184562 and Molecular Cancer Therapeutics 10: 2104-2114, the entire contents of which are incorporated herein by reference. [00132] In one aspect, the DYRK1 inhibitor has the structure of Formula (S-I):
Figure imgf000064_0002
or a pharmaceutically acceptable salt thereof, wherein: XS1 is O, S, NH, or a N-(C1-C3)alkyl; RS1 is a -C(=AS1)-BS1; AS1 is NH or O; BS1 is a ORS5 or a NRS5RS6; RS5 and RS6 are independently hydrogen and a substituted or unsubstituted C1-C8 alkyl; AS1 and BS1 can alternatively independently be nitrogen and/or oxygen and form, with the carbon atom to which they are bound, a heterocycloalkyl; RS2is a hydrogen or an unsubstituted C1-C8 alkyl; RS3 is a substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; RS4 is a hydrogen, halogen, amino, cyano, or substituted or unsubstituted C1-C5 alkyl; each RS7 and RS8 is independently a hydrogen, halogen, hydroxyl, or a substituted or unsubstituted C1-C5 alkyl. [00133] In some embodiments, the DYRK1 inhibitor has the structure of Formula (S-II): pharmaceutically acce S1 S2
Figure imgf000065_0001
ptable salt thereof. R , R , RS3, RS4, RS7, and RS8 are as described above. [00134] In some embodiments, AS1 is NH and BS1 is a ORS5 or NRS5RS6. In some embodiments, AS1 is NH and BS1 is a OCH3. In some embodiments, AS1 is O and BS1 is NH2. [00135] In some embodiments, the DYRK1 inhibitor has the structure of Formula (S-III):
Figure imgf000065_0002
or a pharmaceutically acceptable salt thereof, wherein: each RS9 is independently hydrogen, halogen, ORS5, NRS5RS6, cyano, or substituted or unsubstituted C1-C5 alkyl; and n19 is an integer of 0 to 5. RS5, RS7, and RS8 are as described above. [00136] In some embodiments, n19 is 1 or 2. In some embodiments, RS9 is hydrogen, halogen, ORS5, or NRS5RS6. [00137] In some embodiments, the DYRK1 inhibitor has the structure of Formula (S-IV): or a pharmaceutically acceptable salt thereof. RS5, RS7, RS8 and RS9 are as described above. [00138] In some embodiments, the DYRK1 inhibitor has the structure of:
Figure imgf000066_0001
pharmaceutically acceptable salt thereof. [00139] These compounds of Formula (S-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, U.S. Pat. No. 9,446,044, the entire content of which is incorporated herein by reference. [00140] In one aspect, the DYRK1 inhibitor has the structure of Formula (T-I):
Figure imgf000066_0002
or a pharmaceutically acceptable salt thereof, wherein: RT1 is a hydrogen, halogen, amino, cyano or a substituted or unsubstituted C1-C6 alkyl; Each RT2 and RT3 is independently hydrogen, halogen, ORS5, NRS5RS6, cyano, or substituted or unsubstituted C1-C5 alkyl; RT4 is hydrogen, halogen, ORS5, NRS5RS6, cyano, NO2, or substituted or unsubstituted C1-C5 alkyl; RS5 and RS6 are independently chosen from a hydrogen atom and a substituted or unsubstituted C1-C8 alkyl; n20 is an integer of 0 to 5; and m20 is an integer of 0 to 4. [00141] In some embodiments, RT4 is a -NO2. [00142] In some embodiments, the DYRK1 inhibitor has the structure of Formula (T-II): pharmaceutically acceptabl T2 T3
Figure imgf000067_0001
e salt thereof. R and R are as described above. [00143] In some embodiments, the DYRK1 inhibitor has the structure of:
Figure imgf000067_0002
pharmaceutically acceptable salt thereof. [00144] These compounds of Formula (T-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro according to methods known in the art. [00145] In one aspect, the DYRK1 inhibitor has the structure of Formula (U-I)
Figure imgf000067_0003
or a pharmaceutically acceptable salt thereof, wherein: RU1 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C6 carbocyclic, substituted or unsubstituted 5 to 6 membered heterocyclic, substituted or unsubstituted 5 to 6 membered heteroaryl, or substituted or unsubstituted phenyl; RU2 is a hydrogen, halogen, ORU3, NRU3RU4, cyano, NO2, or substituted or unsubstituted C1- C4 alkyl; each RU3 and RU4 is independently a hydrogen and substituted or unsubstituted C1-C4 alkyl; LU1 is -C(O)NH- or -NHC(O)-; LU2 is a bond, substituted or unsubstituted C1-C4 alkylene, or substituted or unsubstituted 2 to 5 membered heteroalkylene; and n21 is an integer of 0 to 4. [00146] In some embodiments, the DYRK1 inhibitor has the structure of Formula (U-II)
Figure imgf000068_0001
or a pharmaceutically acceptable salt thereof. LU2, RU1 and RU2 are as described above. [00147] In some embodiments, the DYRK1 inhibitor has the structure of Formula (U-III)
Figure imgf000068_0002
or a pharmaceutically acceptable salt thereof. LU2, RU1 and RU2 are as described above. [00148] In some embodiments, the DYRK1 inhibitor has the structure of:
Figure imgf000068_0003
pharmaceutically acceptable salt thereof. [00149] These compounds of Formula (U-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, ACS Chem Neurosci.2021 Nov 17;12(22):4302-4318, the entire content of which is incorporated herein by reference. [00150] In one aspect, the DYRK1 inhibitor has the structure of Formula (V-I): or a pharmaceutically acceptable salt thereof, wherein: RV1 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C6 carbocyclic, substituted or unsubstituted 5 to 6 membered heterocyclic, substituted or unsubstituted 5 to 6 membered heteroaryl, or substituted or unsubstituted phenyl. [00151] In some embodiments, the DYRK1 inhibitor has the structure of:
Figure imgf000069_0001
pharmaceutically acceptable salt thereof. [00152] These compounds of Formula (V-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, WO2009/050352, and J. Med. Chem.201154, 4172, the entire contents of which are incorporated herein by reference. [00153] In one aspect, the DYRK1 inhibitor has the structure of Formula (W-I):
Figure imgf000069_0002
or a pharmaceutically acceptable salt thereof, wherein: RW1 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C6 carbocyclic, substituted or unsubstituted 5 to 6 membered heterocyclic, substituted or unsubstituted 5 to 6 membered heteroaryl, or substituted or unsubstituted phenyl; each RW2 and RW3 is independently a hydrogen, or substituted or unsubstituted C1-C4 alkyl; RW4 is independently a hydrogen, halogen, or substituted or unsubstituted C1-C4 alkyl; and n23 is an integer of 0 to 3. [00154] In some embodiments, the DYRK1 inhibitor has the structure of Formula (W-II): phar W1
Figure imgf000070_0001
maceutically acceptable salt thereof. R is as described above. [00155] In some embodiments, the DYRK1 inhibitor has the structure of:
Figure imgf000070_0002
[00156] These compounds of Formula (W-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, WO2011/041655, BMCL, (2009) 19, 6700 and BMCL, (2011) 21, 3152, the entire contents of which are incorporated herein by reference. [00157] In one aspect, the DYRK1 inhibitor has the structure of Formula (X-I):
Figure imgf000070_0003
or a pharmaceutically acceptable salt thereof, wherein: each RX1 and RX2 is a hydrogen, halogen, ORX3, NRX3RX4, cyano, or substituted or unsubstituted C1-C4 alkyl; each RX3 and RX4 is independently a hydrogen and substituted or unsubstituted C1-C4 alkyl; n24 is an integer of 0 to 5; and m24 is an integer of 0 to 5. [00158] In some embodiments, the DYRK1 inhibitor has the structure of Formula (X-II): pharmaceutically acceptable salt thereof. RX2 is described above. [00159] In some embodiments, the DYRK1 inhibitor has the structure of:
Figure imgf000071_0001
pharmaceutically acceptable salt thereof. [00160] These compounds of Formula (X-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, BMCL, (2006) 16, 3772 and BMCL, (2009) 19, 2324, the entire contents of which are incorporated herein by reference. [00161] In one aspect, the DYRK1 inhibitor has the structure of Formula (Y-I):
Figure imgf000071_0002
or a pharmaceutically acceptable salt thereof, wherein: XY1 is S or O; each RY1 and RY2 is a hydrogen, halogen, ORY3, NRY3RY4, cyano, or substituted or unsubstituted C1-C4 alkyl; each RY3 and RY4 is independently a hydrogen and substituted or unsubstituted C1-C4 alkyl; n25 is an integer of 0 to 5; and m25 is an integer of 0 to 5. [00162] In some embodiments, the DYRK1 inhibitor has the structure of Formula (Y-II): , or a pharmaceutically acceptable salt thereof. RY1 and RY2 are as described above. [00163] In some embodiments, the DYRK1 inhibitor has the structure of
Figure imgf000072_0001
pharmaceutically acceptable salt thereof. [00164] These compounds of Formula (Y-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, WO2011/037962, the entire content of which is incorporated herein by reference. [00165] In one aspect, the DYRK1 inhibitor has the structure of Formula (Z-I):
Figure imgf000072_0002
or a pharmaceutically acceptable salt thereof, wherein: Z1 is CRZ5 or N; Z2 is C or N; RZ1 is substituted or unsubstituted 5 to 6 membered heteroaryl, or substituted or unsubstituted phenyl; each RZ2 is a hydrogen, halogen, ORZ3, NRZ3RZ4, cyano, or substituted or unsubstituted C1-C4 alkyl; each RZ3 and RZ4 is independently a hydrogen and substituted or unsubstituted C1-C4 alkyl; RZ5 is a hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; n26 is an integer of 0 to 5; and m26 is an integer of 0 to 4. [00166] In some embodiments, Z1 is CRZ5. [00167] In some embodiments, the DYRK1 inhibitor has the structure of Formula (Z-II):
Figure imgf000073_0001
pharmaceutically acceptable salt thereof. RZ1, RZ2, RZ3, RZ5, and n26 are described above. [00168] In some embodiments, the DYRK1 inhibitor has the structure of Formula (Z-III):
Figure imgf000073_0002
pharmaceutically acceptable salt thereof. RZ1, RZ2, RZ3, RZ5, and n26 are described above. [00169] In some embodiments, the DYRK1 inhibitor has the structure of Formula (Z-IV):
Figure imgf000073_0003
pharmaceutically acceptable salt thereof. RZ1, RZ2, RZ3, and n26 are described above. [00170] In some embodiments, the DYRK1 inhibitor has the structure of:
Figure imgf000074_0001
Figure imgf000074_0002
pharmaceutically acceptable salts thereof. [00171] These compounds of Formula (Z-I) and its subordinates may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, WO2012/099066, WO2012/098070, and WO2012/098065, the entire contents of which are incorporated herein by reference. [00172] In one aspect, the DYRK1 inhibitor has the following structure:
Figure imgf000074_0003
pharmaceutically acceptable salts thereof, wherein: Ring X and Z are independently substituted or unsubstituted heteroaryl containing one or more nitrogens, or substituted or unsubstituted phenyl; Ring Y is a heteroaryl containing one or more nitrogens; and L is a linker or a bond. [00173] In some embodiments, L is a bond. In some embodiments, L is substituted or unsubstituted C1-C4 alkylene or alkenylene. [00174] In some embodiments, the DYRK1 inhibitor has the following structure: acceptable salts thereof. These compounds may be synthesized and assayed for DYRK1 inhibition activity in vitro and in vivo as described in, for example, J. Med. Chem. (2021) 64, 15, 11709–11728, Bioorg Med Chem. (2020) Jan 1; 28(1): 115193, J. Med. Chem. (2011) 54, 4474, and WO2010/150211, the entire contents of which are incorporated herein by reference. [00175] In one aspect, the DYRK1 inhibitor has the following structure:
Figure imgf000075_0001
pharmaceutically acceptable salts thereof, wherein: Ring X’ is substituted or unsubstituted heteroaryl containing one or more nitrogens, or substituted or unsubstituted phenyl; and Ring Y’ is a heteroaryl containing nitrogen or sulfur; Ring Z’ is substituted or unsubstituted heteroaryl containing nitrogen or sulfur; and L’ is a linker or a bond. [00176] In some embodiments, the DYRK1 inhibitor has the following structure: , , or a pharmaceutically acceptable salt thereof. [00177] These compounds may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, Eur J Med Chem.2022 Feb 5;229:114054, the entire content of which is incorporated herein by reference. [00178] In one aspect, the DYRK1 inhibitors include Haspin-inhibitors having the following structures:
Figure imgf000076_0001
, , or a pharmaceutically acceptable salt thereof. [00179] These compounds may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, Eur J Med Chem.2022 Jun 5;236:114369, the entire content of which is incorporated herein by reference. [00180] In one aspect, the DYRK1 inhibitor has the following structure:
Figure imgf000076_0002
pharmaceutically acceptable salt thereof. [00181] These compounds may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, Biochem J (2008) 415 (3): 353–365, the entire content of which is incorporated herein by reference. [00182] In one aspect, the DYRK1 inhibitor has the following structure: , , or pharmaceutically acceptable salts thereof. [00183] These compounds may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, Biochem J (2003) 371 (1): 199–204, the entire content of which is incorporated herein by reference. [00184] In one aspect, the DYRK1 inhibitor is a macrocyclic compound, for example, having the following structure,
Figure imgf000077_0001
but examples of the DYRK1 inhibitor macrocyclic compounds are not limited thereto. [00185] These compounds may be synthesized and assayed for DYRK1 inhibition activity in vitro as described in, for example, ACS Med Chem Lett.2022 Mar 8;13(4):577-585, the entire content of which is incorporated herein by reference. [00186] While the exemplary compounds of DYRK1 inhibitors which have been known to the present time are disclosed above, additional compounds shown to have DYRK1 inhibition activities can be used without limitation in the combinations described herein. [00187] In some embodiments, the DYRK1 inhibitor is an RNA, such as an antisense RNA. Antisense RNA (asRNA), also referred to as antisense transcript or antisense oligonucleotide, is a single stranded RNA that is complementary to a protein coding messenger RNA (mRNA) with which it hybridizes, and thereby blocks the mRNA’s translation into protein. The antisense RNA can be short (less than 200 nucleotides) or long (200 or more nucleotides) non-coding RNAs (ncRNAs). [00188] In some embodiments, the DYRK1 inhibitor is RNA interference (RNAi), small inhibiting RNA (siRNA), or micro-RNA (miRNA). A small inhibitory or interfering RNA (siRNA) may be a double-stranded RNA molecule, such as, for example, RNA having 19-25 (e.g., 19-23) base pairs in length, that induces RNA interference in a cell. A small hairpin RNA (shRNA) may be an RNA molecule, such as, for example, RNA having approximately 19-25 (e.g., 19-23) base pairs of double stranded RNA linked by a short loop (e.g., about 4-11 nucleotides) that induces RNA interference in a cell. A microRNA (miRNA) can be an RNA molecule that induces RNA interference in a cell having a short (e.g., 19-25 base pairs) sequence of double-stranded RNA linked by a loop and containing one or more additional sequences of double-stranded RNA comprising one or more bulges (e.g., mis-paired or unpaired base pairs). As used herein, the term “miRNA” encompasses endogenous miRNAs as well as exogenous or heterologous miRNAs. [00189] The inhibition of DYRK1 may be evaluated using an enzyme assay for inhibitory activity. Definition [00190] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen (N), oxygen (O), and sulfur (S). [00191] The term "halogen" or "halo" designates -F, -Cl, -Br or –I. Preferred halo gens are -F, -Cl and -Br. [00192] The term "hydroxyl" means -OH. [00193] The term “oxo” as used herein refers to an oxygen atom that has a double bond to another atom (i.e., the substituent =O), particularly to carbon. [00194] The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups and branched-chain alkyl groups. Accordingly, C1-C6 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, and the like. [00195] The term “cycloalkyl” refers to saturated, carbocyclic groups having from 3 to 7 carbons in the ring. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. [00196] The term “alkenyl” refers to a linear or branched hydrocarbyl having a double bond and 2-6 carbon atoms (“C2-C6 alkenyl”). The alkenyl includes vinyl, 1-propenyl, 2- propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like. When the compound of the present disclosure contains an alkenyl group, the compound may exist as the E-form, the Z-form, or any mixture thereof. [00197] The term “alkynyl” refers to a linear or branched hydrocarbyl having a triple bond and 2-6 carbon atoms (“C2-C6 alkynyl). The alkynyl includes ethynyl, propynyl, and the like. [00198] The term "aryl" as used herein includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", "heteroaromatics" or "heteroaryl". The term “aryl” also includes 7- to 14-membered polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic (including heteroaryl), e.g., the other cyclic rings can be fused cycloalkyls, cycloalkenyls, aryls, heteroaryl and/or heterocyclic groups. Single-ring heteroaryl groups may have from 1 to 3 ring heteroatoms and fused polycyclic heteroaryl groups may have from 1 to 5 ring heteroatoms, wherein the ring heteroatoms are selected from N, O and S. [00199] The terms "heterocyclyl," "heterocyclic” or “heterocycloalkyl” group refer to 3- to 10-membered ring structures, more preferably 5- or 6-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles. Heterocyclic groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. [00200] The term “alkylaryl,” “aralkyl”, as used herein, refers to a C1-C6 alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group). [00201] As used herein, the definition of each expression, e.g. alkyl, m, n, R, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. [00202] It will be understood that "substituted", "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. [00203] The term "pharmaceutically-acceptable salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds disclosed herein and inorganic and organic basic addition salts of the compounds disclosed herein. It is understood that the reference to a ROCK2 inhibitor or to a DYRK1 inhibitor includes the neutral compound and any pharmaceutically acceptable salt for of the ROCK2 inhibitor or the DYRK1 inhibitor. The pharmaceutically acceptable salt forms which may be selected on the basis of a chosen route of administration and according to standard pharmaceutical practice. [00204] As set out above, certain embodiments of the ROCK2 and/or DYRK1 inhibitors may contain a basic functional group, such as amino, and are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.66:1-19). [00205] The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non- toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like. [00206] In other cases, the compounds provided in this disclosure may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra). [00207] Certain compounds provided in this disclosure may exist in particular geometric or stereoisomeric forms. The disclosure contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included in this invention. [00208] As defined herein, the term “inhibition”, “inhibit”, “inhibiting” and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In embodiments inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments inhibition refers to reduction of a disease or symptoms of disease. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g., an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation). The term “inhibitor” may include synthetic or biological molecule (e.g., small molecule, nucleic acid, peptide or antibody) inhibiting or negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. Preferred inhibitor is a small molecule. The inhibitor can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the inhibitor or antagonist. In certain instances, activity is 1.5-fold, 2-fold, 3- fold, 4-fold, 5 -fold, 10-fold or lower than the expression or activity in the absence of the inhibitor. Combination therapy [00209] The combination therapy comprising a ROCK2 inhibitor and a DYRK1 inhibitor may be used in the treatment of type I diabetes in a subject. The combination therapy may restore the population of the patient’s beta cells, thereby allowing the patient’s own population of beta cells to control blood sugar levels, and reducing or eliminating the patient’s reliance on exogenous insulin for the control of blood sugar. [00210] The present disclosure provides a method for the treatment of type 1 diabetes in a subject, the method comprising administering to the subject a combination therapy providing a therapeutically effective amount of an inhibitor of ROCK2 and a therapeutically effective amount of an inhibitor of DYRK1. The ROCK2 inhibitor(s) may include one or more compounds having the formulae (A-I), (B-I), (C-I), (D-I), (E-I), (F-I), (G-I), (H-I), (J-I), (K- I), (L-I) and their subordinates, exemplary compounds thereof, or derivatives thereof which may be obtained or known by one of ordinary skill in the art. The DYRK1 inhibitor(s) may include one or compounds having the formulae (M-I), (N-I), (O-I), (P-I), (Q-I), (R-I), (S-I), (T-I), (U-I), (V-I), (W-I), (X-I), (Y-I), (Z-I) and their subordinates, exemplary compounds thereof, or derivatives thereof which may be obtained or known by one of ordinary skill in the art. [00211] In an aspect, the present disclosure provides a method of restoring a population of pancreatic beta-cells in a subject suffering from type 1 diabetes, the method comprising administering to the subject a therapeutically effective amount of a ROCK2 inhibitor and a therapeutically effective amount of a DYRK1 inhibitor. The combination therapy disclosed herein comprises a therapeutically effective amount of a ROCK2 inhibitor and a therapeutically effective amount of a DYRK1 inhibitor to promote the re-growth of beta cells and also promotes the maintenance of the beta cells by inhibiting further autoimmune destruction of the patient’s beta cells. [00212] In another aspect, the present disclosure provides a method of promoting regrowth of pancreatic beta cells in a subject suffering from type 1 diabetes, the method comprising administering to the subject a therapeutically effective amount of a ROCK2 inhibitor and a therapeutically effective amount of a DYRK1 inhibitor. [00213] The ROCK2 and DYRK1 inhibitors for treating type 1 diabetes in the subject may be co-administered. The “co-administration” is meant to include simultaneous or sequential administration of the ROCK2 inhibitor and the DYRK1 inhibitor. The ROCK2 inhibitor and the DYRK1 inhibitor may be administered to the patient as separate dosage forms, i.e., the combination therapy comprises the administration of a dosage form comprising the ROCK2 inhibitor and a dosage form comprising the DYRK1 inhibitor. Alternatively, the ROCK2 inhibitor and the DYRK1 inhibitor may be administered to the patient in a combination formulation, e.g., the dosage form comprises both the ROCK2 inhibitor and the DYRK1 inhibitor. Further, the ROCK2 inhibitor and DYRK1 inhibitor may be administered at the same time, or at separate times. [00214] In some embodiments, the ROCK2 inhibitor and the DYRK1 inhibitor are co- administered. As used herein, the phrase “co-administration” refers to any form of administration of the therapeutic formulations of the ROCK2 inhibitor and the DYRK1 inhibitor such that one of the formulations is administered while the other therapeutic formulation is still effective in the body. Accordingly, the ROCK2 inhibitor and the DYRK1 inhibitor are simultaneously effective in the patient, which may include synergistic effects of the two agents. Thus, the patient who receives such treatment can benefit from a combined effect or synergetic effect of the ROCK2 inhibitor and the DYRK1 inhibitor. Particularly, the combination treatment may result in improved outcomes, such as reduction of severity, delay or elimination of recurrence, or reduced side effects of a primary agent with pre-treatment with the secondary agent. [00215] In some embodiments, the efficacy or therapeutic effects of the DYRK1 inhibitors may be improved by at least about 10 %, 20%, 25%, 30%, 40%, 50%, 60 %, 70%, 80%, 90%, or greater in the combination treatment with the ROCK2 inhibitors when compared to the same treatment with the DYKR1 inhibitors as a single agent, as determined, for example, in glucose tolerance or by measuring blood glucose. In some embodiments, the production of pancreatic insulin producing cells may be increased by at least about 10 %, 20%, 25%, 30%, 40%, 50%, 60 %, 70%, 80%, 90%, or greater in the combination treatment with the ROCK2 inhibitor when compared to the same treatment with the DYKR1 inhibitor as a single agent, as determined, for example, in glucose tolerance or by measuring blood glucose. In some embodiments, the production of pancreatic insulin producing cells may be increased by at least about 10 %, 20%, 25%, 30%, 40%, 50%, 60 %, 70%, 80%, 90%, or greater in the combination treatment with the ROCK2 inhibitor when compared to the same treatment with the DYKR1 inhibitor as a single agent, as determined, for example, by pancreatic β-cell proliferation in the patient. [00216] In some embodiments, the combination therapies using the ROCK2 inhibitor and the DYRK1 inhibitor and methods of co-administrating may also allow reduction in doses and/or frequency of administration of the primary therapeutic agents (i.e. DYRK1) to achieve the same therapeutic effects and/or improvements in comparison to using a single primary agent (i.e. DYRK1) or other existing single treatment. [00217] The administration routes and regimen of the disclosed combination may well vary depending on the condition prior to or after the treatment, extent of progression in insulin production, age and physical condition of the subject, exact combination selected, and other factors. Administration regimen may include multiple doses per period of time, the treatments administered simultaneously or sequentially. When two therapeutic agents are administered sequentially, a first therapeutic agent may be administered 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours before administering a second therapeutic agent. [00218] In some embodiments, the combination therapy includes administering the ROCK2 inhibitor (e.g., suppressing autoimmune using the ROCK2 inhibitors) prior to administering the DYRK1 inhibitor (e.g., promoting pancreatic beta cells using the DYRK1 inhibitors). For example, the therapeutic agent including the ROCK2 inhibitor for autoimmune suppression may be administered 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, or 96 hours before administering the DYRK1 inhibitor. The therapeutic agent including the ROCK2 inhibitor may be administered at the same time (simultaneously) as the therapeutic agent including the DYRK1 inhibitor. In some embodiments, the therapeutic agent including the ROCK2 inhibitor may be additionally administered 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours after administering the therapeutic agent including the DYRK1 inhibitor. [00219] The ROCK2 inhibitor described herein may preferably include a compound having a structure of formular (A-I), (B-I), (C-I), (D-I), (E-I), (F-I), (G-I), (H-I), (J-I), (K-I), (L-I), their subordinates, or exemplary compounds thereof. The ROCK2 inhibitor may be selected from Compound A, Compound B, Compound C, Compound D, belumosudil (KD025), Zelasudil, Y-27632, fasudil, GSK429286A, RKI-1447, TC-S 7001, TC-S 7004, hydroxyfasudil, GSK269962A, ripasudil, AT13148, RX007, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof, but the examples of the ROCK2 inhibitors are not limited thereto. [00220] The DYRK1 inhibitor described herein may preferably include a compound having a structure of formular (M-I), (N-I), (O-I), (P-I), (Q-I), (R-I), (S-I), (T-I), (U-I), (V-I), (W-I), (X-I), (Y-I), (Z-I) and their subordinates, or exemplary compounds thereof. The DYRK1 inhibitor may be selected from is FX-1610, FX-9847, FX-8553, FX-5372, AZ191, paprotrain, harmine, GNF4877, GNF2133, INDY, FINDY, EHT1610, EHT 5372, AZ-Dyrk1B-33, KH- CB20, ARN25068, haspin, JH-XVII-10, leucettine L41, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof, but the examples of the DYRK1 inhibitors are not limited thereto. [00221] In some embodiments, the ROCK2 inhibitor and the DYRK1 inhibitor are formulated in a single composition. Alternatively, the ROCK2 inhibitor and the DYRK1 inhibitor are prepared separately and/or formulated in separate compositions. ROCK2 Inhibitor for the prevention of type 1 diabetes [00222] Also provided are methods of preventing the progression of type 1 diabetes in a subject, comprising administering to the subject a therapeutically effective amount of a ROCK2 inhibitor. This method prevents or delays the progression to clinical type 1 diabetes before irremediable beta cell destruction and insulin deficiency occur in the patient. In one embodiment, this disclosure provides a method of preventing or delaying the onset of type 1 diabetes in a patient that has been diagnosed to have a high risk of developing type 1 diabetes, and/or that is diagnosed to be experiencing the symptoms of the onset, or progression towards, type 1 diabetes, wherein the method comprises administering a therapeutically effective amount of a ROCK 2 inhibitor. [00223] Changes in beta cell function may precede the clinical diagnosis of type 1 diabetes in individuals who are identified as at-risk for the disease based on the presence, for example, of islet autoantibodies. Patient may experience an ongoing and/or intermittently progressive decline in beta cell function, that may begin years before clinical diagnosis of type 1 diabetes, and at a time when glucose tolerance is still normal. During this period there may be signs of ongoing autoimmunity. For example, patients with two or more islet autoantibodies may be classified in stages disease progression towards type 1 diabetes, with further specification according to the level of metabolic dysfunction: stage 1 prior to glucose abnormalities, stage 2 with dysglycemia during an oral glucose tolerance test (OGTT), and stage 3 at clinical presentation with hyperglycemia. During this period, an inhibitor of ROCK2 may be administered to the patient, thereby inhibiting further autoimmune destruction of the patient’s beta cells, and preventing or delaying the progression to type 1 diabetes. In patients where the decline in beta cell function is advanced, a DYRK1 inhibitor may be administered for a period of time in addition to the ROCK 2 inhibitor to restore the population and function of the patient’s beta cells. [00224] The patient may be one that has been recognized or diagnosed to have a high risk of developing type 1 diabetes, and/or that is recognized or diagnosed to be experiencing the symptoms of the onset, or progression towards, type 1 diabetes (i.e., prediabetes). The patient may have one or more of the following: a relative with type 1 diabetes, blood tests suggesting the patient may develop type 1 diabetes, and/or one or more symptoms associated with the development of type 1 diabetes. [00225] Blood tests may include assays for the patient’s blood sugar level, such as a glycated hemoglobin (A1C) test, a random blood sugar test, or a fasted blood sugar test. An A1C between about 5.7 and 6.4% may indicate pre-diabetes. In random blood sugar tests, a blood sample is taken at a random time, with a random blood sugar level of about 200 mg/dL (11.1 mmol/L) or higher suggesting the onset of diabetes. For a fasting blood sugar test, a fasting blood sugar level from about 100 to 125 mg/dL (5.6 to 6.9 mmol/L) may indicate pre- diabetes, and a fasting blood sugar level of about 126 mg/dL (7 mmol/L) or higher on two separate tests may indicate more advanced disease progression or diabetes. [00226] Alternatively or additionally, the blood test(s) may include assays for one or more antibodies that are associated with the development of type 1 diabetes. The antibodies may include one or more of islet cell cytoplasmic autoantibodies (ICA), glutamic acid decarboxylase autoantibodies (GADA), insulinoma-associated-2 autoantibodies (IA-2A), and insulin autoantibodies (IAA). [00227] Additionally or alternatively, the patient may be experiencing the symptoms of the onset, or progression towards, type 1 diabetes may have one or more of the following symptoms: frequent urination, extreme thirst, dry mouth, itchy skin, fatigue, weakness, increased appetite, increased hunger, unexplained weight loss, slow-healing cuts, yeast infections. [00228] The present disclosure provides a method for preventing or delaying the onset of type 1 diabetes in a subject, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of ROCK2. The ROCK2 inhibitor(s) may include one or more compounds having the formulae (A-I), (B-I), (C-I), (D-I), (E-I), (F-I), (G-I), (H-I), (J-I), (K-I), (L-I) and their subordinates, exemplary compounds thereof, or derivatives thereof which may be obtained or known by one of ordinary skill in the art. The ROCK2 inhibitor may be selected from Compound A, Compound B, Compound C, Compound D, belumosudil (KD025), Zelasudil, Y-27632, fasudil, GSK429286A, RKI-1447, TC-S 7001, TC-S 7004, hydroxyfasudil, GSK269962A, ripasudil, AT13148, RX007, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof. Pharmaceutical Compositions [00229] In one aspect, the present disclosure provides pharmaceutically acceptable compositions for use in the treatment of type 1 diabetes which comprise a therapeutically effective amount of a ROCK2 inhibitor and a therapeutically effective amount of a DYRK1 inhibitor, each formulated with one or more pharmaceutically acceptable carriers. As described below, the pharmaceutical compositions of the present disclosure may be formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginal or intrarectal administration, for example, as a suppository, pessary, cream or foam; (5) sublingual administration; (6) ocular administration; (7) transdermal administration; or (8) nasal administration. [00230] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals with toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio. [00231] The phrase “pharmaceutically-acceptable carrier” as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), solvent, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier should be compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18)Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. [00232] The compounds of this disclosure may be formulated with conventional carriers and excipients, which can be selected in accord with ordinary practice. Tablets can contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally can be isotonic. All formulations can optionally contain excipients such as those set forth in the “Handbook of Pharmaceutical Excipients” (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. [00233] While it is possible for the ROCK2 inhibitors and/or DYRK1 inhibitors disclosed herein (herein referred to as the “active ingredients”) to be administered alone, it may be preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the disclosure comprise at least one active ingredient, as provided above, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients, particularly those additional therapeutic ingredients as discussed herein. [00234] Pharmaceutical compositions may include compositions wherein the active ingredient (e.g. compounds or combinations described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application may depend, inter alia, on the condition being treated. When administered in methods to treat a disease (e.g., type 1 diabetes), such compositions may contain an amount of active ingredient effective to achieve the desired result, e.g., modulating the activity of a target molecule, and/or reducing, eliminating, or slowing the progression of disease symptoms (e.g., increased insulin secretion in pancreas or regrowth of insulin producing cells). [00235] The formulations include those suitable for the administration routes provided herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. [00236] Formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste. [00237] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom. [00238] When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. [00239] If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs. [00240] The oily phase of the emulsions of this disclosure may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so- called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. [00241] Emulsifying agents and emulsion stabilizers suitable for use in the formulation of the disclosure include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate. Further emulsifying agents and emulsion stabilizers suitable for use in the formulation of the disclosure include Tween® 80. [00242] The choice of suitable oils or fats for the formulation is based on achieving the desired properties. The cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used. [00243] Pharmaceutical formulations according to the present disclosure comprise a combination according to the disclosure together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing an active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing an active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. [00244] Formulations for oral use may be also presented as hard gelatin capsules where an active ingredient is mixed with an inert solid diluent, for example starch, mannitol, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. [00245] Aqueous suspensions of the disclosure contain an active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally-occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. Further non-limiting examples of suspending agents include Cyclodextrin and Captisol (=Sulfobutyl ether beta- cyclodextrin; SEB-beta-CD). [00246] Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. [00247] Dispersible powders and granules of the disclosure suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. [00248] The pharmaceutical compositions of the disclosure may also be in the form of oil- in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally-occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent. [00249] The pharmaceutical compositions of the disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution isotonic sodium chloride solution, and hypertonic sodium chloride solution. [00250] The amount of an active ingredient that may be combined with the carrier material to produce a single dosage form can vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur. [00251] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. [00252] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. [00253] Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35 etc., which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds. [00254] Formulations suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. [00255] The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient. [00256] The disclosure further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor. [00257] Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route. [00258] Compounds of the disclosure are used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds of the disclosure (“controlled release formulations”) in which the release of the active ingredient are controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient. [00259] The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as horse, cattle, swine and sheep; and poultry and pets in general, such as cats and dogs. [00260] In one aspect, the present disclosure also provides a kit that includes a pharmaceutical composition of formulation including the combination described herein. The kit may include a product instruction for administration of the combination, for example, that a first pharmaceutical composition including the ROCK2 inhibitor and a second pharmaceutical composition including the DYRK1 inhibitor are administered (co- administered) simultaneously or subsequently. For example, the kit may instruct administration of the ROCK2 inhibitor formulation administered to a subject prior to administration of DYRK1 inhibitor formulation. EXAMPLES Example 1 [00261] ADP-Glo kinase assay (Promega). The ADP-Glo™ Kinase Assay is a luminescent ADP detection assay that allows measurement of kinase activity based on the amount of ADP produced during a kinase reaction. The kinase reaction is performed in the presence of ATP, S6K substrate (KRRRLASLR) and the ROCK kinase in the appropriate Kinase Reaction Buffer (1x). Upon termination of the reaction, the unconsumed ATP is depleted by addition of ADP-Glo™ Reagent. Next, Kinase Detection Reagent is added to convert ADP to ATP and allow the newly synthesized ATP to be measured using a luciferase/luciferin reaction. The luminescence is proportional to the produced ADP and consequently to the kinase activity. The ADP-Glo™ Kinase Assay was performed in a 384 well plate format as follows. [00262] Kinase Detection Reagent Preparation: The Kinase Detection Buffer was thawed at room temperature (RT). If a precipitate was present, the buffer was incubated at 37 °C with constant swirling for 15 minutes to dissolve the precipitate or the precipitate was removed from the buffer by carefully pipetting the supernatant from the bottle. After equilibrating both the Kinase Detection Buffer and Kinase Detection Substrate to room temperature, the entire volume of Kinase Detection Buffer was transferred into the bottle containing Kinase Detection Substrate to reconstitute the lyophilized substrate, followed by gentile mixing to obtain a homogeneous solution. [00263] Kinase Reaction Buffer Preparation: Kinase reaction buffer was prepared freshly before each experiment. The formulation of this buffer is provided in Table 1 below: Table 1. Formulation of kinase reaction buffer (1x) for ADP-Glo kinase assay. Reagent: Final concentration Stock concentration Tris, pH 7.5 40 mM 500 mM in H2O DTT 0.05 mM 100 mM in H2O MgCl2 20 mM 500 mM in H2O BSA 0.1 mg/mL 5.0 mg/mL [00264] ADP-Glo Reagents Preparation. Three mixes were prepared on ice before running the assay: Mix 1 – containing ROCK1 or ROCK2 in Kinase Reaction Buffer (1x) Mix 2 – containing S6K peptide in Kinase Reaction Buffer (1x) Mix 3 – containing ATP in Kinase Reaction Buffer (1x) [00265] The final conditions for performing the ADP-Glo kinase assay are proved in Table 2 below: Table 2. Final conditions for ADP-Glo kinase assay for ROCK (concentration in final volume 5 µL). Final concentrations: ROCK1 ROCK2 Kinase 0.1 ng/µL 0.1 ng/µL S6K substrate 170 µM 170 µM ATP 10 µM 40 µM Timepoint 120 min 120 min DMSO 1% 1% [00266] The ratios of reagent volumes in the assay were 1:1:2 of kinase reaction to ADP- Glo™ Reagent to Kinase Detection Reagent. For 384-well plates, volumes were: 5 μl of kinase reaction, 5 μl of ADP-Glo™ Reagent and 10 μl of Kinase Detection Reagent. [00267] Generating a standard curve for conversion of ATP to ADP. To estimate the amount of ADP produced in the kinase reaction, a standard curve that represents the luminescence corresponding to the conversion of ATP to ADP was prepared based on the ATP concentration used in the kinase reaction. These conversion curves represent the amounts of ATP and ADP available in a reaction at the specified conversion percentage ranging from 100% conversion to 0% conversion. The standard samples used to generate an ATP-to-ADP conversion curve are created by combining the appropriate volumes of ATP and ADP stock solutions. [00268] Determination of IC50 values of kinase inhibitors [00269] Each plate contained a positive control (1 µM Comp. A for ROCK2 and 1 µM RKI-1447 for ROCK1); a vehicle control (1% DMSO); a blank control (kinase reaction buffer (1x)); a low control (substrate and ATP, without kinase); and an autophosphorylation control (kinase and ATP, without substrate). Test and reference compounds were diluted in 100% DMSO to obtain 10 mM stock solutions. Each compound was tested in 8-serial dilutions in duplicate. The final concentration of DMSO in the reaction was 1% (up to 50 nL). [00270] 5 μl/well Kinase Reaction Buffer (1x) was dispensed to blank control wells. 2 μl/well Kinase Reaction Buffer (1x) was dispensed to control without protein (low control) and without substrate (autophosphorylation) wells. The plate was sealed with adhesive film followed by a short spin (1 min, 1000 rpm). [00271] 2 µl/well kinase (2.5x) solution was dispensed into relevant wells of the assay plate. The plate was sealed with adhesive film followed by a short spin (1 min, 1000 rpm). [00272] 2 µl/well S6K substrate (2.5x) solution was dispensed into relevant wells of the assay plate. The plate was sealed with adhesive film followed by a short spin (1 min, 1000 rpm). [00273] 1 µl/well ATP (5x) solution was dispensed into relevant wells of the assay plate. The final volume of reaction was 15 μl. The plate was sealed with adhesive film followed by a short spin (1 min, 1000 rpm). [00274] The plate was incubated at 25 ˚C for 120 minutes with 450 rpm shaking speed. [00275] After the incubation was completed the kinase reaction was terminated, residual ATP was depleted from the kinase reaction and ADP was converted to ATP, that is measured in luciferase/luciferin reaction. 5 µl of ADP-Glo™ Reagent was dispensed to stop the kinase reaction and deplete the unconsumed ATP. The plate was sealed with adhesive film followed by a short spin (1 min, 1000 rpm), and was incubated at 25 ˚C for 40 minutes with 450 rpm shaking speed. [00276] 10 µl of Kinase Detection Reagent was dispensed to convert ADP to ATP and introduce luciferase and luciferin to detect ATP. The plate was sealed with adhesive film followed by a short spin (1 min, 1000 rpm), and was incubated at 25 ˚C for 60 minutes with 450 rpm shaking speed. [00277] Following a 5-minute dark adaptation, luminescence was measured using a PHERAstar FSX Multimode Plate Reader (BMG Labtech). Table 3 Compound ROCK2 IC50 (nM) ROCK1 IC50 (nM) Comp. A 5.44 5115.05 Comp. B 473 > 50000 Comp. C 36.67 > 50000 Comp. D 82.6 4004.37 Example 2 [00278] The combination of a DYRK1 inhibitor and a ROCK2 inhibitor provided prolonged glucose control in a mouse model of diabetes. [00279] Figure 1 shows results of a glucose tolerance test in mice at time course 5 days after treatment. The treatment groups were treated with: DYRK1 inhibitor compounds (FX7742, FX8474), and FX8474 in combination with a ROCK2 inhibitor compound (Compound A) in comparison to control groups of (i) a no treatment group without diabetes, and (ii) a no treatment group having diabetes. [00280] Figure 2 shows levels of the fasted glucose in blood of the mice 5 days after treatment. The treatment groups were treated with: DYRK1 inhibitor compounds (FX7742, FX8474), respectively, and FX8474 in combination with ROCK2 inhibitor compound (Compound A) in comparison to control groups of (i) a no treatment group without diabetes, and (ii) a no treatment group having diabetes.

Claims

WE CLAIM: 1. A method for treating type I diabetes in a subject comprising administering to the subject (i) a therapeutically effective amount of an inhibitor of Rho associated coiled-coil containing protein kinase 2 (ROCK2), and (ii) a therapeutically effective amount of an inhibitor of a dual specificity tyrosine-phosphorylation-regulated kinase 1 (DYRK1).
2. The method of claim 1, wherein the ROCK2 inhibitor has a structure of Formula A-I:
Figure imgf000098_0001
or pharmaceutically acceptable salt thereof, wherein: RA1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)- RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; RA2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; alternatively, RA1 and RA2 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, ox1o, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, - O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, C1-C3 perfluoro alkyl, -NRA11-(C1-C6 alkyl)NRA11RA12, and -NRA11-(C1-C6 alkyl)-ORA11; RA3 and RA4 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1-C(=O)NRA11RA12; alternatively RA3 and RA4 are taken together with the nitrogen to which they are attached to provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - ORA11, ox1o, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, - C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; the dotted lines represent optional double bonds; each RA5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, ox1o, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)- RA11, - C(=O)ORA11, -(C1-C6 alkyl)
Figure imgf000099_0001
x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; n1 is 0 to 3; XA1 is CRA6 or N; XA2 is CHRA6, NRA7, O or S; XA3 is C, CH or N; XA4 is N or CH; XA5 is N or CH; each RA6 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)- RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; each RA7 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)- NRA11RA12, alkyl)x1-C(=O)ORA11, and - (C1-C6 alkyl)
Figure imgf000100_0001
each x1 is independently selected from 0 and 1; and each RA11 and RA12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RA11 and RA12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoro alkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. 3. The method of claim 2, wherein the ROCK2 inhibitor has a structure of Formula A-II: or pharmaceutically acceptable salt thereof, wherein: RA1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; RA2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; alternatively, RA1 and RA2 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O- (C1-C6 alkyl)-O-(C1-C6 alkyl), -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, C1-C3 perfluoro alkyl, -NRA11-(C1-C6 alkyl)NRA11RA12, and -NRA11-(C1-C6 alkyl)- ORA11; RA3 and RA4 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl,
3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1-C(=O)NRA11RA12; alternatively RA3 and RA4 are taken together with the nitrogen to which they are attached to provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring to heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - ORA11, oxo, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)
Figure imgf000102_0001
C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; the dotted lines represent optional double bonds; each RA5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- alkyl)- C6 alkyl)x1-
Figure imgf000102_0003
C6 alkyl)
Figure imgf000102_0002
C(=O)ORA11, -(C1-C6 alkyl)
Figure imgf000102_0004
x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; n1 is 0 to 3; RA7 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, - (C1-C6 alkyl) alkyl)x1- C(=O)
Figure imgf000102_0005
each x1 is independently selected from 0 and 1; and each RA11 and RA12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RA11 and RA12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoro alkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
4. The method of claim 2, wherein the ROCK2 inhibitor has a structure of Formula A- III:
Figure imgf000103_0001
or pharmaceutically acceptable salt thereof, wherein: RA1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; RA2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6
Figure imgf000103_0002
alternatively, RA1 and RA2 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O- (C1-C6 alkyl)-O-(C1-C6 alkyl), -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, C1-C3 perfluoro alkyl, -NRA11-(C1-C6 alkyl)NRA11RA12, and -NRA11-(C1-C6 alkyl)- ORA11; RA3 and RA4 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1-C(=O)NRA11RA12; alternatively RA3 and RA4 are taken together with the nitrogen to which they are attached to provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring to heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - ORA11, oxo, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, - C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; the dotted lines represent optional double bonds; each RA5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, - C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; n1 is 0 to 3; RA7 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, - (C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)
Figure imgf000105_0001
alkyl)x1- C(=O)NRA11RA12; each x1 is independently selected from 0 and 1; and each RA11 and RA12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RA11 and RA12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoro alkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. 5. The method of claim 1, wherein the ROCK2 inhibitor has a structure of Formula B-I:
Figure imgf000105_0002
or pharmaceutically acceptable salt thereof, wherein XB1 is N or CH; XB2 is N or CH; XB3 is N or CRB3; XB4 is N or CRB4; XB5 is selected from the group consisting of C, CH and N; a1 is selected from 1 or 2; the dotted lines represent optional double bonds; each RB1 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, oxo, -CN, C1-C3 perfluoro alkyl, -ORB11, and -NRB11RB12; or alternatively, two RB1 attached to the same carbon or to adjacent carbons are taken together to form a 3- to 6-membered ring, which may optionally contain 0 to 2 ring heteroatoms selected from O, S and N, and which may be unsubstituted or optionally substituted by 1 to 3 substituents selected from halo, C1-C3 alkyl, NH2, OH, and O-C1-C3 alkyl; b1 is selected from 0, 1, and 2; RB2 is selected from H, halo, C1-C3 alkyl, NH2, OH, and O-C1-C3 alkyl; RB3 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1- C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, -C(=O)ORB11, -(C1- C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11- (C1-C6 alkyl)x2-C(=O)ORB11; RB4 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1- C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)
Figure imgf000106_0001
x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, -C(=O)ORB11, -(C1- C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11- (C1-C6 alkyl)x2-C(=O)ORB11; alternatively, RB3 and RB4 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O- (C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, and -NRB11-(C1-C6 alkyl)- ORB11; each RB5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O- (C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)- NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1- C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, - C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2- C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; n2 is 0 to 3; RB6 and RB7 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O- (C1-C6 alkyl)-NRB11RB12, -O-(C1-C6 alkyl)-C(=O)NRB11RB12, -(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, -C(=O)ORB11, -(C1- C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11- (C1-C6 alkyl)x2-C(=O)ORB11; alternatively, RB6 and RB7 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C10 aryl, C5- C10 heteroaryl, 3- to 10-membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C10 aryl), -C1-C6 alkyl-(C5-C10 heteroaryl), -C1- C6 alkyl-(3- to 10-membered heterocyclyl), halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, - O-(C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, and -C(=O)-N(RB8)(RB9), and wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; RB8 and RB9 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl,
5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, and -(C1-C6 alkyl)x2-C(=O)NRB11RB12, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; alternatively RB8 and RB9 are taken together with the nitrogen to which they are attached provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoro alkyl, -ORB11, oxo, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, - NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11- (C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2- C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, - C(=O)- RB11, -C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; each x2 is independently selected from 0 and 1; and each RB11 and RB12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RB11 and RB12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
6. The method of claim 5, wherein the ROCK2 inhibitor has a structure of the formula B-V:
Figure imgf000109_0001
RB3 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1- C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, -C(=O)ORB11, -(C1- C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11- (C1-C6 alkyl)x2-C(=O)ORB11; RB4 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1- C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, -C(=O)ORB11, -(C1- C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11- (C1-C6 alkyl)x2-C(=O)ORB11; alternatively, RB3 and RB4 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O- (C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, and -NRB11-(C1-C6 alkyl)- ORB11; RB8 and RB9 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, and -(C1-C6 alkyl)x2-C(=O)NRB11RB12, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; alternatively RB8 and RB9 are taken together with the nitrogen to which they are attached provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoro alkyl, -ORB11, oxo, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, - NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11- (C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, - C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2- C(=O)- RB11, -C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O) alkyl)x2-C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2-C(=O)
Figure imgf000110_0001
RB10 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C10 aryl, C5-C10 heteroaryl, 3- to 10-membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C10 aryl), -C1- C6 alkyl-(C5-C10 heteroaryl), -C1-C6 alkyl-(3- to 10-membered heterocyclyl), - (C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)NRB11RB12, -(C1-C6 alkyl)-ORB11, and - C(=O)-N(RB11)( RB12), and wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, - OH, and NH2; each x2 is independently selected from 0 and 1; and each RB11 and RB12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RB11 and RB12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
7. The method of claim 1, wherein the ROCK2 inhibitor is selected from a compound having the formula (A-I), (B-I), (C-I), (D-I), (E-I), (F-I), (G-I), (H-I), (J-I), (K-I), (L- I) and their subordinates, exemplary compounds thereof, derivatives thereof, or pharmaceutically acceptable salts thereof..
8. The method of claim 1, wherein the ROCK2 inhibitor is selected from
Figure imgf000111_0001
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1, wherein the ROCK2 inhibitor is selected from belumosudil (KD025), zelasudil, Y-27632, Fasudil, GSK429286A, RKI-1447, Azaindole 1 (TC-S 7001), Hydroxyfasudil, GSK269962A, Ripasudil, AT13148, RX007, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof.
10. The method according to any one of claims 1 to 9, wherein the DYRK1 inhibitor has a structure of Formula (M-I):
Figure imgf000112_0001
or a tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein each RM1, RM3, and RM4 is independently selected from the group consisting of (i) H, halogen, CN, NO2, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl; wherein each substitutable carbon atom in the aforementioned moieties is independently substituted or unsubstituted with one or more, same or different substituents RM7; (ii) C(=O)RM5, C(=O)ORM6, C(=O)SRM6, C(=O)N(RM6a)(RM6b), ORM6, S(=O)n13RM6, S(=O)n13N(RM6a)(RM6b), S(=O)n13ORM6, N(RM6a)(RM6b), N(RM6)C(=O)RM5, N(RM6)C(=O)ORM6, N(RM6)C(=O)N(RM6a)(RM6b), N(RM6)S(=O)n13RM6, N(RM6)S(=O)n13N(RM6a)(RM6b), N(RM6)S(=O)n13ORM6; (iii) a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic or bicyclic moieties is independently substituted or unsubstituted with one or more, same or different substituents R8; RM2 is selected from the group consisting of H, halogen, CN, NO2, C1-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy and C1-C6-haloalkoxy; RM5, RM6, RM6a, RM6b are independently selected from the group consisting of H, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkylcarbonyl, wherein each substitutable carbon atom in the aforementioned moieties is independently substituted or unsubstituted with one or more, same or different substituents RM9; and a 3- to 9- membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic moieties is independently substituted or unsubstituted with one or more, same or different substituents RM10; RM7 is selected from the group consisting of halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C(=O)RM5, C(=O)ORM6, C(=O)SRM6, C(=O)N(RM6a)(RM6b), ORM6, S(=O)n13RM6, S(=O)n13N(RM6a)(RM6b), S(=O)n13ORM6, N(RM6a)(RM6b), N(RM6)C(=O)RM5, N(RM6)C(=O)ORM6, N(RM6)C(=O)N(RM6a)(RM6b), N(RM6)S(=O)n13(RM6), N(RM6)S(=O)n13N(RM6a)(RM6b), N(RM6)S(=O)n13ORM6; and a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non- oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned cyclic or bicyclic moieties is substituted or unsubstituted with one or more, same or different substituents RM8; RM8 is selected from the group consisting of halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6- alkylcarbonyl, N(RM6a)(RM6b), ORM6 and S(=O)n13RM6; RM9 is selected from the group consisting of halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6- alkylcarbonyl, N(RM11a)(RM11b), ORM11 and S(=O)n13RM11; and a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic moieties is substituted or unsubstituted with one or more, same or different substituents RM10; RM10 is selected from halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6- haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6-alkylcarbonyl, N(RM11a)(RM11b), ORM11 and S(=O)n13RM11; RM11, RM11a, RM11b are independently selected from the group consisting of H, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl; and wherein n13 is 0, 1 or 2.
11. The method according to any one of claims 1 to 9, wherein the DYRK1 inhibitor is a compound having the formula (M-I), (N-I), (O-I), (P-I), (Q-I), (R-I), (S-I), (T-I), (U- I), (V-I), (W-I), (X-I), (Y-I), (Z-I) and their subordinates, exemplary compounds thereof, derivatives thereof, or pharmaceutically acceptable salts thereof.
12. The method according to any one of claims 1 to 9, wherein the DYRK1 inhibitor is selected from FX-1610, FX-9847, FX-8553, FX-5372, FX-7742, FX-8474, AZ191, Paprotrain, Harmine, GNF4877, GNF2133, INDY, FINDY, EHT1610, EHT 5372, AZ-Dyrk1B-33, KH-CB20, ARN25068, Haspin, JH-XVII-10, Leucettine L41, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof.
13. The method any one of claims 1-12, wherein the ROCK2 inhibitor and the DYRK1 inhibitor are administered simultaneously.
14. The method of any one of claim 1-12, wherein the ROCK2 inhibitor and the DYRK1 inhibitor are administered subsequently.
15. The method of any one of claims 1-12, wherein the ROCK2 inhibitor is administered in advance of administering the DYRK1 inhibitor.
16. A method of for promoting the proliferation of a pancreatic beta cells in a subject by administering a combination of an effective amount of a Rho associated coiled-coil containing protein kinase 2 (ROCK2) and an effective amount of a dual specificity tyrosine-phosphorylation-regulated kinase 1 (DYRK1) inhibitor.
17. The method of claim 16, wherein the ROCK2 inhibitor has a structure of Formula A- I:
Figure imgf000115_0001
or pharmaceutically acceptable salt thereof, wherein: RA1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)- RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; RA2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl) A11 A11
Figure imgf000115_0002
alkyl)x1-C(=O)R , and -NR - (C1-C6 alkyl)x1-C(=O)ORA11; alternatively, RA1 and RA2 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, ox1o, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, - O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, C1-C3 perfluoro alkyl, -NRA11-(C1-C6 alkyl)NRA11RA12, and -NRA11-(C1-C6 alkyl)-ORA11; RA3 and RA4 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1-C(=O)NRA11RA12; alternatively RA3 and RA4 are taken together with the nitrogen to which they are attached to provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - ORA11, ox1o, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, - C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; the dotted lines represent optional double bonds; each RA5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, ox1o, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)- RA11, - C(=O)ORA11, -(C1-C6 alkyl)
Figure imgf000116_0001
x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; n1 is 0 to 3; XA1 is CRA6 or N; XA2 is CHRA6, NRA7, O or S; XA3 is C, CH or N; XA4 is N or CH; XA5 is N or CH; each RA6 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)- RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; each RA7 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)- NRA11RA12, alkyl)x1-C(=O)ORA11, and - (C1-C6 alkyl)
Figure imgf000117_0001
each x1 is independently selected from 0 and 1; and each RA11 and RA12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RA11 and RA12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoro alkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
18. The method of claim 17, wherein the ROCK2 inhibitor has a structure of Formula A- II: or pharmaceutically acceptable salt thereof, wherein: RA1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; RA2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; alternatively, RA1 and RA2 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O- (C1-C6 alkyl)-O-(C1-C6 alkyl), -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, C1-C3 perfluoro alkyl, -NRA11-(C1-C6 alkyl)NRA11RA12, and -NRA11-(C1-C6 alkyl)- ORA11; RA3 and RA4 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1-C(=O)NRA11RA12; alternatively RA3 and RA4 are taken together with the nitrogen to which they are attached to provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring to heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - ORA11, oxo, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)
Figure imgf000119_0001
C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; the dotted lines represent optional double bonds; each RA5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- alkyl)- C6 alkyl)x1-
Figure imgf000119_0003
C6 alkyl)
Figure imgf000119_0002
C(=O)ORA11, -(C1-C6 alkyl)
Figure imgf000119_0004
x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; n1 is 0 to 3; RA7 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, - (C1-C6 alkyl) alkyl)x1- C(=O)
Figure imgf000119_0005
each x1 is independently selected from 0 and 1; and each RA11 and RA12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RA11 and RA12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoro alkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
19. The method of claim 17, wherein the ROCK2 inhibitor has a structure of Formula A- III:
Figure imgf000120_0001
or pharmaceutically acceptable salt thereof, wherein: RA1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; RA2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6
Figure imgf000120_0002
alternatively, RA1 and RA2 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O- (C1-C6 alkyl)-O-(C1-C6 alkyl), -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, C1-C3 perfluoro alkyl, -NRA11-(C1-C6 alkyl)NRA11RA12, and -NRA11-(C1-C6 alkyl)- ORA11; RA3 and RA4 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1-C(=O)NRA11RA12; alternatively RA3 and RA4 are taken together with the nitrogen to which they are attached to provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring to heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - ORA11, oxo, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, - C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; the dotted lines represent optional double bonds; each RA5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, - C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; n1 is 0 to 3; RA7 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, - (C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)
Figure imgf000122_0001
alkyl)x1- C(=O)NRA11RA12; each x1 is independently selected from 0 and 1; and each RA11 and RA12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RA11 and RA12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoro alkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
20. The method of claim 16, wherein the ROCK2 inhibitor has a structure of Formula B- I:
Figure imgf000122_0002
or pharmaceutically acceptable salt thereof, wherein: XB1 is N or CH; XB2 is N or CH; XB3 is N or CRB3; XB4 is N or CRB4; XB5 is selected from the group consisting of C, CH and N; a1 is selected from 1 or 2; the dotted lines represent optional double bonds; each RB1 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, oxo, -CN, C1-C3 perfluoro alkyl, -ORB11, and -NRB11RB12; or alternatively, two RB1 attached to the same carbon or to adjacent carbons are taken together to form a 3- to 6-membered ring, which may optionally contain 0 to 2 ring heteroatoms selected from O, S and N, and which may be unsubstituted or optionally substituted by 1 to 3 substituents selected from halo, C1-C3 alkyl, NH2, OH, and O-C1-C3 alkyl; b1 is selected from 0, 1, and 2; RB2 is selected from H, halo, C1-C3 alkyl, NH2, OH, and O-C1-C3 alkyl; RB3 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1- C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, -C(=O)ORB11, -(C1- C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11- (C1-C6 alkyl)x2-C(=O)ORB11; RB4 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1- C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, -C(=O)ORB11, -(C1- C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11- (C1-C6 alkyl)x2-C(=O)ORB11; alternatively, RB3 and RB4 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O- (C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, and -NRB11-(C1-C6 alkyl)- ORB11; each RB5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O- (C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)- NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1- C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, - C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2- C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; n2 is 0 to 3; RB6 and RB7 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O- (C1-C6 alkyl)-NRB11RB12, -O-(C1-C6 alkyl)-C -(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-C(=O)NRB11RB12, -NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl) (C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, - B11
Figure imgf000124_0001
OR , -(C1- C6 alkyl)x2-C (C1-C6 alkyl)
Figure imgf000124_0002
alternatively, RB6 and RB7 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C10 aryl, C5- C10 heteroaryl, 3- to 10-membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C10 aryl), -C1-C6 alkyl-(C5-C10 heteroaryl), -C1- C6 alkyl-(3- to 10-membered heterocyclyl), halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, - O-(C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, and -C(=O)-N(RB8)(RB9), and wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; RB8 and RB9 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, and -(C1-C6 alkyl)x2-C(=O)NRB11RB12, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; alternatively RB8 and RB9 are taken together with the nitrogen to which they are attached provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoro alkyl, -ORB11, oxo, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, - NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11- (C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2- C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, - C(=O)- RB11, -C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; each x2 is independently selected from 0 and 1; and each RB11 and RB12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RB11 and RB12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
21. The method of claim 20, wherein the ROCK2 inhibitor has a structure of the formula B-V:
Figure imgf000126_0001
or a pharmaceutically acceptable salt thereof, wherein: RB3 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1- C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, -C(=O)ORB11, -(C1- C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11- (C1-C6 alkyl)x2-C(=O)ORB11; RB4 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1- C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)
Figure imgf000126_0002
(C1-C6 alkyl)x2-C(=O)ORB11; alternatively, RB3 and RB4 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O- (C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, and -NRB11-(C1-C6 alkyl)- ORB11; RB8 and RB9 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, and -(C1-C6 alkyl)x2-C(=O)NRB11RB12, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; alternatively RB8 and RB9 are taken together with the nitrogen to which they are attached provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoro alkyl, -ORB11, oxo, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, - NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11- (C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, - C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2- C(=O)- RB11, -C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O) alkyl)x2-C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2-C(=O)
Figure imgf000127_0001
RB10 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C10 aryl, C5-C10 heteroaryl, 3- to 10-membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C10 aryl), -C1- C6 alkyl-(C5-C10 heteroaryl), -C1-C6 alkyl-(3- to 10-membered heterocyclyl), - (C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)NRB11RB12, -(C1-C6 alkyl)-ORB11, and - C(=O)-N(RB11)( RB12), and wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, - OH, and NH2; each x2 is independently selected from 0 and 1; and each RB11 and RB12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RB11 and RB12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
22. The method of claim 16, wherein the ROCK2 inhibitor is selected from a compound having the formula (A-I), (B-I), (C-I), (D-I), (E-I), (F-I), (G-I), (H-I), (J-I), (K-I), (L- I) and their subordinates, exemplary compounds thereof, derivatives thereof, or pharmaceutically acceptable salts thereof.
23. The method of claim 16, wherein the ROCK2 inhibitor is selected from
Figure imgf000128_0001
or a pharmaceutically acceptable salt thereof.
24. The method of claim 16, wherein the ROCK2 inhibitor is selected from belumosudil (KD025), Zelasudil, Y-27632, Fasudil, GSK429286A, RKI-1447, Azaindole 1 (TC-S 7001), Hydroxyfasudil, GSK269962A, Ripasudil, AT13148, RX007, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof.
25. The method according to any one of claims 16 to 24, wherein the DYRK1 inhibitor has a structure of Formula (M-I):
Figure imgf000129_0001
or a tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein each RM1, RM3, and RM4 is independently selected from the group consisting of (i) H, halogen, CN, NO2, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl; wherein each substitutable carbon atom in the aforementioned moieties is independently substituted or unsubstituted with one or more, same or different substituents RM7; (ii) C(=O)RM5, C(=O)ORM6, C(=O)SRM6, C(=O)N(RM6a)(RM6b), ORM6, S(=O)n13RM6, S(=O)n13N(RM6a)(RM6b), S(=O)n13ORM6, N(RM6a)(RM6b), N(RM6)C(=O)RM5, N(RM6)C(=O)ORM6, N(RM6)C(=O)N(RM6a)(RM6b), N(RM6)S(=O)n13RM6, N(RM6)S(=O)n13N(RM6a)(RM6b), N(RM6)S(=O)n13ORM6; (iii) a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic or bicyclic moieties is independently substituted or unsubstituted with one or more, same or different substituents R8; RM2 is selected from the group consisting of H, halogen, CN, NO2, C1-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy and C1-C6-haloalkoxy; RM5, RM6, RM6a, RM6b are independently selected from the group consisting of H, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkylcarbonyl, wherein each substitutable carbon atom in the aforementioned moieties is independently substituted or unsubstituted with one or more, same or different substituents RM9; and a 3- to 9- membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic moieties is independently substituted or unsubstituted with one or more, same or different substituents RM10; RM7 is selected from the group consisting of halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C(=O)RM5, C(=O)ORM6, C(=O)SRM6, C(=O)N(RM6a)(RM6b), ORM6, S(=O)n13RM6, S(=O)n13N(RM6a)(RM6b), S(=O)n13ORM6, N(RM6a)(RM6b), N(RM6)C(=O)RM5, N(RM6)C(=O)ORM6, N(RM6)C(=O)N(RM6a)(RM6b), N(RM6)S(=O)n13(RM6), N(RM6)S(=O)n13N(RM6a)(RM6b), N(RM6)S(=O)n13ORM6; and a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non- oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned cyclic or bicyclic moieties is substituted or unsubstituted with one or more, same or different substituents RM8; RM8 is selected from the group consisting of halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6- alkylcarbonyl, N(RM6a)(RM6b), ORM6 and S(=O)n13RM6; RM9 is selected from the group consisting of halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6- alkylcarbonyl, N(RM11a)(RM11b), ORM11 and S(=O)n13RM11; and a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic moieties is substituted or unsubstituted with one or more, same or different substituents RM10; RM10 is selected from halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6- haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6-alkylcarbonyl, N(RM11a)(RM11b), ORM11 and S(=O)n13RM11; RM11, RM11a, RM11b are independently selected from the group consisting of H, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl; and n13 is 0, 1 or 2.
26. The method according to any one of claims 16 to 24, wherein the DYRK1 inhibitor is a compound having the formula (M-I), (N-I), (O-I), (P-I), (Q-I), (R-I), (S-I), (T-I), (U- I), (V-I), (W-I), (X-I), (Y-I), (Z-I) and their subordinates, exemplary compounds thereof, derivatives thereof, or pharmaceutically acceptable salts thereof.
27. The method according to any one of claims 16 to 24, wherein the DYRK1 inhibitor is selected from FX-1610, FX-9847, FX-8553, FX-5372, FX-7742, FX-8474, AZ191, Paprotrain, Harmine, GNF4877, GNF2133, INDY, FINDY, EHT1610, EHT 5372, AZ-Dyrk1B-33, KH-CB20, ARN25068, Haspin, JH-XVII-10, Leucettine L41, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof.
28. The method according to any one of claims 16 to 27, wherein the ROCK2 inhibitor and the DYRK1 inhibitor are administered simultaneously.
29. The method according to any one of claims 16 to 27, wherein the ROCK2 inhibitor and the DYRK1 inhibitor are administered subsequently.
30. The method according to any one of claims 16 to 27, wherein the ROCK2 inhibitor is administered in advance of administering the DYRK1 inhibitor.
31. The method according to any one of claims 16 to 30, wherein the subject has, or is diagnosed with Type I diabetes.
32. A method of promoting regrowth of a pancreatic beta cell in a patient suffering from type 1 diabetes comprising administering a combination of an effective amount of a Rho associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor and an effective amount of a dual specificity tyrosine-phosphorylation-regulated kinase 1 (DYRK1) inhibitor.
33. The method of claim 32, wherein the ROCK2 inhibitor has a structure of Formula A- I:
Figure imgf000132_0001
or pharmaceutically acceptable salt thereof, wherein: RA1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)- RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; RA2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; alternatively, RA1 and RA2 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, ox1o, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, - O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, C1-C3 perfluoro alkyl, -NRA11-(C1-C6 alkyl)NRA11RA12, and -NRA11-(C1-C6 alkyl)-ORA11; RA3 and RA4 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1-C(=O)NRA11RA12; alternatively RA3 and RA4 are taken together with the nitrogen to which they are attached to provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - ORA11, ox1o, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, - C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; the dotted lines represent optional double bonds; each RA5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, ox1o, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)- RA11, - C(=O)ORA11, -(C1-C6 alkyl)
Figure imgf000133_0001
x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; n1 is 0 to 3; XA1 is CRA6 or N; XA2 is CHRA6, NRA7, O or S; XA3 is C, CH or N; XA4 is N or CH; XA5 is N or CH; each RA6 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)- RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; each RA7 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)- NRA11RA12, alkyl)x1-C(=O)ORA11, and - (C1-C6 alkyl)
Figure imgf000134_0001
each x1 is independently selected from 0 and 1; and each RA11 and RA12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RA11 and RA12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoro alkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
34. The method of claim 33, wherein the ROCK2 inhibitor has a structure of Formula A- II: or pharmaceutically acceptable salt thereof, wherein: RA1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; RA2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; alternatively, RA1 and RA2 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O- (C1-C6 alkyl)-O-(C1-C6 alkyl), -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, C1-C3 perfluoro alkyl, -NRA11-(C1-C6 alkyl)NRA11RA12, and -NRA11-(C1-C6 alkyl)- ORA11; RA3 and RA4 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1-C(=O)NRA11RA12; alternatively RA3 and RA4 are taken together with the nitrogen to which they are attached to provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring to heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - ORA11, oxo, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)
Figure imgf000136_0001
C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; the dotted lines represent optional double bonds; each RA5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- alkyl)- C6 alkyl)x1-
Figure imgf000136_0003
C6 alkyl)
Figure imgf000136_0002
C(=O)ORA11, -(C1-C6 alkyl)
Figure imgf000136_0004
x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; n1 is 0 to 3; RA7 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, - (C1-C6 alkyl) alkyl)x1- C(=O)
Figure imgf000136_0005
each x1 is independently selected from 0 and 1; and each RA11 and RA12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RA11 and RA12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoro alkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
35. The method of claim 33, wherein the ROCK2 inhibitor has a structure of Formula A- III:
Figure imgf000137_0001
or pharmaceutically acceptable salt thereof, wherein: RA1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; RA2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6
Figure imgf000137_0002
alternatively, RA1 and RA2 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O- (C1-C6 alkyl)-O-(C1-C6 alkyl), -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, C1-C3 perfluoro alkyl, -NRA11-(C1-C6 alkyl)NRA11RA12, and -NRA11-(C1-C6 alkyl)- ORA11; RA3 and RA4 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1-C(=O)NRA11RA12; alternatively RA3 and RA4 are taken together with the nitrogen to which they are attached to provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring to heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - ORA11, oxo, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, - C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; the dotted lines represent optional double bonds; each RA5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, - C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; n1 is 0 to 3; RA7 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, - (C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)
Figure imgf000139_0001
alkyl)x1- C(=O)NRA11RA12; each x1 is independently selected from 0 and 1; and each RA11 and RA12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RA11 and RA12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoro alkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
36. The method of claim 32, wherein the ROCK2 inhibitor has a structure of Formula B- I:
Figure imgf000139_0002
or pharmaceutically acceptable salt thereof, wherein XB1 is N or CH; XB2 is N or CH; XB3 is N or CRB3; XB4 is N or CRB4; XB5 is selected from the group consisting of C, CH and N; a1 is selected from 1 or 2; the dotted lines represent optional double bonds; each RB1 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, oxo, -CN, C1-C3 perfluoro alkyl, -ORB11, and -NRB11RB12; or alternatively, two RB1 attached to the same carbon or to adjacent carbons are taken together to form a 3- to 6-membered ring, which may optionally contain 0 to 2 ring heteroatoms selected from O, S and N, and which may be unsubstituted or optionally substituted by 1 to 3 substituents selected from halo, C1-C3 alkyl, NH2, OH, and O-C1-C3 alkyl; b1 is selected from 0, 1, and 2; RB2 is selected from H, halo, C1-C3 alkyl, NH2, OH, and O-C1-C3 alkyl; RB3 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1- C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, -C(=O)ORB11, -(C1- C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11- (C1-C6 alkyl)x2-C(=O)ORB11; RB4 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1- C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, -C(=O)ORB11, -(C1- C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11- (C1-C6 alkyl)x2-C(=O)ORB11; alternatively, RB3 and RB4 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O- (C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, and -NRB11-(C1-C6 alkyl)- ORB11; each RB5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O- (C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)- NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1- C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, - C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2- C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; n2 is 0 to 3; RB6 and RB7 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O- (C1-C6 alkyl)-NRB11RB12, -O-(C1-C6 alkyl)-C -(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-C(=O)NRB11RB12, -NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl) (C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, - B11
Figure imgf000141_0001
OR , -(C1- C6 alkyl)x2-C (C1-C6 alkyl)
Figure imgf000141_0002
alternatively, RB6 and RB7 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C10 aryl, C5- C10 heteroaryl, 3- to 10-membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C10 aryl), -C1-C6 alkyl-(C5-C10 heteroaryl), -C1- C6 alkyl-(3- to 10-membered heterocyclyl), halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, - O-(C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, and -C(=O)-N(RB8)(RB9), and wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; RB8 and RB9 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, and -(C1-C6 alkyl)x2-C(=O)NRB11RB12, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; alternatively RB8 and RB9 are taken together with the nitrogen to which they are attached provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoro alkyl, -ORB11, oxo, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, - NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11- (C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2- C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, - C(=O)- RB11, -C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; each x2 is independently selected from 0 and 1; and each RB11 and RB12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RB11 and RB12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
37. The method of claim 36, wherein the ROCK2 inhibitor has a structure of the formula B-V:
Figure imgf000143_0001
or a pharmaceutically acceptable salt thereof, wherein: RB3 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1- C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, -C(=O)ORB11, -(C1- C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11- (C1-C6 alkyl)x2-C(=O)ORB11; RB4 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1- C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, -C(=O)ORB11, -(C1- C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11- (C1-C6 alkyl)x2-C(=O)ORB11; alternatively, RB3 and RB4 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O- (C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, and -NRB11-(C1-C6 alkyl)- ORB11; RB8 and RB9 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, and -(C1-C6 alkyl)x2-C(=O)NRB11RB12, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; alternatively RB8 and RB9 are taken together with the nitrogen to which they are attached provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoro alkyl, -ORB11, oxo, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, - NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11- (C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, - C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2- C(=O)- RB11, -C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O) alkyl)x2-C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2-C(=O)
Figure imgf000144_0001
RB10 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C10 aryl, C5-C10 heteroaryl, 3- to 10-membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C10 aryl), -C1- C6 alkyl-(C5-C10 heteroaryl), -C1-C6 alkyl-(3- to 10-membered heterocyclyl), - (C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)NRB11RB12, -(C1-C6 alkyl)-ORB11, and - C(=O)-N(RB11)( RB12), and wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, - OH, and NH2; each x2 is independently selected from 0 and 1; and each RB11 and RB12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RB11 and RB12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
38. The method of claim 32, wherein the ROCK2 inhibitor is selected from a compound having the formula (A-I), (B-I), (C-I), (D-I), (E-I), (F-I), (G-I), (H-I), (J-I), (K-I), (L- I) and their subordinates, exemplary compounds thereof, derivatives thereof, or pharmaceutically acceptable salts thereof..
39. The method of claim 32, wherein the ROCK2 inhibitor is selected from
Figure imgf000145_0001
or a pharmaceutically acceptable salt thereof.
40. The method of claim 32, wherein the ROCK2 inhibitor is selected from belumosudil (KD025), Zelasudil, Y-27632, Fasudil, GSK429286A, RKI-1447, Azaindole 1 (TC-S 7001), Hydroxyfasudil, GSK269962A, Ripasudil, AT13148, RX007, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof.
41. The method according to any one of claims 32 to 40, wherein the DYRK1 inhibitor has a structure of Formula (M-I):
Figure imgf000146_0001
or a tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein each RM1, RM3, and RM4 is independently selected from the group consisting of (i) H, halogen, CN, NO2, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl; wherein each substitutable carbon atom in the aforementioned moieties is independently substituted or unsubstituted with one or more, same or different substituents RM7; (ii) C(=O)RM5, C(=O)ORM6, C(=O)SRM6, C(=O)N(RM6a)(RM6b), ORM6, S(=O)n13RM6, S(=O)n13N(RM6a)(RM6b), S(=O)n13ORM6, N(RM6a)(RM6b), N(RM6)C(=O)RM5, N(RM6)C(=O)ORM6, N(RM6)C(=O)N(RM6a)(RM6b), N(RM6)S(=O)n13RM6, N(RM6)S(=O)n13N(RM6a)(RM6b), N(RM6)S(=O)n13ORM6; (iii) a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic or bicyclic moieties is independently substituted or unsubstituted with one or more, same or different substituents R8; RM2 is selected from the group consisting of H, halogen, CN, NO2, C1-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy and C1-C6-haloalkoxy; RM5, RM6, RM6a, RM6b are independently selected from the group consisting of H, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkylcarbonyl, wherein each substitutable carbon atom in the aforementioned moieties is independently substituted or unsubstituted with one or more, same or different substituents RM9; and a 3- to 9- membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic moieties is independently substituted or unsubstituted with one or more, same or different substituents RM10; RM7 is selected from the group consisting of halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C(=O)RM5, C(=O)ORM6, C(=O)SRM6, C(=O)N(RM6a)(RM6b), ORM6, S(=O)n13RM6, S(=O)n13N(RM6a)(RM6b), S(=O)n13ORM6, N(RM6a)(RM6b), N(RM6)C(=O)RM5, N(RM6)C(=O)ORM6, N(RM6)C(=O)N(RM6a)(RM6b), N(RM6)S(=O)n13(RM6), N(RM6)S(=O)n13N(RM6a)(RM6b), N(RM6)S(=O)n13ORM6; and a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non- oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned cyclic or bicyclic moieties is substituted or unsubstituted with one or more, same or different substituents RM8; RM8 is selected from the group consisting of halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6- alkylcarbonyl, N(RM6a)(RM6b), ORM6 and S(=O)n13RM6; RM9 is selected from the group consisting of halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6- alkylcarbonyl, N(RM11a)(RM11b), ORM11 and S(=O)n13RM11; and a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic moieties is substituted or unsubstituted with one or more, same or different substituents RM10; RM10 is selected from halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6- haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6-alkylcarbonyl, N(RM11a)(RM11b), ORM11 and S(=O)n13RM11; RM11, RM11a, RM11b are independently selected from the group consisting of H, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl; and n13 is 0, 1 or 2.
42. The method according to any one of claims 32 to 40, wherein the DYRK1 inhibitor is a compound having the formula (M-I), (N-I), (O-I), (P-I), (Q-I), (R-I), (S-I), (T-I), (U- I), (V-I), (W-I), (X-I), (Y-I), (Z-I) and their subordinates, exemplary compounds thereof, derivatives thereof, or a pharmaceutically acceptable salt thereof.
43. The method according to any one of claims 32 to 40, wherein the DYRK1 inhibitor is selected from FX-1610, FX-9847, FX-8553, FX-5372, FX-7742, FX-8474, AZ191, Paprotrain, Harmine, GNF4877, GNF2133, INDY, FINDY, EHT1610, EHT 5372, AZ-Dyrk1B-33, KH-CB20, ARN25068, Haspin, JH-XVII-10, Leucettine L41, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof.
44. The method according to any one of claims 32 to 43, wherein the ROCK2 inhibitor and the DYRK1 inhibitor are administered simultaneously.
45. The method according to any one of claims 32 to 43, wherein the ROCK2 inhibitor and the DYRK1 inhibitor are administered subsequently.
46. The method according to any one of claims 32 to 43, wherein the ROCK2 inhibitor is administered in advance of administering the DYRK1 inhibitor.
47. A combination for treating type I diabetes in a subject comprising: an effective amount of a Rho associated coiled coil containing protein kinase 2 (ROCK2) inhibitor, and an effective amount of a dual specificity tyrosine-phosphorylation-regulated kinase 1 (DYRK1) inhibitor.
48. The combination of claim 47, wherein the ROCK2 inhibitor has a structure of Formula A-I:
Figure imgf000149_0001
or pharmaceutically acceptable salt thereof, wherein: RA1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O) x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)- -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl) A11
Figure imgf000149_0002
-NR - (C1-C6 alkyl)x1-C(=O)ORA11; RA2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; alternatively, RA1 and RA2 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, ox1o, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, - O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, C1-C3 perfluoro alkyl, -NRA11-(C1-C6 alkyl)NRA11RA12, and -NRA11-(C1-C6 alkyl)-ORA11; RA3 and RA4 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1-C(=O)NRA11RA12; alternatively RA3 and RA4 are taken together with the nitrogen to which they are attached to provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - ORA11, ox1o, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, - C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; the dotted lines represent optional double bonds; each RA5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, ox1o, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)- RA11, - C(=O)ORA11, -(C1-C6 alkyl)
Figure imgf000150_0001
x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; n1 is 0 to 3; XA1 is CRA6 or N; XA2 is CHRA6, NRA7, O or S; XA3 is C, CH or N; XA4 is N or CH; XA5 is N or CH; each RA6 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)- RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; each RA7 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)- NRA11RA12, alkyl)x1-C(=O)ORA11, and - (C1-C6 alkyl)
Figure imgf000151_0001
each x1 is independently selected from 0 and 1; and each RA11 and RA12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RA11 and RA12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoro alkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
49. The combination of claim 48, wherein the ROCK2 inhibitor has a structure of Formula A-II: or pharmaceutically acceptable salt thereof, wherein: RA1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; RA2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; alternatively, RA1 and RA2 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O- (C1-C6 alkyl)-O-(C1-C6 alkyl), -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, C1-C3 perfluoro alkyl, -NRA11-(C1-C6 alkyl)NRA11RA12, and -NRA11-(C1-C6 alkyl)- ORA11; RA3 and RA4 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1-C(=O)NRA11RA12; alternatively RA3 and RA4 are taken together with the nitrogen to which they are attached to provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring to heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - ORA11, oxo, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)
Figure imgf000153_0001
C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; the dotted lines represent optional double bonds; each RA5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- alkyl)- C6 alkyl)x1-
Figure imgf000153_0003
C6 alkyl)
Figure imgf000153_0002
C(=O)ORA11, -(C1-C6 alkyl)
Figure imgf000153_0004
x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; n1 is 0 to 3; RA7 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, - (C1-C6 alkyl) alkyl)x1- C(=O)
Figure imgf000153_0005
each x1 is independently selected from 0 and 1; and each RA11 and RA12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RA11 and RA12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoro alkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
50. The combination of claim 48, wherein the ROCK2 inhibitor has a structure of Formula A-III:
Figure imgf000154_0001
or pharmaceutically acceptable salt thereof, wherein: RA1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6 alkyl)x1-C(=O)ORA11; RA2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORA11, -O-(C1- C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O-(C1-C6 alkyl)- NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)-NRA11RA12, - NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1-C6 alkyl)x1- C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, -C(=O)ORA11, -(C1- C6 alkyl)x1-C alkyl)x1-C(=O)RA11, and -NRA11- (C1-C6
Figure imgf000154_0002
alternatively, RA1 and RA2 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O- (C1-C6 alkyl)-O-(C1-C6 alkyl), -NRA11RA12, -O-(C1-C6 alkyl)-NRA11RA12, C1-C3 perfluoro alkyl, -NRA11-(C1-C6 alkyl)NRA11RA12, and -NRA11-(C1-C6 alkyl)- ORA11; RA3 and RA4 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, and -(C1-C6 alkyl)x1-C(=O)NRA11RA12; alternatively RA3 and RA4 are taken together with the nitrogen to which they are attached to provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring to heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, - ORA11, oxo, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, - C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; the dotted lines represent optional double bonds; each RA5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORA11, -O-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-ORA11, -NRA11RA12, -O- (C1-C6 alkyl)-NRA11RA12, -(C1-C6 alkyl)-NRA11RA12, -NRA11-(C1-C6 alkyl)- NRA11RA12, -NRA11-(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)x1-C(=O)RA11, -O-(C1- C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)x1-C(=O)ORA11, -C(=O)-RA11, - C(=O)ORA11, -(C1-C6 alkyl)x1-C(=O)NRA11RA12, -NRA11-(C1-C6 alkyl)x1- C(=O)RA11, and -NRA11-(C1-C6 alkyl)x1-C(=O)ORA11; n1 is 0 to 3; RA7 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-ORA11, -(C1-C6 alkyl)-NRA11RA12, - (C1-C6 alkyl)x1-C(=O)RA11, -(C1-C6 alkyl)
Figure imgf000156_0001
alkyl)x1- C(=O)NRA11RA12; each x1 is independently selected from 0 and 1; and each RA11 and RA12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RA11 and RA12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoro alkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
51. The combination of claim 47, wherein the ROCK2 inhibitor has a structure of Formula B-I:
Figure imgf000156_0002
or pharmaceutically acceptable salt thereof, wherein: XB1 is N or CH; XB2 is N or CH; XB3 is N or CRB3; XB4 is N or CRB4; XB5 is selected from the group consisting of C, CH and N; a1 is selected from 1 or 2; the dotted lines represent optional double bonds; each RB1 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, oxo, -CN, C1-C3 perfluoro alkyl, -ORB11, and -NRB11RB12; or alternatively, two RB1 attached to the same carbon or to adjacent carbons are taken together to form a 3- to 6-membered ring, which may optionally contain 0 to 2 ring heteroatoms selected from O, S and N, and which may be unsubstituted or optionally substituted by 1 to 3 substituents selected from halo, C1-C3 alkyl, NH2, OH, and O-C1-C3 alkyl; b1 is selected from 0, 1, and 2; RB2 is selected from H, halo, C1-C3 alkyl, NH2, OH, and O-C1-C3 alkyl; RB3 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1- C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, -C(=O)ORB11, -(C1- C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11- (C1-C6 alkyl)x2-C(=O)ORB11; RB4 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1- C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, -C(=O)ORB11, -(C1- C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11- (C1-C6 alkyl)x2-C(=O)ORB11; alternatively, RB3 and RB4 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O- (C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, and -NRB11-(C1-C6 alkyl)- ORB11; each RB5 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, oxo, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O- (C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)- NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1- C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, - C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2- C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; n2 is 0 to 3; RB6 and RB7 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O- (C1-C6 alkyl)-NRB11RB12, -O-(C1-C6 alkyl)-C -(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-C(=O)NRB11RB12, -NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl) (C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, - B11
Figure imgf000158_0001
OR , -(C1- C6 alkyl)x2-C (C1-C6 alkyl)
Figure imgf000158_0002
alternatively, RB6 and RB7 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C10 aryl, C5- C10 heteroaryl, 3- to 10-membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C10 aryl), -C1-C6 alkyl-(C5-C10 heteroaryl), -C1- C6 alkyl-(3- to 10-membered heterocyclyl), halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, - O-(C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, and -C(=O)-N(RB8)(RB9), and wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; RB8 and RB9 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, and -(C1-C6 alkyl)x2-C(=O)NRB11RB12, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; alternatively RB8 and RB9 are taken together with the nitrogen to which they are attached provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoro alkyl, -ORB11, oxo, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, - NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11- (C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2- C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, - C(=O)- RB11, -C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2-C(=O)ORB11; each x2 is independently selected from 0 and 1; and each RB11 and RB12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RB11 and RB12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
52. The combination of claim 51, wherein the ROCK2 inhibitor has a structure of the formula B-V:
Figure imgf000160_0001
or a pharmaceutically acceptable salt thereof, wherein: RB3 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1- C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2- C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, -C(=O)- RB11, -C(=O)ORB11, -(C1- C6 alkyl)x2-C(=O)NRB11RB12, -NRB11-(C1-C6 alkyl)x2-C(=O)RB11, and -NRB11- (C1-C6 alkyl)x2-C(=O)ORB11; RB4 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoro alkyl, -ORB11, -O-(C1- C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, -NRB11RB12, -O-(C1-C6 alkyl)- NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-NRB11RB12, - NRB11-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)x2-C(=O)RB11, -O-(C1-C6 alkyl)x2-
Figure imgf000160_0002
alternatively, RB3 and RB4 are taken together to form a 5- or 6-membered saturated or unsaturated fused ring which may contain from 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O- (C1-C6 alkyl)-O-(C1-C6 alkyl), -NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, C1-C3 perfluoro alkyl, -NRB11-(C1-C6 alkyl)NRB11RB12, and -NRB11-(C1-C6 alkyl)- ORB11; RB8 and RB9 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, -(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2-C(=O)ORB11, and -(C1-C6 alkyl)x2-C(=O)NRB11RB12, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; alternatively RB8 and RB9 are taken together with the nitrogen to which they are attached provide (i) a 4- to 6-membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5- to 10- membered hetero bicyclic ring system having from 0 to 3 additional ring heteroatoms selected from N, O and S; wherein the heterocyclic ring or the bicyclic ring system are unsubstituted or are substituted with from 1 to 4 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoro alkyl, -ORB11, oxo, -O-(C1-C6 alkyl)-ORB11, -(C1-C6 alkyl)-ORB11, - NRB11RB12, -O-(C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)-NRB11RB12, -NRB11- (C1-C6 alkyl)-NRB11RB12, -NRB11-(C1-C6 alkyl)-ORB11, - C(=O)RB11, -O-(C1-C6 alkyl)x2-C(=O)RB11, -(C1-C6 alkyl)x2- C(=O)- RB11, -C(=O)ORB11, -(C1-C6 alkyl)x2-C(=O) alkyl)x2-C(=O)RB11, and -NRB11-(C1-C6 alkyl)x2-C(=O)
Figure imgf000161_0001
RB10 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C10 aryl, C5-C10 heteroaryl, 3- to 10-membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C10 aryl), -C1- C6 alkyl-(C5-C10 heteroaryl), -C1-C6 alkyl-(3- to 10-membered heterocyclyl), - (C1-C6 alkyl)-NRB11RB12, -(C1-C6 alkyl)NRB11RB12, -(C1-C6 alkyl)-ORB11, and - C(=O)-N(RB11)( RB12), and wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, - OH, and NH2; each x2 is independently selected from 0 and 1; and each RB11 and RB12 are independently selected from the group consisting of H and C1- C6 alkyl; or alternatively, RB11 and RB12 are taken together when both are attached to the same nitrogen to form a 4- to 7- membered heterocyclic ring having from 0 to 2 additional ring heteroatoms selected from the group consisting of N, O and S, and which heterocyclic ring is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, - OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.
53. The method of claim 47, wherein the ROCK2 inhibitor is selected from a compound having the formula (A-I), (B-I), (C-I), (D-I), (E-I), (F-I), (G-I), (H-I), (J-I), (K-I), (L- I) and their subordinates, exemplary compounds thereof, derivatives thereof, or a pharmaceutically acceptable salt thereof.
54. The combination of claim 47, wherein the ROCK2 inhibitor is selected from
Figure imgf000162_0001
or a pharmaceutically acceptable salt thereof.
55. The combination of claim 47, wherein the ROCK2 inhibitor is selected from belumosudil (KD025), Zelasudil, Y-27632, Fasudil, GSK429286A, RKI-1447, Azaindole 1 (TC-S 7001), Hydroxyfasudil, GSK269962A, Ripasudil, AT13148, RX007, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof.
56. The combination according to any one of claims 47 to 55, wherein the DYRK1 inhibitor has a structure of Formula (M-I):
Figure imgf000163_0001
or a tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein: each RM1, RM3, and RM4 is independently selected from the group consisting of (i) H, halogen, CN, NO2, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl; wherein each substitutable carbon atom in the aforementioned moieties is independently substituted or unsubstituted with one or more, same or different substituents RM7; (ii) C(=O)RM5, C(=O)ORM6, C(=O)SRM6, C(=O)N(RM6a)(RM6b), ORM6, S(=O)n13RM6, S(=O)n13N(RM6a)(RM6b), S(=O)n13ORM6, N(RM6a)(RM6b), N(RM6)C(=O)RM5, N(RM6)C(=O)ORM6, N(RM6)C(=O)N(RM6a)(RM6b), N(RM6)S(=O)n13RM6, N(RM6)S(=O)n13N(RM6a)(RM6b), N(RM6)S(=O)n13ORM6; (iii) a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic or bicyclic moieties is independently substituted or unsubstituted with one or more, same or different substituents R8; RM2 is selected from the group consisting of H, halogen, CN, NO2, C1-C6-alkyl, C1-C6- haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy and C1-C6-haloalkoxy; RM6a, RM6b are independently selected from the group consisting of H, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkylcarbonyl, wherein each substitutable carbon atom in the aforementioned moieties is independently substituted or unsubstituted with one or more, same or different substituents RM9; and a 3- to 9- membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic moieties is independently substituted or unsubstituted with one or more, same or different substituents RM10; RM7 is selected from the group consisting of halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C(=O)RM5, C(=O)ORM6, C(=O)SRM6, C(=O)N(RM6a)(RM6b), ORM6, S(=O)n13RM6, S(=O)n13N(RM6a)(RM6b), S(=O)n13ORM6, N(RM6a)(RM6b), N(RM6)C(=O)RM5, N(RM6)C(=O)ORM6, N(RM6)C(=O)N(RM6a)(RM6b), N(RM6)S(=O)n13(RM6), N(RM6)S(=O)n13N(RM6a)(RM6b), N(RM6)S(=O)n13ORM6; and a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring and a 6- to 14-membered saturated, partially unsaturated or fully unsaturated carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non- oxidized, and wherein each substitutable carbon or hetero-atom in the aforementioned cyclic or bicyclic moieties is substituted or unsubstituted with one or more, same or different substituents RM8; RM8 is selected from the group consisting of halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6- alkylcarbonyl, N(RM6a)(RM6b), ORM6 and S(=O)n13RM6; RM9 is selected from the group consisting of halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6- alkylcarbonyl, N(RM11a)(RM11b), ORM11 and S(=O)n13RM11; and a 3- to 9-membered saturated, partially unsaturated or fully unsaturated carbocyclic or heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic moieties is substituted or unsubstituted with one or more, same or different substituents RM10; RM10 is selected from halogen, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6- haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6-alkylcarbonyl, N(RM11a)(RM11b), ORM11 and S(=O)n13RM11; RM11, RM11a, RM11b are independently selected from the group consisting of H, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl; and n13 is 0, 1 or 2.
57. The combination according to any one of claims 47 to 55, wherein the DYRK1 inhibitor is a compound having the formula (M-I), (N-I), (O-I), (P-I), (Q-I), (R-I), (S- I), (T-I), (U-I), (V-I), (W-I), (X-I), (Y-I), (Z-I) and their subordinates, exemplary compounds thereof, derivatives thereof, or pharmaceutically acceptable salts thereof..
58. The method according to any one of claims 47 to 55, wherein the DYRK1 inhibitor is selected from FX-1610, FX-9847, FX-8553, FX-5372, FX-7742, FX-8474, AZ191, Paprotrain, Harmine, GNF4877, GNF2133, INDY, FINDY, EHT1610, EHT 5372, AZ-Dyrk1B-33, KH-CB20, ARN25068, Haspin, JH-XVII-10, Leucettine L41, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof
59. The combination according to any one of claims 47 to 58, wherein the ROCK2 inhibitor and the DYRK1 inhibitor are contained in a same formulation.
60. The combination according to any one of claims 47 to 58, wherein the ROCK2 inhibitor and the DYRK1 inhibitor are contained in separate pharmaceutical dosage forms.
61. A kit comprising a combination of any one of claims 47 to 60.
62. The kit of claim 61, wherein the kit comprises an instruction that the ROCK2 inhibitor and the DYRK1 inhibitor are administered to a subject simultaneously.
63. The kit of claim 61, wherein the kit comprises an instruction that the ROCK2 inhibitor and the DYRK1 inhibitor are administered to a subject subsequently.
64. The kit of claim 61, wherein the kit comprises an instruction that the ROCK2 inhibitor is administered to a subject prior to administration of DYRK1 inhibitor.
65. A method for delaying or preventing the progression to type 1 diabetes in a patient that has been diagnosed to have a high risk of developing type 1 diabetes, and/or that is diagnosed to be experiencing the symptoms of the onset, or progression towards, type 1 diabetes, wherein the method comprises administering a therapeutically effective amount of a ROCK 2 inhibitor.
66. The method of claim 65, wherein the patient has one or more of a relative with type 1 diabetes, blood tests suggesting the patient may develop type 1 diabetes, and/or one or more symptoms associated with the development of type 1 diabetes.
67. The method of claim 66, wherein the blood test comprises one or more of a glycated hemoglobin (A1C) test, a random blood sugar test, or a fasted blood sugar test.
68. The method according claim 66 or 67, wherein the blood test(s) comprises an assays for one or more antibodies that are associated with the development of type 1 diabetes.
69. The method of claim 68, wherein the blood test assays for the presence of one or more of islet cell cytoplasmic autoantibodies (ICA), glutamic acid decarboxylase autoantibodies (GADA), insulinoma-associated-2 autoantibodies (IA-2A), and insulin autoantibodies (IAA).
70. The method according to any one of claims 65 to 69, wherein the patient is experiencing one or more of frequent urination, extreme thirst, dry mouth, itchy skin, fatigue, weakness, increased appetite, increased hunger, unexplained weight loss, slow-healing cuts, yeast infections.
71. The method according to any one of claims 65 to 70, wherein the ROCK2 inhibitor is selected from compounds having the formulae (A-I), (B-I), (C-I), (D-I), (E-I), (F-I), (G-I), (H-I), (J-I), (K-I), or (L-I), or a pharmaceutically acceptable salt thereof.
72. The method according to any one of claims 65 to 71, wherein the ROCK2 inhibitor is selected from
Figure imgf000167_0001
or a pharmaceutically acceptable salt thereof.
73. The method according to any one of claims 65 to 71, wherein the ROCK2 inhibitor is selected from belumosudil (KD025), Zelasudil, Y-27632, Fasudil, GSK429286A, RKI-1447, Azaindole 1 (TC-S 7001), Hydroxyfasudil, GSK269962A, Ripasudil, AT13148, RX007, and derivatives, isomers, hydrates, or pharmaceutically acceptable salts thereof.
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