IP Library › Patent Application 17423761

Patent Application

App. No. 17/423,761

METHODS OF TREATING CARTILAGE DISORDERS THROUGH INHIBITION OF CLK AND DYRK

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Patent No.: US None
App. No.: 17/423,761

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Abstract

Provided herein are methods of treating cartilage disorders in a subject using a dual CLK/DYRK inhibitor, or a pharmaceutically acceptable salt of solvate thereof, or a combination of a CLK inhibitor, or a pharmaceutically acceptable salt of solvate thereof, and DYRK inhibitor or, pharmaceutically acceptable salt or solvate thereof.

Claims (315)

1 . A method of treating osteoarthritis in a subject, the method comprising administering a therapeutically effective amount of a single compound, wherein the single compound is a dual DYRK1A/CLK2 and/or CLK3 inhibitor, which inhibits CLK2 and/or CLK3 at an IC 50 value of less than 100 nM and DYRK1A at an IC 50 value of less than 100 nM, or a pharmaceutically acceptable salt or solvate thereof, to a subject identified as having an elevated level of a biomarker associated with inflammation.

2 . A method of selecting a subject for treatment, the method comprising:

(a) performing a diagnostic test on the subject to confirm osteoarthritis; and

(b) selecting the subject for treatment, wherein the treatment includes administration of a single compound, wherein the single compound is a dual DYRK1A/CLK2 and/or CLK3 inhibitor, which inhibits CLK2 and/or CLK3 at an IC 50 value of less than 100 nM and DYRK1A at an IC 50 value of less than 100 nM, or a pharmaceutically acceptable salt or solvate thereof.

3 . The method of claim 2 , wherein the diagnostic test comprises at least one of joint aspiration, X-ray, and MRI.

4 . A method of selecting a subject for treatment, the method comprising selecting a subject identified as having an elevated level of a biomarker associated with inflammation for treatment with a therapeutically effective amount of a single compound, wherein the single compound is a dual DYRK1A/CLK2 and/or CLK3 inhibitor, which inhibits DYRK1A at an IC 50 value of less than 100 nM and CLK2 and/or CLK3 at an IC 50 value of less than 100 nM, or a pharmaceutically acceptable salt or solvate thereof.

5 .- 8 . (canceled)

9 . A method of modifying the progression of osteoarthritis in a subject in need thereof, the method comprising:

(a) identifying a subject, wherein the subject has an elevated level of Wnt pathway activity in a sample from the subject, as compared to a reference level; and

(b) administering to the subject a therapeutically effective amount of a single compound, wherein the single compound is a dual DYRK1A/CLK2 and/or CLK3 inhibitor, which inhibits CLK2 and/or CLK3 at an IC 50 value of less than 100 nM and DYRK1A at an IC 50 value of less than 100 nM, or a pharmaceutically acceptable salt or solvate thereof.

10 . A method of treating osteoarthritis in a subject, the method comprising administering a therapeutically effective amount of a single compound, wherein the single compound is a dual DYRK1A/CLK2 and/or CLK3 inhibitor, which inhibits CLK2 and/or CLK3 at an IC 50 value of less than 100 nM and DYRK1A at an IC 50 value of less than 100 nM, or a pharmaceutically acceptable salt or solvate thereof, to a subject identified as having an elevated level of Wnt pathway activity in a sample from the subject, as compared to a reference level.

11 . A method of selecting a subject for treatment, the method comprising:

(a) detecting an elevated level of Wnt pathway activity in a sample from the subject, as compared to a reference level; and

(b) selecting the subject for treatment, wherein the treatment includes administration of a single compound, wherein the single compound inhibits CLK2 and/or CLK3 at an IC 50 value of less than 100 nM and DYRK1A at an IC 50 value of less than 100 nM, or a pharmaceutically acceptable salt or solvate thereof.

12 . A method of selecting a subject for treatment, the method comprising selecting a subject identified as having an elevated level of Wnt pathway activity in a sample from the subject as compared to a reference level, and treating the subject with a therapeutically effective amount of a single compound, wherein the single compound is a dual DYRK1A/CLK2 and/or CLK3 inhibitor, which inhibits CLK2 and/or CLK3 at an IC 50 value of less than 100 nM and DYRK1A at an IC 50 value of less than 100 nM, or a pharmaceutically acceptable salt or solvate thereof.

13 . A method of inducing chondrogenesis in a subject in need thereof, the method comprising

(a) detecting an elevated level of Wnt pathway activity in a sample from the subject, as compared to a reference level; and

14 . A method of treating osteoarthritis in a subject in need thereof, the method comprising:

(a) detecting an elevated level of a biomarker associated with inflammation in a sample of the subject; and

15 . A method of treating osteoarthritis in a subject in need thereof, the method comprising:

(a) identifying a subject, wherein the subject is identified when a sample of the subject has an elevated level of a biomarker associated with inflammation; and

16 . A method of selecting a subject for treatment, the method comprising:

(a) detecting an elevated level of a biomarker associated with inflammation in a sample of the subject; and

17 .- 41 . (canceled)

42 . The method of claim 1 , wherein the method induces chondrogenesis.

43 . The method of claim 1 , wherein the method induces chondrocyte differentiation.

44 . The method of claim 1 , wherein the method increases chondrocyte function.

45 . The method of claim 1 , wherein the method prevents cartilage breakdown.

46 . The method of claim 1 , wherein the method prevents chondrocyte catabolic effects.

47 . The method of claim 1 , wherein the method induces cartilage growth.

48 . (canceled)

49 . The method of claim 1 , wherein chondrogenesis is increased compared to the chondrogenesis observed prior to administration of the single compound or a pharmaceutically acceptable salt of solvate thereof.

50 .- 59 . (canceled)

60 . The method of claim 1 , wherein the administration of the single compound or a pharmaceutically acceptable salt or solvate thereof, is parenteral.

61 . The method of claim 1 , wherein the administration of the single compound or a pharmaceutically acceptable salt or solvate there is intra-articular.

62 . The method of claim 61 , wherein the intra-articular administration is ultrasound-guided.

63 . The method of claim 61 , wherein the administration is directed to one or more joints.

64 . The method of claim 63 , wherein the one or more joints is selected from the group consisting of: shoulder, elbow, wrist, finger, sacroiliac, hip, knee, ankle, toe, and neck.

65 . (canceled)

66 . The method of claim 61 , wherein the single compound or a pharmaceutically acceptable salt or solvate thereof, is administered once.

67 . (canceled)

68 . The method of claim 61 , wherein the single compound or a pharmaceutically acceptable salt or solvate thereof, is administered more than once with each injection separated by at least 1 week.

69 . (canceled)

70 . The method of claim 61 , wherein the single compound or a pharmaceutically acceptable salt or solvate thereof, is administered more than once with each injection separated by at least 3 months.

71 . (canceled)

72 . The method of claim 61 , wherein the single compound or a pharmaceutically acceptable salt or solvate is administered more than once with each injection separated by 3 months to 60 months.

73 . The method of claim 1 , wherein the first compound, the second compound, and the dual DYRK1A/CLK2 and/or CLK3 inhibitor are each independently selected from a compound of Formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is selected from the group consisting of H, halide, and unsubstituted —(C 1-3 alkyl);

R 2 is selected from the group consisting of unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 1-9 haloalkyl), —(C 1-2 alkylene) p (C 3-6 carbocyclyl) optionally substituted with 1-12 R 4 , -monocyclic heterocyclyl optionally substituted with 1-10 R 5 , -phenyl optionally substituted with 1-5 R 6 , -heteroaryl optionally substituted with 1-4 R 7 , —CO 2 R 8 , —OR 9 , and —(C═O)R 10 ; wherein —(C 1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;

R 3 is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 11 , —(C 1-4 alkylene) p phenyl optionally substituted with 1-5 R 12 , -heteroaryl optionally substituted with 1-4 R 13 , and —(C 1-4 alkylene)OR 14 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 4 is halide;

each R 5 is independently selected from the group consisting of halide and unsubstituted —(C 1-9 alkyl);

each R 6 is independently selected from the group consisting of unsubstituted —(C 1-9 alkyl), unsubstituted —(C 1-9 haloalkyl), —OR 15 , and —(C 1-4 alkylene) p N(R 16 ) 2 ; wherein —(C 1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;

each R 7 is independently selected from the group consisting of halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 1-9 haloalkyl), —OR 15 , —CO 2 R 17 , —NR 18 (C═O)R 19 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 20 , and —(C 1-4 alkylene) p N(R 16 ) 2 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

R 8 is unsubstituted —(C 1-9 alkyl);

R 9 is unsubstituted —(C 1-9 alkyl);

R 10 is -aryl optionally substituted with 1-5 R 21 ;

each R 11 is independently selected from the group consisting of halide and unsubstituted —(C 1-9 alkyl);

each R 12 is independently selected from the group consisting of —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 20 , -aryl optionally substituted with 1-5 R 22 , —(C 1-4 alkylene)N(R 16 ) 2 , and —OR 23 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 13 is independently selected from the group consisting of halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 1-9 haloalkyl), —(C 1-4 alkylene) p N(R 16 ) 2 , —OR 23 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 20 , -aryl optionally substituted with 1-5 R 22 , and -heteroaryl optionally substituted with 1-4 R 24 ; wherein —(C 1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;

R 14 is selected from the group consisting of unsubstituted —(C 1-4 alkyl) and -aryl optionally substituted with 1-5 R 22 ;

each R 15 is independently selected from the group consisting of unsubstituted —(C 1-9 alkyl) and -heterocyclyl optionally substituted with 1-10 R 20 ;

each R 16 is independently selected from the group consisting of H and unsubstituted —(C 1-9 alkyl);

each R 17 is unsubstituted —(C 1-9 alkyl);

each R 18 is independently selected from the group consisting of H and unsubstituted —(C 1-9 alkyl);

each R 19 is unsubstituted —(C 1-9 alkyl);

each R 20 is independently selected from the group consisting of halide and unsubstituted —(C 1-9 alkyl);

each R 21 is independently selected from the group consisting of halide and unsubstituted —(C 1-9 alkyl);

each R 22 is independently selected from the group consisting of halide and unsubstituted —(C 1-9 alkyl);

each R 23 is independently selected from the group consisting of unsubstituted —(C 1-9 alkyl), —(C 1-4 alkylene)OR 25 , and —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 20 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 24 is independently selected from the group consisting of halide and unsubstituted —(C 1-9 alkyl);

each R 25 is independently selected from the group consisting of H and unsubstituted —(C 9 alkyl);

L 1 is selected from the group consisting of a bond, —CH═CH—, —C≡C—, —(CH 2 ) p NR 18 (C═O)—, —(C═O)NR 18 (CH 2 ) p —, —NR 18 (C═O)NR 18 —, —NH(CH 2 ) p —, and —(CH 2 ) p NH—;

L 2 is selected from the group consisting of a bond, —(C═O)NR 18 —, —NR 18 (C═O)—, —NHCH 2 —, and —CH 2 NH—; and

each p is independently an integer of 0 or 1.

74 . The method of claim 1 , wherein the first compound, the second compound, and the dual DYRK1A/CLK2 and/or CLK3 inhibitor are each independently selected from a compound of Formula (II):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is selected from the group consisting of H and halide;

R 2 is a 6-membered -heteroaryl optionally substituted with 1-4 R 3 ;

each R 3 is selected from the group consisting of —OR 4 , —NHR 5 , and —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 6 ; wherein —(C 1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;

each R 4 is independently selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 7 and —CH 2 CH(R 8 )NH 2 ;

each R 5 is independently selected from the group consisting of —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 9 and -carbocyclyl optionally substituted with 1-12 R 10 ; wherein —(C 1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;

each R 6 is independently selected from the group consisting of halide, —NH 2 , —OH, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and unsubstituted —(C 1-6 haloalkyl);

each R 7 is independently selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and unsubstituted —(C 1-6 haloalkyl);

each R 8 is independently selected from the group consisting of —(C 1-4 alkylene)aryl optionally substituted with 1-5 R 11 and —(C 1-4 alkylene)heteroaryl optionally substituted with 1-4 R 12 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 9 is independently selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and unsubstituted —(C 1-6 haloalkyl);

each R 10 is independently selected from the group consisting of halide, —OH, —NH 2 , unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and unsubstituted —(C 1-6 haloalkyl);

each R 11 is independently selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and unsubstituted —(C 1-6 haloalkyl);

each R 12 is independently selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and unsubstituted —(C 1-6 haloalkyl); and

each p is independently 0 or 1.

75 . The method of claim 1 , wherein the first compound, the second compound, and the dual DYRK1A/CLK2 and/or CLK3 inhibitor are each independently selected from a compound of Formula (III):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is selected from the group consisting of H, halide, and methyl;

R 2 is a -heteroaryl optionally substituted with 1-4 R 4 ;

R 3 is selected from the group consisting of H, -aryl optionally substituted with 1-5 R 5 , -heteroaryl optionally substituted with 1-4 R 6 , —C 1-6 alkyl optionally substituted with (i) phenyl optionally substituted with 1-5 R 11 or (ii) —OR 15 , and carbocyclyl optionally substituted with phenyl;

each R 4 is independently selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), unsubstituted —(C 1-6 haloalkyl), —(C 1-4 alkylene) p N(R 7 )(R 8 ), —NHC(═O)R 9 , —(C 1-4 alkylene) p OR 10 , unsubstituted -carbocyclyl, —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 14 , —(C 1-4 alkylene) p aryl optionally substituted with 1-5 R 11 , and —(C 1-4 alkylene) p heteroaryl optionally substituted with 1-4 R 12 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 5 is independently selected from the group consisting of halide, —CN, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), unsubstituted —(C 1-6 haloalkyl), —(C 1-4 alkylene) p aryl optionally substituted with 1-5 R 13 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 14 , —C(═O)N(R 15 ) 2 , —NHC(═O)R 16 , —(C 1-4 alkylene) p N(R 17 )(R 18 ), —SO 2 R 19 , and —OR 20 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 6 is independently selected from the group consisting of halide, —CN, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), unsubstituted —(C 1-6 haloalkyl), —(C 1-4 alkylene) p aryl optionally substituted with 1-5 R 13 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 14 , —C(═O)N(R 15 ) 2 , —NHC(═O)R 16 , —(C 1-4 alkylene) p N(R 17 )(R 18 ), —SO 2 R 19 , and —OR 20 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 7 is independently selected from the group consisting of H, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), and unsubstituted —(C 2-6 alkynyl);

each R 8 is independently selected from the group consisting of H, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and -heterocyclyl optionally substituted with 1-10 R 21 ;

alternatively, R 7 and R 8 are taken together to form a -heterocyclyl ring optionally substituted with 1-10 R 21 ;

each R 9 is independently selected from the group consisting of —N(R 22 ) 2 , -carbocyclyl optionally substituted with 1-12 R 23 , -heterocyclyl optionally substituted with 1-10 R 21 , and -aryl optionally substituted with 1-5 R 24 ;

each R 10 is independently selected from the group consisting of H, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), unsubstituted —(C 1-6 haloalkyl), and -heterocyclyl optionally substituted with 1-10 R 21 ;

each R 12 is independently selected from the group consisting of halide, —(C 1-4 alkylene) p OH, unsubstituted —(C 6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and unsubstituted —(C 1-6 haloalkyl); wherein —(C 1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;

each R 13 is independently selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and unsubstituted —(C 1-6 haloalkyl);

each R 14 is independently selected from the group consisting of halide, —(C 1-4 alkylene) p OH, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and unsubstituted —(C 1-6 haloalkyl); wherein —(C 1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;

each R 15 is independently selected from the group consisting of H, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and -carbocyclyl optionally substituted with 1-12 R 23 ;

alternatively, two adjacent R 15 are taken together to form a -heterocyclyl ring optionally substituted with 1-10 R 21 ;

each R 16 is independently selected from the group consisting of unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and -carbocyclyl optionally substituted with 1-12 R 23 ;

each R 17 is independently selected from the group consisting of H, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), and unsubstituted —(C 2-6 alkynyl);

each R 18 is independently selected from the group consisting of H, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), —(C 1-4 alkylene)N(CH 3 ) 2 , and -heterocyclyl ring optionally substituted with 1-10 R 21 ; wherein —(C 1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;

each R 19 is independently selected from the group consisting of unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), and unsubstituted —(C 2-6 alkynyl).

each R 20 is independently selected from the group consisting of H, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), unsubstituted —(C 1-6 haloalkyl), —CH(CH 2 OH) 2 , —(C 1-4 alkylene) p heterocyclyl ring optionally substituted with 1-10 R 21 , and -aryl optionally substituted with 1-5 R 24 ; wherein —(C 1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;

each R 21 is independently selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and unsubstituted —(C 1-6 haloalkyl);

each R 22 is independently selected from the group consisting of unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), and unsubstituted —(C 2-6 alkynyl);

each R 23 is independently selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and unsubstituted —(C 1-6 haloalkyl);

each R 24 is independently selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and unsubstituted —(C 1-6 haloalkyl);

Y is selected from the group consisting of —C(R 1 )═ and —N═; and

each p is independently 0 or 1.

76 . The method of claim 1 , wherein the first compound, the second compound, and the dual DYRK1A/CLK2 and/or CLK3 inhibitor are each independently selected from a compound of Formula (IV):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is a -heteroaryl optionally substituted with 1-2 R 3 ;

R 2 is selected from the group consisting of H, halide, -aryl optionally substituted with 1-5 R 4 -heteroaryl optionally substituted with 1-4 R 5 , and -heterocyclyl ring optionally substituted with 1-10 R 6 ;

each R 3 is independently selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), unsubstituted —(C 1-6 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 7 , —C(═O)N(R 8 ) 2 , —NHC(═O)R 9 , —(C 1-4 alkylene) p N(R 10 )(R 11 ), —(C 1-4 alkylene) p OR 12 , and -carbocyclyl optionally substituted with 1-12 R 13 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 4 is independently selected from the group consisting of halide, —CN, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), unsubstituted —(C 1-6 haloalkyl), —(C 1-4 alkylene) p NHSO 2 R 14 , —NR 15 (C 1-4 alkylene)NR 15 R 16 , —(C 1-4 alkylene) p NR 15 R 16 , —OR 17 , and -heterocyclyl optionally substituted with 1-10 R 19 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 5 is independently selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), unsubstituted —(C 1-6 haloalkyl), and —C(═O)R 18 ;

each R 6 is independently selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and unsubstituted —(C 1-6 haloalkyl);

each R 7 is independently selected from the group consisting of halide, —NH 2 , unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and unsubstituted —(C 1-6 haloalkyl);

each R 8 is independently selected from the group consisting of H, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), -heterocyclyl optionally substituted with 1-10 R 19 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 20 ; wherein —(C 1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;

each R 9 is independently selected from the group consisting of unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), unsubstituted —(C 1-6 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 19 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 20 ; —(C 1-4 alkylene) p aryl optionally substituted with 1-5 R 21 , —(C 1-4 alkylene) p N(R 22 ) 2 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 10 is independently selected from the group consisting of H, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), and unsubstituted —(C 2-6 alkynyl);

each R 11 is independently selected from the group consisting of H, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 20 ; and —(C 1-4 alkylene) p aryl optionally substituted with 1-5 R 21 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 12 is independently selected from the group consisting of H, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), unsubstituted —(C 1-6 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 19 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 20 ; —(C 1-4 alkylene) p aryl optionally substituted with 1-5 R 21 , —(C 1-4 alkylene) p N(R 22 ) 2 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 14 is independently selected from the group consisting of unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), and unsubstituted —(C 2-6 alkynyl);

each R 15 is independently selected from the group consisting of H, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), and unsubstituted —(C 2-6 alkynyl);

each R 16 is independently selected from the group consisting of H, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), and unsubstituted —(C 2-6 alkynyl);

each R 17 is independently selected from the group consisting of H, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), unsubstituted —(C 1-6 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 19 , and, —(C 1-4 alkylene) p N(R 22 ) 2 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 18 is independently selected from the group consisting of unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), and unsubstituted —(C 2-6 alkynyl);

each R 19 is independently selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and unsubstituted —(C 1-6 haloalkyl);

each R 20 is independently selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), unsubstituted —(C 2-6 alkynyl), and unsubstituted —(C 1-6 haloalkyl);

each R 22 is independently selected from the group consisting of H, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 2-6 alkenyl), and unsubstituted —(C 2-6 alkynyl);

each R 23 is independently selected from the group consisting of H and halide;

R 24 is selected from the group consisting of H, halide, and —OR 17 ;

Y 1 is selected from the group consisting of —CH═ and —N═;

Y 2 is selected from the group consisting of —C(R 2 )═ and —N═;

with the proviso that when Y 1 is —N═ then Y 2 is —C(R 2 )═;

Y 3 is selected from the group consisting of —C(R 24 )═ and —N═;

Y 4 and Y 5 are independently selected from the group consisting of —C(R 23 )═ and —N═;

Z 1 , Z 2 , and Z 3 are independently selected from the group consisting of —C(R 23 )═ and —N═;

if Y 2 is nitrogen then Y 3 , Y 4 , and Y 5 are carbon, and R 2 is absent;

if Y 3 is nitrogen then Y 4 and Y 5 are carbon;

if Y 4 is nitrogen then Y 3 and Y 5 are carbon;

if Y 5 is nitrogen then Y 3 and Y 4 are carbon;

if Z 1 is nitrogen then Z 2 and Z 3 are carbon;

if Z 2 is nitrogen then Z 1 and Z 3 are carbon;

if Z 3 is nitrogen then Z 1 and Z 2 are carbon; and

each p is independently 0 or 1.

77 . The method of claim 1 , wherein the first compound, the second compound, and the dual DYRK1A/CLK2 and/or CLK3 inhibitor are each independently selected from a compound of Formula (V):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 , R 2 , R 4 , and R 5 are independently absent or selected from the group consisting of H, halide, unsubstituted —(C 1-3 haloalkyl), and unsubstituted —(C 1-3 alkyl);

R 3 is selected from the group consisting of -aryl optionally substituted with 1-5 R 7 and -heteroaryl optionally substituted with 1-4 R 8 ;

R 6 is selected from the group consisting of —(C 1-4 alkylene) p aryl optionally substituted with 1-5 R 9 , —(C 2-4 alkenylene) p aryl optionally substituted with 1-5 R 9 , —(C 1-4 alkylene) p heteroaryl optionally substituted with 1-6 R 10 ; —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 11 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 12 , —(C 1-4 alkylene)N(R 13 )(R 14 ), —N(R 15 )(R 16 ), —CF(C 1-9 alkyl) 2 , —(C 1-4 alkylene) p O(C 3-9 alkyl), and —(C 2-9 alkynyl) optionally substituted with one or more halides; wherein each alkyl of —CF(C 1-9 alkyl) 2 is, independently, optionally substituted with one or more halides; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; wherein —(C 1-4 alkenylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 7 is selected from the group consisting of halide and —N(R 17 ) 2 ;

each R 8 is independently selected from the group consisting of H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —CN, —N(R 15 )(R 18 ), —(C 1-4 alkylene) p XR 19 , —C(═O)N(R 18 ) 2 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 20 , and -carbocyclyl optionally substituted with 1-12 R 21 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

alternatively, two adjacent R 8 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 22 and -carbocyclyl optionally substituted with 1-12 R 21 ;

each R 9 is independently selected from the group consisting of halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —XR 23 , —C(═O)N(R 18 ) 2 , —(C 1-4 alkylene) p N(R 24 ) 2 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 22 , and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 21 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 10 is independently selected from the group consisting of halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —CN, —XR 23 , —C(═O)N(R 18 ) 2 , —(C 1-4 alkylene) p N(R 24 ) 2 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 22 , and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 21 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 11 is independently selected from the group consisting of halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —(C 1-4 alkylene) p OR 19 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 22 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 21 , —N(R 15 )(R 25 ), —C(═O)(R 26 ), —(C 1-4 alkylene)C(═O)OR 27 , —(C 1-4 alkylene)aryl optionally substituted with one or more halides, —(C 1-4 alkylene) p heteroaryl optionally substituted with one or more halides, and —SO 2 (R 28 ); wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

alternatively, two R 11 attached to the same carbon atom can together represent ═O to form a carbonyl group;

each R 12 is independently selected from the group consisting of halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —(C 1-4 alkylene) p OR 19 , —N(R 15 )(R 29 ), —C(═O)(R 26 ), —C(═O)OR 27 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 22 , and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 21 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

R 13 is selected from the group consisting of H, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 20 , and -carbocyclyl optionally substituted with 1-12 R 21 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 14 is selected from the group consisting of unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 20 , and -carbocyclyl optionally substituted with 1-12 R 21 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

each R 15 is selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), and unsubstituted —(C 1-5 haloalkyl);

R 16 is selected from the group consisting of —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 20 , and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 21 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

R 17 is independently selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), and unsubstituted —(C 1-5 haloalkyl);

alternatively, two adjacent R 17 are taken together to form a -heterocyclyl ring optionally substituted with 1-10 R 22 ;

R 18 is independently selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —(C═O)R 15 , and —(C 1-4 alkylene) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl); wherein —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 19 is independently selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl), and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 21 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 20 independently is selected from the group consisting of halide, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —CN, —OH, —N(R 15 ) 2 , and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 21 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 21 is independently selected from the group consisting of halide, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), and —CN;

each R 22 is independently selected from the group consisting of halide, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —CN, —OH, —N(R 15 ) 2 , —C(═O)R 34 , and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 21 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 23 is independently selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —(C 1-4 alkylene)N(R 15 ) 2 , —(C 1-4 alkylene) p aryl optionally substituted with 1-10 R 30 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-12 R 31 , and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 21 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 24 is independently selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl), and —(C 1-4 alkylene)N(R 15 ) 2 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 25 is selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 32 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 21 , —(C 1-4 alkylene)OR 33 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

R 26 is selected from the group consisting of H, unsubstituted —(C 3-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —(C 1-4 alkylene) p aryl optionally substituted with one or more halides or unsubstituted —(C 1-5 alkyl), —(C 1-4 alkylene) p heteroaryl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl), and —(C 1-4 alkylene) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl); wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

R 27 is selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —(C 1-4 alkylene) p aryl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl), —(C 1-4 alkylene) p heteroaryl optionally substituted with one or more halides or unsubstituted —(C 1-5 alkyl), and —(C 1-4 alkylene) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl); wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

R 28 is selected from the group consisting of unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —(C 1-4 alkylene) p aryl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl), —(C 1-4 alkylene) p heteroaryl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl), and —(C 1-4 alkylene) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl); wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

each R 29 is selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 32 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 21 , —(C 1-4 alkylene)OR 33 , and —C(═O)O(C 1-5 alkyl); wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 30 is independently selected from the group consisting of halide, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), and —CN;

each R 31 is independently selected from the group consisting of halide, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), —CN, —OH, —C(═O)R 34 , —N(R 24 ) 2 , and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 21 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 32 is independently selected from the group consisting of halide and unsubstituted —(C 1-5 alkyl);

each R 33 is independently selected from the group consisting of H and unsubstituted —(C 1-5 alkyl);

each R 34 is independently selected from the group consisting of —O(C 1-5 alkyl) and a heteroaryl optionally substituted with 1-6 R 35 ;

each R 35 is a -heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl);

each X is selected from the group consisting of O and S;

Y 3 is CH or nitrogen;

Y 1 , Y 2 , Y 4 , and Y 5 are independently selected from the group consisting of CH and nitrogen;

wherein

if Y 1 is nitrogen then Y 2 , Y 4 , and Y 5 are carbon, Y 3 is CH, and R 4 is absent;

if Y 2 is nitrogen then Y 1 , Y 4 , and Y 5 are carbon, Y 3 is CH, and R 5 is absent;

if Y 3 is nitrogen then Y 1 , Y 2 , Y 4 , and Y 5 are carbon;

if Y 4 is nitrogen then Y 1 , Y 2 , and Y 5 are carbon, Y 3 is CH, and R 1 is absent;

if Y 5 is nitrogen then Y 1 , Y 2 , and Y 4 are carbon, Y 3 is CH, and R 2 is absent; and

each p is independently 0 or 1.

78 . The method of claim 1 , wherein the first compound, the second compound, and the dual DYRK1A/CLK2 and/or CLK3 inhibitor are each independently selected from a compound of Formula (VI):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

Ring A is a 5-6-membered heteroaryl optionally substituted with 1-4 R 1 ;

L is -L 1 -L 2 -L 3 -L 4 -;

L 1 is selected from the group consisting of unsubstituted —(C 1-3 alkylene)-, —NR 2 —, —NR 3 (C═O)—, —(C═O)NR 3 —, and —O—;

L 2 is selected from the group consisting of unsubstituted —(C 1-6 alkylene)- and —NR 2 —;

L 3 is selected from the group consisting of unsubstituted —(C 1-6 alkylene)-, —O—, and -carbocyclylene- optionally substituted with one or more halides;

L 4 is selected from the group consisting of unsubstituted —(C 1-6 alkylene)-, —O—, —NR 2 —, —NR 3 (C═O)—, —(C═O)NR 3 —, -arylene- substituted with 1-5 R 4 , and -heteroarylene- optionally substituted with 1-4 R 5 ;

with the proviso that —NR 2 — and —O— are not adjacent to each other;

with the proviso that two —NR 2 — and/or two —O— are not adjacent to each other;

with the proviso that two —NR 3 (C═O)— and/or —(C═O)NR 3 —, are not adjacent to each other;

each R 1 is selected from the group consisting of halide, unsubstituted —(C 1-3 alkyl), unsubstituted —(C 1-3 haloalkyl), and —CN;

each R 2 is selected from the group consisting of H and unsubstituted —(C 1-6 alkyl);

each R 3 is selected from the group consisting of H and unsubstituted —(C 1-6 alkyl);

each R 4 is selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 1-6 haloalkyl), and —CN;

each R 5 is selected from the group consisting of halide, unsubstituted —(C 1-6 alkyl), unsubstituted —(C 1-6 haloalkyl), and —CN;

Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are independently selected from the group consisting of CH and nitrogen; wherein

if Y 1 is nitrogen then Y 2 and Y 3 are CH;

if Y 2 is nitrogen then Y 1 and Y 3 are CH;

if Y 3 is nitrogen then Y 1 and Y 2 are CH;

if Y 4 is nitrogen then Y 5 and Y 6 are CH;

if Y 5 is nitrogen then Y 4 and Y 6 are CH; and

if Y 6 is nitrogen then Y 4 and Y 5 are CH.

79 . The method of claim 1 , wherein the first compound, the second compound, and the dual DYRK1A/CLK2 and/or CLK3 inhibitor are each independently selected from a compound of Formula (VII):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

Ring A is a 5-6-membered heteroaryl optionally substituted with 1-3 R 1 ;

L is -L 1 -L 2 -L 3 -L 4 -

L 1 is selected from the group consisting of unsubstituted —(C 1-3 alkylene)-, —NR 2 —, —NR 3 (C═O)—, —(C═O)NR 3 —, and —O—;

L 2 is selected from the group consisting of unsubstituted —(C 1-6 alkylene)-, —NR 2 —, —NR 3 (C═O)—, and —(C═O)NR 3 —;

L 3 is selected from the group consisting of unsubstituted —(C 1-6 alkylene)-, —O—, and carbocyclylene optionally substituted with one or more halides;

L 4 is selected from the group consisting of unsubstituted —(C 1-6 alkylene)-, —O—, —NR 2 —, —NR 3 (C═O)—, —(C═O)NR 3 —, -arylene substituted with 1-5 R 4 , and -heteroarylene optionally substituted with 1-4 R 5 ;