Pharmaceutical compounds for the treatment of complement-mediated disorders

Abstract

The present disclosure provides pharmaceutical compounds for treating medical disorders such as complement-mediated disorders, including complement C1-mediated disorders.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 822,553, filed March 22, 2019, and U.S. Provisional Patent Application No. 62 / 951,669, filed December 20, 2019, the entireties of each of which are incorporated by reference herein for all purposes.

[0002] Provided herein are pharmaceutical compounds for treating medical disorders such as complement-mediated disorders, including complement C1-mediated disorders. [Background technology]

[0003] The complement system is part of the innate immune system, which does not adapt to changes throughout the host's life, but is recruited and used by the adaptive immune system. For example, the complement system assists or complements the ability of antibodies and phagocytes to eliminate pathogens. This elaborate regulatory pathway allows for a rapid response to pathogens while protecting host cells from destruction. More than 30 proteins and protein fragments make up the complement system. These proteins act through opsonization (enhancing phagocytosis of antigens), chemotaxis (attraction of macrophages and neutrophils), cytolysis (rupture of the membrane of foreign cells), and agglutination (clustering and binding of pathogens to each other).

[0004] The complement system has three pathways, the classical pathway, the alternative pathway and the lectin pathway. The classical pathway is triggered by antibody-antigen complexes containing the antibody isotypes IgG and IgM. The antibody-antigen complex binds to C1, which initiates the degradation of C4 and C2 to generate C3 convertase, which then cleaves C3 into C3a and C3b. C3a interacts with its C3a receptor to recruit white blood cells, while C3b binds to the C3 convertase to form C5 convertase. C5 convertase breaks C5 down into C5a and C5b. Like C3a, C5a interacts with its C5a receptor to recruit white blood cells, while C5b interacts with C6, C7, C8 and C8, which together form the cylindrical membrane attack complex (MAC), which causes the cell to swell and burst. These immune responses can be inhibited by preventing C1 from binding to the antibody-antigen complex.

[0005] Given the variety of serious diseases mediated by dysfunction of the complement system, there is a clear medical need to provide pharma- ceutically acceptable compounds, methods, compositions and methods of manufacture for inhibiting the complement system in patients in need thereof.

[0006] It is therefore an object of the present invention to provide compounds and uses thereof and compositions for treating disorders resulting from or amplified by a dysfunction of the complement system.It is another object of the present invention to provide compounds, uses, compositions, combinations and processes of manufacture that are capable of inhibiting C1s (complement 1 esterase) and thereby treating disorders mediated by said enzyme. Summary of the Invention [Means for solving the problem]

[0007] The present disclosure includes compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, or pharma- ceutically acceptable salts, prodrugs, isotopic analogs, N-oxides, or isolated isomers thereof, optionally in a pharma- ceutically acceptable composition. In one embodiment, the compounds described herein, or salts or compositions thereof, are used to treat a medical disorder that is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade), e.g., a cellular disorder or abnormality that adversely affects the ability of a cell to participate in or respond to normal complement activity, including the classical complement pathway, or an undesirable complement-mediated response to a medical treatment, such as surgery or other medical procedure or administration of a pharmaceutical or biopharmaceutical, a blood transfusion, or administration of other allogeneic tissue or bodily fluid.

[0008] These compounds can be used to treat medical conditions in a host, typically a human, in need thereof. The active compounds can act as inhibitors of the complement classical pathway by inhibiting complement C1s. In one embodiment, a method is provided for the treatment of disorders mediated by complement activity, comprising the administration of an effective amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, or a pharma- ceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharma- ceutically acceptable composition, as described in more detail below.

[0009] In one embodiment, the disorder is associated with the classical complement pathway and the compound inhibits the classical pathway. In yet another embodiment, the disorder is associated with the alternative complement cascade pathway. In a further embodiment, the disorder is associated with the complement lectin pathway. Alternatively, the active compound, or salt or prodrug thereof, may act via a mechanism of action different from the complement cascade to treat the disorders described herein. In another embodiment, the active compound, and / or salt or prodrug thereof, inhibits a combination of these pathways.

[0010] In another embodiment, a method is provided for treating a host, typically a human, with a disorder mediated by the complement system, comprising administering a prophylactic antibiotic or vaccine to reduce the likelihood of bacterial infection during treatment with one of the compounds described herein. In certain embodiments, the host, typically a human, is administered a prophylactic vaccine before, during, or after treatment with one of the compounds described herein. In certain embodiments, the host, typically a human, is administered a prophylactic antibiotic before, during, or after treatment with one of the compounds described herein. In some embodiments, the infection is a meningococcal infection (e.g., septicemia and / or meningitis), an Aspergillus infection, or an infection caused by an encapsulated organism, such as Streptococcus pneumoniae or Haemophilus influenza type b (Hib), especially in children. In other embodiments, the vaccine or antibiotic is administered to the patient after contracting an infection caused by or associated with inhibition of the complement system.

[0011] In one embodiment of the disclosure, a compound of formula I, II, III, IV, V, VI, VII, VIII, or IX, optionally in a pharma- ceutically acceptable carrier: [ka] [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof, is provided, During the ceremony, each n is independently 1, 2, or 3; each m is independently 0, 1, 2, or 3; [ka] is either a single or double bond, Z is CH 2 , C(CH 2 ), or C(O), X 1 is S, O, and N(R 30 ), X 2 is a bond, N(R 30 ), and -ON(R 30 )- is selected from X 3 is N and C(R 17 ), X 4 is N and C(R 18 ), where X 3 and X 4 can be N, X 5 is C or Si, X 6 teeth, [ka] is selected from X 7 is O, S, N(R 30 ), and CR 5 R 6 is selected from R 1 and R 2 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 2 ~C 6Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 R is independently selected from the group consisting of heterocycle, aryl, heteroaryl, cyano, and nitro, and is other than hydrogen, halogen, cyano, and nitro. 1 Groups and R 2 Each of the groups is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; R 3 and R 4 is hydrogen, C(O)R 31 , -SR 30 , and -OR 30 are independently selected from Or, R 3 and R 4 is hydrogen, CN, C(O)R 31 , -SR 30 , and -OR 30 are independently selected from Or, R 3 and R 4 Instead, combine and C 1 ~C 6 Alkyl, C1 ~C 6 Haloalkyl, -OR 30 and oxo, forming an oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from: [ka] teeth, [ka] It may be Each R 5 and R 6 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) 2 where R 5 Groups and R 6 The groups may optionally be replaced by a carbon-carbon double bond when they are on adjacent carbons, for example: [ka] is optionally [ka] Including, R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -OR30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 R is independently selected from the group consisting of heterocycle, aryl, and heteroaryl, and is other than hydrogen and halogen. 7 Group, R 8 Group, R 9 Group, R 10 Group, R 11 Groups and R 12 Each of the groups is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; Or, R 7 and R 8 may be taken together with the carbons to which they are attached to form a 3- to 6-membered carbocyclic spiro ring or a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; Or, R 7 and R 8 together with the carbons to which they are attached, [ka] or may form a carbonyl; Or, R 9 and R 10may be joined together with the atom to which they are attached to form a 3- to 6-membered carbocyclic spiro ring or a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; Or, R 9 and R 10 together with the atoms to which they are attached, [ka] or may form a carbonyl; Or, R 11 and R 12 may be taken together with the carbons to which they are attached to form a 3- to 6-membered carbocyclic spiro ring or a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; Or, R 11 and R 12 together with the carbons to which they are attached, [ka] or may form a carbonyl; Or, R 7 and R 9 together with the atoms to which they are attached form a 3- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; or Or, R 9 and R 11 together with the atoms to which they are attached form a 3- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; or Or, R 7 and R 11 form one or two carbon bridges together with the atoms to which they are attached, e.g. [ka] is optionally [ka] or [ka] It may be Each R 13 is hydrogen or C 1 ~C 6 independently selected from alkyl, R 14 , R 15 , and R 16 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -C 1 ~C 6 Alkyl-aryl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 R is independently selected from the group consisting of heterocycle, aryl, heteroaryl, cyano, and nitro, and is other than hydrogen, halogen, cyano, and nitro. 14 , R 15 , and R 16 Each of the groups is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31, -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; Or, R 14 , R 15 , and R 16 is hydrogen, halogen, SF 5 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -C 1 ~C 6 Alkyl-aryl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 R is independently selected from the group consisting of heterocycle, aryl, heteroaryl, cyano, and nitro, and is other than hydrogen, halogen, cyano, and nitro. 14 , R 15 , and R 16 Each of the groups is SF 5 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; R 17 and R 18 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) 2 are independently selected from Or, R 17 and R 18 form a double bond with the carbon to which they are attached, R 19 and R 20 is hydrogen, C 1 ~C 6 Alkyl, C 5 ~C 10 Bicyclic carbocycle, C 4 ~C 6 Heterocycle, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -N(R 30 ) 2 , -(CH 2 ) n -R 33 , and [ka] are independently selected from R 21 is C 1 ~C 6 Alkyl and -OC 1 ~C 6 alkyl; Or, R 21 is C 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkyl, -OC 1 ~C 6is selected from alkyl, aryl, -O-aryl, heteroaryl, or -O-heteroaryl; R 21 Each of the groups is SF 5 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; Each R 30 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, aryl, heteroaryl, heterocycle, and C(O)R 31 are independently selected from Each R 31 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 32 , -SR 32 , -N(R 32 ) 2 , heterocycle, aryl, and heteroaryl; Each R 32 is hydrogen, C 1 ~C 6 Alkyl, and C 1 ~C 6 haloalkyl; Each R 33 is hydrogen, guanidine, heteroaryl, aryl, -C 6 H 5 -OR 30 ;-OR30 , -SR 30 , -SeR 30 , -N(R 30 ) 2 , and -C(O)R 31 are independently selected from wherein for compounds of formula I and formula II, at least one of the following is satisfied: aX 3 is C(R 17 ) and X 4 is C(R 18 ) is; bR 17 is a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) 2 Selected from; cX 5 is Si; dZ is C(CH 2 ) is; eZ is CH 2 is; fR 7 and R 8 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; gR 9 and R 10 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; hR11 and R 12 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; iR 7 and R 9 together with the atoms to which they are attached form a 3- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; R 10 or R 12 is not hydrogen; jR 9 and R 11 together with the atoms to which they are attached form a 3- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; R 8 or R 10 is not hydrogen; kR 7 and R 11 form one or two carbon bridges together with the atoms to which they are attached; lX 6 teeth, [ka] Selected from; mR 3 and R 4 At least one of the groups is CN, -SR 30 or C(O)R 31 is; or nR 3 and R 4 is combined with C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30and oxo to form an oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from:

[0012] In one embodiment, compound IX of formula [ka] or a pharma- ceutically acceptable salt thereof.

[0013] In another embodiment, compound IX of formula [ka] or a pharma- ceutically acceptable salt thereof.

[0014] In an alternative embodiment, compound IX of formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0015] In another embodiment, the compound of the disclosure is represented by formula X, XI, or XII: [ka] A compound represented by the formula: or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof; During the ceremony, R 22 -C 1 ~C 6 Alkyl-R 23 , -C 2 ~C 6 Alkenyl-R 23 , -C 2 ~C 6 Alkynyl-R 23 and bicyclic cycloalkyl-R 23Selected from R 22 Each of the 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; R 23 is hydrogen, sugar, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , and -S(O) 2 R 31 is selected from All other variables are as defined herein. wherein for compounds of formula X and formula XI, at least one of the following is satisfied: aX 3 is C(R 17 ) and X 4 is C(R 18 ) is; bR 17 is a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) 2 Selected from; cX 5 is Si; dZ is C(CH 2 ) is; eZ is CH2 is; fR 7 and R 8 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; gR 9 and R 10 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; hR 9 and R 11 together with the atoms to which they are attached form a 3- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; R 10 is not hydrogen; iR 11 and R 12 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; jR 7 and R 9 together with the atoms to which they are attached form a 3- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; R 10 is not hydrogen; kR 7 and R 11 form one or two carbon bridges together with the atoms to which they are attached; lR 22 must contain at least three ORs. 30 substituted with a group; mR 23 is a sugar; nR 3 and R 4 At least one of the groups is CN, -SR 30 or C(O)R 31 is; or oR 3 and R 4 is combined with C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 and oxo to form an oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from:

[0016] In one embodiment, R 23 is hydrogen, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , and -S(O) 2 R 31 is selected from.

[0017] In one embodiment, the compound of formula X is selected from: [ka]

[0018] In one embodiment, R 23 -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31, and -S(O) 2 R 31 is selected from.

[0019] In another embodiment, a compound of formula X, XI, or XII, optionally in a pharma- ceutically acceptable carrier, is [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof.

[0020] In an alternative embodiment, the compound of formula XII is [ka] or a pharma- ceutically acceptable salt thereof.

[0021] In another embodiment, the compound of the present disclosure has the formula XIII: [ka] A compound represented by the formula: or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof; During the ceremony, X 7 is O, S, N(R 30 ), and CR 5 R 6 is selected from o is 0, 1, or 2; Each R 25 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30, -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 R is independently selected from the group consisting of heterocycle, aryl, heteroaryl, cyano, and nitro, and is other than hydrogen, halogen, cyano, and nitro. 25 Each of the groups is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from: heterocycle, aryl, heteroaryl, cyano, and nitro; Each R 25 is hydrogen, SF 5 , halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 R is independently selected from the group consisting of heterocycle, aryl, heteroaryl, cyano, and nitro, and is other than hydrogen, halogen, cyano, and nitro. 25 Each of the groups is C 1 ~C 6 Alkyl, C 2~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; R 26 teeth, [ka] Selected from or Or, R 26 teeth, [ka] is selected from R 27 teeth, [ka] Selected from or Or, R 27 teeth, [ka] and R 34 teeth, [ka] is selected from X 11 N and CR 1 is selected from X 12 N and CR 2is selected from where each of the other variables is as defined herein.

[0022] In another embodiment, the compound of the present disclosure is of formula XIV: [ka] A compound represented by the formula: or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof; wherein the variables are as defined herein, and for compounds of formula XIV, at least one of the following is satisfied: aX 1 is O or N(R 30 ) is; bR 14 is not hydrogen; cR 1 is not hydrogen; dR 2 is not hydrogen; eR 3 is not hydrogen; or fR 4 is not hydrogen.

[0023] In another embodiment, the compound of formula XIII or XIV, optionally in a pharma- ceutically acceptable carrier, is [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof.

[0024] In another embodiment, the compound of the present disclosure is of formula XV: [ka] A compound represented by the formula: or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof; During the ceremony, each X 8 and X 9 are O, S, and NR 30 , C.R. 9 R 10 , C.R. 5 R 6 and C.H. 2 where X is independently selected from 8 and X 9 cannot both be the same group, and all other variables are as defined herein.

[0025] In an alternative embodiment, [ka] teeth, [ka] For example, in this embodiment, the formula [ka] The compound is [ka] can be replaced with

[0026] In another embodiment, the compound of the disclosure has the formula XVI, XVII, or XVIII, optionally in a pharma- ceutically acceptable carrier: [ka] [ka] A compound represented by the formula: or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof; During the ceremony, X 10 teeth, [ka] is selected from R 35 is C 3 ~C 10 Alkyl or C 3 ~C 10 haloalkyl; All other variables are as defined herein.

[0027] In another embodiment, the compound of the present disclosure has the formula XIX or formula XX: [ka] A compound represented by the formula: or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof; During the ceremony, R 29 is a halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, and heteroaryl; R other than hydrogen and halogen; 29 Each of the groups is C 1 ~C 6 Alkyl, C 2 ~C6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; All other variables are as defined herein.

[0028] In an alternative embodiment, R 29 is hydrogen.

[0029] Also disclosed are pharmaceutical compositions comprising a compound or salt of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX in combination with a pharma- ceutically acceptable carrier.

[0030] Thus, the present disclosure includes at least the following features: a. a compound of the present disclosure or a pharma- ceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharma- ceutically acceptable composition; b. Fatty liver and conditions resulting from fatty liver, such as nonalcoholic steatohepatitis (NASH), hepatitis, cirrhosis, and liver failure; dermatomyositis; amyotrophic lateral sclerosis; biologics (e.g., CAR Cytokine or inflammatory responses to T-cell therapy; hereditary angioedema (HAE), chronic immune thrombocytopenia (ITP), cold agglutinin disease, cold agglutinin syndrome, warm autoimmune hemolytic anemia, cryoglobulinemia, bullous pemphigoid, common variable immunodeficiency, endotoxemia, sepsis, multiple organ dysfunction syndrome, hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), acute kidney injury, kidney transplantation, graft rejection, antibody-mediated rejection, delayed graft function, end-stage renal disease, myasthenia gravis, systemic lupus erythematosus (SLE), paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid arthritis, multiple sclerosis, age-related macular degeneration (AMD), retinal degeneration, other ophthalmic diseases (e.g., geographic atrophy), respiratory or cardiovascular disease; disorders of the central or peripheral nervous system, ischemia-reperfusion injury or stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), Alzheimer's disease (AD), multiple sclerosis, neuromyelitis optica (NMO), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD), demyelinating myelinating diseases, demyelinating leukodystrophy diseases, and the development of neuroinflammatory disorders; c. A pharma- ceutically acceptable composition of a compound of the present disclosure, or a pharma- ceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, in a pharma- ceutically acceptable carrier; d. A compound of the present disclosure, or a pharma- ceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharma- ceutically acceptable composition, for use in the treatment or prevention of a disorder mediated by the complement pathway, e.g., the classical complement pathway; e. Fatty liver and conditions resulting from fatty liver, such as nonalcoholic steatohepatitis (NASH), hepatitis, cirrhosis, and liver failure; dermatomyositis; amyotrophic lateral sclerosis; biologics (e.g., CAR Cytokine responses or inflammatory responses to T-cell therapy; hereditary angioedema (HAE), chronic immune thrombocytopenia (ITP), cold agglutinin disease, cold agglutinin syndrome, warm autoimmune hemolytic anemia, cryoglobulinemia, bullous pemphigoid, common variable immunodeficiency, endotoxemia, sepsis, multiple organ dysfunction syndrome, hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), acute kidney injury, kidney transplantation, graft rejection, antibody-mediated rejection, delayed graft function, end-stage renal disease, myasthenia gravis, systemic lupus erythematosus (SLE), paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid arthritis, multiple sclerosis, age-related macular degeneration (AMD), retinal degeneration, other ophthalmic diseases (e.g., geographic atrophy), respiratory or cardiovascular disease; use of a compound of the present disclosure as described herein, or a pharmacologic acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmacologic composition, in the manufacture of a medicament for the treatment or prevention of disorders including, but not limited to, disorders of the central or peripheral nervous system, ischemia-reperfusion injury or stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), Alzheimer's disease (AD), multiple sclerosis, neuromyelitis optica (NMO), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD), demyelinating myelinating diseases, demyelinating leukodystrophy diseases, and the development of neuroinflammatory disorders; f. A process for producing a medicament intended for therapeutic use for treating or preventing a disorder, or generally for treating or preventing a disorder mediated by the classical complement pathway, characterized in that a compound or an embodiment of the active compound of the disclosure is used in the manufacture; g. A compound of the present disclosure described herein or a salt thereof in substantially pure form (e.g., at least 90 or 95%); h. A compound of the present disclosure as described herein, or a pharma- ceutical acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a carrier to form a pharma- ceutical acceptable composition, for use in treating a medical disorder that is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade), a cellular disorder or abnormality that adversely affects the ability of a cell to participate in or respond to normal complement activity, or an undesirable complement-mediated response to a medical treatment, such as surgery or other medical procedure or administration of a pharmaceutical or biopharmaceutical, blood transfusion, or administration of other allogeneic tissue or bodily fluid. i. Each of (a)-(h) above, or each collection of moieties herein and each active compound made therefrom or use thereof, shall be deemed and considered to be specifically and individually disclosed, since such description is for space purposes only and is not intended to describe only the genus or subgenus for such indications. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] term Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed invention belongs.

[0032] Any compound of the formula described herein includes other isomers, such as enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates, and rotamers, as if each were specifically set forth, unless otherwise specified or excluded by context.

[0033] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" means "and / or." The recitation of ranges of values ​​is intended merely to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise specified herein, and each separate value is incorporated herein as if it were individually recited herein. The endpoints of all ranges are included within the range and are independently combinable. All methods described herein may be performed in any suitable order unless otherwise specified herein or clearly contradicted by context. The use of examples or exemplary language (e.g., "such as") is intended merely to better illustrate the invention and does not limit the scope of the invention unless otherwise asserted.

[0034] The present disclosure includes compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX that contain an isotopic substitution of at least one desired atom in an amount greater than the natural abundance of that isotope, i.e., enriched.

[0035] Examples of isotopes that may be incorporated into the compounds of the invention include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 18 F 31 P, 32 P, 35 S, 36 CI, and 125 In one embodiment, the isotopically labeled compounds are used in metabolic studies ( 14 C), reaction kinetic studies (e.g., 2 H or 3H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiation treatment of patients. 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by carrying out the procedures disclosed in the schemes or examples and preparation methods described below, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0036] By way of general example and without limitation, isotopes of hydrogen, e.g., deuterium ( 2 H) and tritium ( 3 H) may be optionally used anywhere in the structures described to achieve the desired result. Alternatively or additionally, isotopes of carbon, such as 13 C and 14 C may be used. In one embodiment, isotope substitution replaces hydrogen with deuterium at one or more positions on a molecule to improve the efficacy of a drug, e.g., pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, deuterium may be attached to a carbon at the site of bond cleavage during metabolism (α-deuterium kinetic isotope effect) or next to or near the site of bond cleavage (β-deuterium kinetic isotope effect).

[0037] Isotopic substitution, for example deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced with deuterium. In certain embodiments, the isotope is enriched at any position of interest to 80, 85, 90, 95 or 99% or more. In one embodiment, deuterium is enriched at a desired position to 80, 85, 90, 95 or 99%. Unless otherwise stated, enrichment at any point is above natural abundance, and in one embodiment, is sufficient to alter the detectable properties of the drug in humans.

[0038] In one embodiment, the replacement of hydrogen atoms with deuterium atoms can occur in any formula of the present disclosure. In one embodiment, the replacement of hydrogen atoms with deuterium atoms occurs within any R group. In one embodiment, the R group is R 1 , R 2 , R 3 , R 4、 R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 25 , R 26 , R 27 , R 29 , R 30 , R 31 , R 32 , R 33 , R 200 , and R 201 For example, if any of the R groups is or includes, e.g., through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in a non-limiting embodiment, CD 3、 CH 2 CD 3 , CD 2 CD 3 , C.D.H. 2 , CD 2 H, C.D. 3 , C.H.D.C.H. 2 D, C.H. 2 CD 3 , C.H.D.C.H.D. 2 , O.C.D.H. 2 , OCD 2 H, or OCD 3etc. In certain other embodiments, the R group has a "'" or "a" designation, which, in one embodiment, can be deuterated. In certain other embodiments, when two substituents on a central core ring combine to form a cyclopropyl ring, the unsubstituted methylene carbon can be deuterated.

[0039] The compounds of the present disclosure may form solvates with solvents, including water. Thus, in one embodiment, the present disclosure includes solvated forms of active compounds. The term "solvate" refers to a molecular complex of a compound of the present disclosure (including its salts) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethylsulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex of a compound of the present disclosure with water. Pharmaceutically acceptable solvates according to the present disclosure include those in which the solvent of crystallization may be isotopically substituted, e.g., D 2 O, d 6 -Acetone, d 6 -DMSO. The solvates may be in liquid or solid form.

[0040] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment of a substituent. For example, -(C=O)NH 2 is attached through the carbon of the keto (C=O) group.

[0041] As used herein, the term "substituted" means that any one or more hydrogens on the specified atom or group are replaced with a moiety selected from the indicated group, provided that the replacement does not exceed the normal valence of the specified atom and the resulting compound is stable. For example, when a substituent is oxo (i.e., =O), two hydrogens on the atom are replaced. For example, a pyridyl group substituted with oxo is a pyridone. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.

[0042] A stable active compound refers to a compound that can be isolated and formulated into a dosage form with a shelf life of at least one month. A stable manufacturing intermediate or precursor of an active compound is stable if it does not decompose within the time period required for reaction or other use. A stable moiety or substituent is one that does not decompose, react, or disintegrate within the time period required for use. A non-limiting example of an unstable moiety is one that is bonded to a heteroatom in an unstable configuration, as is commonly known and identifiable by those skilled in the art.

[0043] Any suitable group may be present at the "substituted" or "optionally substituted" positions that will form a stable molecule and fulfill the desired objectives of the present disclosure, such as halogen (which may be independently F, Cl, Br, or I); cyano; hydroxyl; nitro; azido; alkanoyl (C 2 ~C 6alkanoyl groups, etc.; carboxamido; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, e.g., phenoxy; thioalkyl, including those with one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups, including those with one or more sulfonyl linkages; aryl (e.g., phenyl, biphenyl, naphthyl, etc., where each ring is either substituted or unsubstituted); arylalkyl, e.g., having 1-3 single or fused rings and 6 to about 14 or 18 ring carbon atoms (benzyl is an exemplary arylalkyl group); arylalkoxy, e.g., having 1-3 single or fused rings (benzyloxy is an exemplary arylalkoxy group). or a saturated or partially unsaturated heterocycle having 1-3 single or fused rings containing one or more N, O, or S atoms, or a heteroaryl having 1-3 single or fused rings containing one or more N, O, or S atoms, such as, but not limited to, coumarin, quinoline, isoquinoline, quinazoline, pyridine, pyrazole, oxadiazole, triazole, pyrazine, pyrimidine, furan, pyrrole, thienyl, thiazole, triazine, oxazole, isoxazole, imidazole, indole, benzofuran, benzothiazole, tetrahydrofuran, tetrahydropyran, piperidine, morpholine, piperazine, and pyrrolidine. Such groups may be further substituted, for example, with hydroxy, alkyl, alkoxy, halogen, and amino. In certain embodiments, "optionally substituted" refers to halogen, hydroxyl, amino, cyano, -CHO, -COOH, -CONH, -CH, -CHOH ... 2 , C 1 ~C 6 Alkyl, including alkyl, C 2 ~C 6 Alkenyl, including alkenyl, C 2 ~C 6 Alkynyl, including alkynyl, -C 1 ~C 6 Alkoxy, C 2 ~C 6 Alkanoyl, including alkanoyl (mono and di-C 1 ~C 6Alkylamino)C 0 ~C 2 Alkyl, C 1 ~C 6 Haloalkyl, including haloalkyl, hydroxyC 1 ~C 6 Alkyl, ester, carbamate, urea, sulfonamide, -C 1 ~C 6 Alkyl(heterocyclo), C 1 ~C 6 Alkyl(heteroaryl), -C 1 ~C 6 Alkyl(C 3 ~C 7 Cycloalkyl), OC 1 ~C 6 Alkyl(C 3 ~C 7 Cycloalkyl), B(OH) 2 , phosphate, phosphonate and C 1 ~C 6 Contains one or more substituents independently selected from haloalkoxy, including haloalkoxy.

[0044] "Alkyl" is a branched or straight chain saturated hydrocarbon group. In one embodiment, an alkyl contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one embodiment, an alkyl contains 1 to about 8 carbon atoms. In certain embodiments, an alkyl is selected from the group consisting of C 1 ~C 2 , C 1 ~C 3 , C 1 ~C 4 , C 1 ~C 5 or C 1 ~C 6 As used herein, a particular range refers to an alkyl group with each member of the range stated as a separate species. For example, C 1 ~C 6The term alkyl, as used herein, is intended to denote straight or branched chain alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, each of which is intended to be described as an independent species. For example, C 1 ~C 4 The term alkyl, as used herein, is intended to denote straight or branched chain alkyl groups having 1, 2, 3, or 4 carbon atoms, each of which is described as an independent species. 0 ~C n By converting the alkyl group to another group, e.g. (C 3 ~C 7 Cycloalkyl)C 0 ~C 4 Alkyl, or -C 0 ~C 4 Alkyl(C 3 ~C 7 When used in combination with cycloalkyl, the indicated group, in this case cycloalkyl, is joined to a single covalent bond (C 0 The alkyl group is either directly attached to the alkyl group through an alkyl chain, in this case 1, 2, 3, or 4 carbon atoms. The alkyl group can also be -OC 0 ~C 4 Alkyl(C 3 ~C 7 The alkyl group may be linked via another group, such as a heteroatom, such as cycloalkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, and hexyl. Alkyl groups may be optionally substituted independently with one or more substituents described herein.

[0045] It is understood that when a term containing "alk" is used, "cycloalkyl" or "carbocycle" can also be considered part of the definition, unless the context clearly excludes otherwise. For example, but not limited to, terms such as alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkeneoxy, haloalkyl, etc. can all be considered to include cyclic forms of alkyl, unless the context clearly excludes otherwise.

[0046] "Alkenyl" refers to a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at any stable point along the chain. A non-limiting example is C 2 ~C 8 Alkenyl, C 2 ~C 7 Alkenyl, C 2 ~C 6 Alkenyl, C 2 ~C 5 Alkenyl and C 2 ~C 4 Alkenyl. A particular range used herein refers to an alkenyl group with each member of the range described as an independent species as described above for the alkyl moiety. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. Alkenyl groups can be optionally independently substituted with one or more substituents described herein.

[0047] "Alkynyl" refers to a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds which may occur at any stable point along the chain, e.g., C 2 ~C 8 Alkynyl or C 2 ~C 6Alkynyl. As used herein, a particular range refers to an alkynyl group with each member described as an independent species of the range, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. Alkynyl groups can be optionally independently substituted with one or more substituents described herein.

[0048] "Haloalkyl" refers to both branched and straight chain alkyl groups substituted with one or more halogen atoms up to the maximum number of halogen atoms permitted. Examples of haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl. Haloalkyl groups can be optionally substituted independently with one or more substituents described herein.

[0049] "Halo" or "halogen" refers independently to either fluoro, chloro, bromo or iodo.

[0050] "Aryl" refers to an aromatic group containing only carbon in one or more aromatic rings. In one embodiment, an aryl group is 6 to 14 or 18 ring atoms containing 1 to 3 single or fused rings, with no heteroatoms as ring members. Where indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitutions may include fusion to 4-7 or 5-7 membered saturated or partially unsaturated cyclic groups, optionally containing 1, 2 or 3 heteroatoms independently selected from N, O, B, P, Si and S, to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, the aryl group is a pendant group. An example of a pendant ring is a phenyl group substituted with a phenyl group. The aryl group may be optionally substituted independently with one or more substituents described herein.

[0051] The term "heterocycle" refers to saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from N, S, and O. The term "heterocycle" includes monocyclic 3- to 12-membered ring systems and bicyclic 5- to 16-membered ring systems (which may include fused, bridged, or spiro, bicyclic ring systems). Rings containing -OO-, -OS-, or -SS- moieties are not included. Examples of saturated heterocyclic groups include 4- to 7-membered saturated monocyclic groups containing 1-4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl]; 4- to 6-membered saturated monocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms [e.g., morpholinyl]; and 3- to 6-membered saturated heteromonocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclic radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1, Examples of heterocyclic rings include, but are not limited to, 2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. "Bicyclic heterocycle" includes groups in which a heterocyclic radical is fused to an aryl radical, and the point of attachment is the heterocyclic ring. "Bicyclic heterocycle" also includes heterocyclic radicals fused to a carbocyclic radical.For example, partially unsaturated fused heterocyclic groups containing 1 to 5 nitrogen atoms, such as indoline, isoindoline, partially unsaturated fused heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated fused heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated fused heterocyclic groups containing 1 to 2 oxygen or sulfur atoms are all included. Heterocyclic groups may be optionally substituted independently with one or more substituents described herein.

[0052] Non-limiting examples of bicyclic heterocycles include: [ka] Examples include:

[0053] Unless otherwise indicated or apparent from the context, the term "bicyclic heterocycle" includes cis and trans diastereomers. Non-limiting examples of chiral bicyclic heterocycles include: [ka] Examples include:

[0054] "Heteroaryl" refers to a stable monocyclic, bicyclic, or polycyclic aromatic ring containing 1-3, or in some embodiments 1-2, or 3, heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S), with the remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5-, 6-, or 7-membered aromatic ring containing 1-3, or in some embodiments 1-2, heteroatoms selected from N, O, S, B, or P, with the remaining ring atoms being carbon. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have 5 or 6 ring atoms. In some embodiments, the bicyclic heteroaryl group is an 8-10 membered heteroaryl group, i.e., a group containing 8 or 10 ring atoms in which one 5-, 6-, or 7-membered aromatic ring is fused to a second aromatic or non-aromatic ring, with the point of attachment being the aromatic ring. If the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In one embodiment, the total number of S and O atoms in the heteroaryl group is 2 or less. In another embodiment, the total number of S and O atoms in the aromatic heterocycle is 1 or less.Examples of heteroaryl groups include pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzoyl, and benzoyl. Heteroaryl groups include, but are not limited to, zofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl. Heteroaryl groups can be optionally substituted independently with one or more substituents described herein.

[0055] "Dosage form" refers to a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, solutions, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalation forms, transdermal forms, buccal, sublingual, topical, gels, mucosal, etc. "Dosage form" can also include implants, such as optical implants.

[0056] A "pharmaceutical composition" is a composition that contains at least one active agent and at least one other substance, such as a pharma- ceutical carrier. A "pharmaceutical combination" is a combination of at least two active agents, which may be combined in a single dosage form or may be provided together in separate dosage forms with instructions that the active agents are used together to treat any of the disorders described herein.

[0057] "Pharmaceutically acceptable salts" are derivatives of the compounds of the present disclosure, where the parent compound is modified by making its inorganic and organic pharma- ceutically acceptable acid or base addition salts. Salts of the compounds of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg, or K hydroxides, carbonates, bicarbonates, etc.) or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the compounds of the present invention further include solvates of the compounds and compound salts.

[0058] Examples of pharma- ceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include salts that are acceptable for human consumption, such as quaternary ammonium salts of the parent compound formed from inorganic or organic acids. Examples of such salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as those derived from acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH 2 ) 1~4These include salts prepared from organic acids such as -COOH, or using a different acid that produces the same counterion. Additional lists of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0059] The term "carrier" applied to a pharmaceutical composition / combination according to the present disclosure refers to a diluent, excipient, or vehicle provided with an active compound.

[0060] "Pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" may be used interchangeably and refer to an excipient useful for preparing a pharmaceutical composition / combination that is generally safe, acceptable for human consumption, and not biologically or otherwise unsuitable for administration to a host, generally to humans. In one embodiment, an excipient acceptable for veterinary use is used. In one embodiment, an excipient acceptable for mammalian use, particularly human use, is used.

[0061] A "patient" or "host" or "subject" is a human or non-human animal in need of treatment or prevention of any of the disorders specifically described herein, including, but not limited to, modulation of the classical complement pathway or a condition treatable with one of the compounds described herein. Typically, the host is a human. A "patient" or "host" or "subject" also refers to, for example, mammals, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, birds, etc.

[0062] As used herein, "prodrug" refers to a compound that is converted to a parent drug when administered to a host in vivo. As used herein, the term "parent drug" refers to any of the compounds described herein. Prodrugs can be used to achieve any desired effect, including enhancing the properties of the parent drug or improving the pharmaceutical or pharmacokinetic properties of the parent drug, and extending the in vivo half-life of the drug. Prodrug strategies provide options in adjusting the conditions for the in vivo production of the parent drug. Non-limiting examples of prodrug strategies include covalent attachment of a removable group or a portion of a removable group, such as, but not limited to, acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation, or anhydride, among others.

[0063] "Providing a compound with at least one additional active agent" can mean, for example, that in one embodiment, the compound and the additional active agent(s) are provided simultaneously in a single dosage form, are provided together in separate dosage forms, or are provided in separate dosage forms. In one embodiment, the administration of the compound is spaced apart in time during which both the compound and the at least one additional active agent are present in the patient's bloodstream. In certain embodiments, the compound and the additional active agent do not need to be prescribed to the patient by the same medical professional. In certain embodiments, the one or more additional active agents do not require a prescription. Administration of the compound or at least one additional active agent can be via any suitable route, such as oral tablets, oral capsules, oral liquids, inhalation, injection, suppositories, parenteral, sublingual, buccal, intravenous, intra-aortic, transdermal, polymer-controlled delivery, non-polymer-controlled delivery, nano- or microparticles, liposomes, and / or topical contact. In one embodiment, instructions for administration in the form of a combination therapy are provided on the drug label.

[0064] A "therapeutically effective amount" of a pharmaceutical composition / combination of the present disclosure means an amount effective to provide a therapeutic benefit, such as alleviation of symptoms or reduction or attenuation of the disease itself, when administered to a host. In one embodiment, a therapeutically effective amount is an amount sufficient to prevent or significantly reduce a detectable level of hemolysis in the patient's blood, serum, or tissues from increasing significantly.

[0065] N-Oxide In certain embodiments, any of the active compounds can be provided to a patient in need thereof in its N-oxide form. In one embodiment, the N-oxide of the active compound or a precursor of the active compound is used in the preparation scheme. In yet another embodiment, the N-oxide is a metabolite of administration of one of the active compounds herein and may have independent activity. The N-oxide can be formed by treating the compound of interest with an oxidizing agent, such as a suitable peroxyacid or peroxide, to generate the N-oxide compound. For example, a heteroaryl group, such as a pyridyl group, can be treated with an oxidizing agent such as sodium percarbonate under mild reaction conditions in the presence of a rhenium-based catalyst to generate the N-oxide compound. Those skilled in the art will appreciate that appropriate protecting groups may be required to carry out the chemical reaction. See Jain, SLet al., “Rhenium-Catalyzed Highly Efficient Oxidations of Tertiary Nitrogen Compounds to N-Oxides Using Sodium Percarbonate as Oxygen Source, Synlett, 2261-2663, 2006.

[0066] In another aspect of the present disclosure, any active compound containing sulfur can be provided to a patient in need thereof in sulfoxide or sulfone form. In a different embodiment, a sulfoxide or sulfone of the active compound or one of the precursors of the active compound is used in the preparation scheme. The sulfur atom in the selected compounds described herein can be oxidized using known methods to produce a sulfoxide. [ka] or sulfone [ka] can be formed. For example, the compound 1,3,5-triazo-2,4,6-triphosphorine-2,2,4,4,6,6-tetrachloride (TAPC) is an efficient promoter for the oxidation of sulfides to sulfoxides. See Bahrami, M. et al., “TAPC-Promoted Oxidation of Sulfides and Deoxygenation of Sulfoxides”, J. Org. Chem., 75, 6208-6213 (2010). Oxidation of sulfides with 30% hydrogen peroxide catalyzed by tantalum carbide gives sulfoxides in high yields. See Kirihara, A., et al., “Tantalum Carbide or Niobium Carbide Catalyzed Oxidation of Sulfides with Hydrogen Peroxide: Highly Efficient and Chemoselective Syntheses of Sulfoxides and Sulfones”, Synlett, 1557-1561 (2010). Sulfides can be oxidized to sulfones, for example, using niobium carbide as a catalyst. See Kirihara, A., et al., “Tantalum Carbide or Niobium Carbide Catalyzed Oxidation of Sulfides with Hydrogen Peroxide: Highly Efficient and Chemoselective Syntheses of Sulfoxides and Sulfones”, Synlett, 1557-1561 (2010). Urea-hydrogen peroxide adduct is a stable, inexpensive and easy-to-handle reagent for the oxidation of sulfides to sulfones.See Varma, RS and Naicker, KP, "The Urea-Hydrogen Peroxide Complex: Solid-State Oxidative Protocols for Hydroxylated Aldehydes and Ketones (Dakin Reaction), Nitriles, Sulfides, and Nitrogen Heterocycles", Org. Lett., 1, 189-191 (1999). One skilled in the art will recognize that in oxidizing sulfur atoms to produce the desired compounds, other heteroatoms, such as nitrogen, may need to be protected and then deprotected.

[0067] "Alkyl" embodiments In one embodiment, "alkyl" refers to 1 ~C 10 Alkyl, C 1 ~C 9 Alkyl, C 1 ~C 8 Alkyl, C 1 ~C 7 Alkyl, C 1 ~C 6 Alkyl, C 1 ~C 5 Alkyl, C 1 ~C 4 Alkyl, C 1 ~C 3 Alkyl, or C 1 ~C 2 It is an alkyl.

[0068] In one embodiment, the "alkyl" has 1 carbon.

[0069] In one embodiment, the "alkyl" has 2 carbons.

[0070] In one embodiment, the "alkyl" has 3 carbons.

[0071] In one embodiment, the "alkyl" has 4 carbons.

[0072] In one embodiment, the "alkyl" has 5 carbons.

[0073] In one embodiment, the "alkyl" has 6 carbons.

[0074] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0075] Further non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0076] Further non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0077] Further non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0078] Further non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and activated pentyl.

[0079] "Haloalkyl" Embodiments In one embodiment, "haloalkyl" is C 1 ~C 10 Haloalkyl, C 1 ~C 9 Haloalkyl, C 1 ~C 8 Haloalkyl, C 1 ~C 7 Haloalkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 5 Haloalkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 3 Haloalkyl and C 1 ~C 2 It is haloalkyl.

[0080] In one embodiment, the "haloalkyl" has 1 carbon.

[0081] In one embodiment, a "haloalkyl" has 1 carbon and 1 halogen.

[0082] In one embodiment, a "haloalkyl" has 1 carbon and 2 halogens.

[0083] In one embodiment, a "haloalkyl" has 1 carbon and 3 halogens.

[0084] In one embodiment, the "haloalkyl" has 2 carbons.

[0085] In one embodiment, the "haloalkyl" has 3 carbons.

[0086] In one embodiment, the "haloalkyl" has 4 carbons.

[0087] In one embodiment, the "haloalkyl" has 5 carbons.

[0088] In one embodiment, the "haloalkyl" has 6 carbons.

[0089] Non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0090] Further non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0091] Further non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0092] Further non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0093] "Aryl" Embodiments In one embodiment, an "aryl" is a six carbon aromatic group (phenyl).

[0094] In one embodiment, an "aryl" is a 10 carbon aromatic group (naphthyl).

[0095] In one embodiment, the "aryl" is a "substituted aryl."

[0096] "Heteroaryl" Embodiments In one embodiment, a "heteroaryl" is a 5-membered aromatic group containing 1, 2, or 3 nitrogen atoms.

[0097] Non-limiting examples of 5-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

[0098] Further non-limiting examples of 5-membered "heteroaryl" groups include: [ka]

[0099] In one embodiment, "heteroaryl" is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (ie, pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0100] Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include: [ka] [ka]

[0101] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0102] Non-limiting examples of "heteroaryl" groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole.

[0103] Further non-limiting examples of "heteroaryl" groups that are bicyclic include: [ka]

[0104] Further non-limiting examples of "heteroaryl" groups that are bicyclic include: [ka]

[0105] Further non-limiting examples of "heteroaryl" groups that are bicyclic include: [ka]

[0106] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0107] Non-limiting examples of "heteroaryl" groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0108] Further non-limiting examples of "heteroaryl" groups that are bicyclic include: [ka]

[0109] In an alternative embodiment, the heteroaryl is tetrazole.

[0110] "Cycloalkyl" Embodiments In one embodiment, "cycloalkyl" is C 3 ~C 8 Cycloalkyl, C 3 ~C 7 Cycloalkyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 5 Cycloalkyl, C 3 ~C 4 Cycloalkyl, C 4 ~C 8 Cycloalkyl, C 5 ~C 8 Cycloalkyl, or C 6 ~C 8 It is cycloalkyl.

[0111] In one embodiment, the "cycloalkyl" has 3 carbons.

[0112] In one embodiment, a "cycloalkyl" has 4 carbons.

[0113] In one embodiment, a "cycloalkyl" has 5 carbons.

[0114] In one embodiment, a "cycloalkyl" has 6 carbons.

[0115] In one embodiment, the "cycloalkyl" has 7 carbons.

[0116] In one embodiment, a "cycloalkyl" has 8 carbons.

[0117] In one embodiment, a "cycloalkyl" has 9 carbons.

[0118] In one embodiment, the "cycloalkyl" has 10 carbons.

[0119] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0120] Heterocycle embodiments In one embodiment, "heterocycle" refers to a cyclic ring having one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0121] In one embodiment, "heterocycle" refers to a cyclic ring having one nitrogen, one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0122] In one embodiment, "heterocycle" refers to a cyclic ring having two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0123] In one embodiment, "heterocycle" refers to a cyclic ring having one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0124] In one embodiment, "heterocycle" refers to a cyclic ring having one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0125] Non-limiting examples of "heterocycles" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane.

[0126] Further non-limiting examples of "heterocycle" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

[0127] Further non-limiting examples of "heterocycles" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0128] Further non-limiting examples of "heterocycles" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0129] Non-limiting examples of "heterocycles" include: [ka]

[0130] Further non-limiting examples of "heterocycle" include: [ka]

[0131] Further non-limiting examples of "heterocycle" include: [ka]

[0132] Non-limiting examples of "heterocycles" include: [ka]

[0133] Non-limiting examples of "heterocycles" include: [ka]

[0134] Further non-limiting examples of "heterocycle" include: [ka]

[0135] Further non-limiting examples of "heterocycle" include: [ka]

[0136] "Sugar" embodiments In one embodiment, a "sugar" is a compound of formula C 3 H 5 O 3 , C 4 H 7 O 4 , C 5 H 9 O 5 , C 6 H 11 O 6 , C 7 H 13 O 7 , or C 8 H 15 O 8 This refers to the compound.

[0137] Non-limiting examples of sugars include: [ka] Examples include:

[0138] Further embodiments of the present invention: In one embodiment, [ka] is selected from: [ka] [ka]

[0139] In one embodiment, [ka] is selected from: [ka]

[0140] In one embodiment, R 22 teeth, [ka] is selected from.

[0141] In one embodiment, R 22 teeth, [ka] is selected from.

[0142] In one embodiment, [ka] teeth, [ka] is selected from.

[0143] In one embodiment, [ka] teeth, [ka] [ka] is selected from.

[0144] In one embodiment, [ka] teeth, [ka] is selected from.

[0145] In another embodiment, [ka] teeth, [ka] is selected from.

[0146] In another embodiment, [ka] teeth, [ka] is selected from.

[0147] In another embodiment, [ka] teeth, [ka] It is.

[0148] In another embodiment, [ka] teeth, [ka] It is.

[0149] In one embodiment, R 26 teeth, [ka] is selected from.

[0150] In one embodiment, R 27 teeth, [ka] is selected from.

[0151] In one embodiment, [ka] teeth, [ka] is selected from.

[0152] In one embodiment, R21 is selected from: [ka]

[0153] In one embodiment, there is provided a compound of formula I selected from: [ka] [ka] [ka]

[0154] In one embodiment, there is provided a compound of formula I selected from: [ka] [ka]

[0155] In one embodiment, there is provided a compound of formula I selected from: [ka] [ka] [ka]

[0156] In one embodiment, the compound of the present disclosure is selected from: [ka] [ka] [ka]

[0157] In one embodiment, the compound of the present disclosure is selected from: [ka] [ka]

[0158] In one embodiment, there is provided a compound of formula I selected from: [ka] [ka]

[0159] In one embodiment, there is provided a compound of formula I selected from: [ka] [ka] [ka]

[0160] In one embodiment, there is provided a compound of formula I selected from: [ka] [ka] [ka]

[0161] In one embodiment, there is provided a compound of formula I selected from: [ka] [ka]

[0162] In one embodiment, there is provided a compound of formula I selected from: [ka] [ka]

[0163] In one embodiment, a compound of formula IV is provided that is selected from: [ka] [ka] [ka]

[0164] In one embodiment, a compound of formula V is provided that is selected from: [ka] [ka]

[0165] In another embodiment, the compound of formula I, optionally in a pharma- ceutically acceptable carrier, is selected from: [ka] [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof, where all variables are as defined herein.

[0166] In another embodiment, the compound of formula I, optionally in a pharma- ceutically acceptable carrier, is selected from: [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof, where all variables are as defined herein.

[0167] In another embodiment, the compound of formula I, optionally in a pharma- ceutically acceptable carrier, is selected from: [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof. (In the formula, R 200 is a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) and all other variables are as defined herein.

[0168] In another embodiment, the compound of formula I, optionally in a pharma- ceutically acceptable carrier, is selected from: [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof. (In the formula, [ka] is selected from 3- to 6-membered carbocyclic rings and 4- to 6-membered heterocyclic rings containing 1 or 2 heteroatoms independently selected from N, O, and S; for example, [ka] may be selected from In an alternative embodiment, [ka] is a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) 2 optionally substituted with 1, 2, 3, or 4 substituents independently selected from All other variables are as defined herein.

[0169] In another embodiment, the compound of formula I, optionally in a pharma- ceutically acceptable carrier, is selected from: [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof. (In the formula, [ka] is a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently selected from N, O, and S, for example, in one embodiment, [ka] teeth, [ka] , [ka] may be selected from In this embodiment, R 8 and R 10 At least one of the is not hydrogen, All other variables are as defined herein.

[0170] In another embodiment, the compound of formula I, optionally in a pharma- ceutically acceptable carrier, is selected from: [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof. (In the formula, [ka] is a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently selected from N, O, and S, for example, in one embodiment, In this embodiment, R 10 and R 12 At least one of the is not hydrogen, All other variables are as defined herein.

[0171] In an alternative embodiment, the compound of the present disclosure, optionally in a pharma- ceutically acceptable carrier, is selected from: [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof. (In the formula, [ka] is a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently selected from N, O, and S, where [ka] is a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) 2 and is substituted with 1, 2, 3, or 4 substituents selected from All other variables are as defined herein.

[0172] In another embodiment, the compound of formula X, optionally in a pharma- ceutically acceptable carrier, is selected from: [ka] [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof, where all variables are as defined herein.

[0173] In another embodiment, the compound of formula X, optionally in a pharma- ceutically acceptable carrier, is selected from: [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof, where all variables are as defined herein.

[0174] In another embodiment, the compound of formula X, optionally in a pharma- ceutically acceptable carrier, is selected from: [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof. (In the formula, R 200 is a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) and all other variables are as defined herein.

[0175] In another embodiment, the compound of formula X, optionally in a pharma- ceutically acceptable carrier, is selected from: [ka] [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof. (In the formula, [ka] is selected from 3- to 6-membered carbocyclic rings and 4- to 6-membered heterocyclic rings containing 1 or 2 heteroatoms independently selected from N, O, and S; In an alternative embodiment, [ka] is a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) 2 optionally substituted with 1, 2, 3, or 4 substituents independently selected from All other variables are as defined herein.

[0176] In another embodiment, the compound of formula X, optionally in a pharma- ceutically acceptable carrier, is selected from: [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof. (In the formula, [ka] is a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently selected from N, O, and S; In this embodiment, R 8 and R 10 At least one of the is not hydrogen, All other variables are as defined herein.

[0177] In another embodiment, the compound of formula X, optionally in a pharma- ceutically acceptable carrier, is selected from: [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof. (In the formula, [ka] is a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently selected from N, O, and S, for example, in one embodiment, In this embodiment, R 10 and R 12 At least one of the is not hydrogen, All other variables are as defined herein.

[0178] In an alternative embodiment, the compound of the present disclosure, optionally in a pharma- ceutically acceptable carrier, is selected from: [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof. (In the formula, [ka] is a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently selected from N, O, and S, where [ka] is a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) 2 and is substituted with 1, 2, 3, or 4 substituents selected from All other variables are as defined herein.

[0179] In one embodiment, the 3- to 8-membered carbocyclic ring is a 4- to 8-membered carbocyclic ring. In another embodiment, the 3- to 8-membered carbocyclic ring is a 4- to 8-membered carbocyclic ring.

[0180] In one embodiment, R 7 and R 9 together with the atoms to which they are attached form a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S.

[0181] In one embodiment, R 9 and R 11 together with the atoms to which they are attached form a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S.

[0182] In one embodiment, [ka] is a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S.

[0183] In another embodiment, the compound of formula XIV, optionally in a pharma- ceutically acceptable carrier, is selected from: [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof, where all variables are as defined herein.

[0184] In another embodiment, the compound of formula XIV, optionally in a pharma- ceutically acceptable carrier, is selected from: [ka] [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof. (In the formula, R 201 is a halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, and heteroaryl, R other than halogen; 201 Each of the groups is C 1 ~C 6 Alkyl, CC 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; All other variables are as defined herein.

[0185] In certain embodiments of the present disclosure, R 9and R 11 together with the atoms to which they are attached form cyclopropane.

[0186] In one embodiment, the compound of the present disclosure is selected from: [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0187] In certain embodiments, the compound of the present disclosure is selected from: [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0188] In certain embodiments, the compound of the present disclosure is selected from: [ka] [ka] , or a pharma- ceutically acceptable salt thereof.

[0189] In certain embodiments, the compound of the present disclosure is selected from: [ka] [ka] or a pharma- ceutically acceptable salt thereof (In the formula, each R 40 is an independent SF 5 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, and nitro).

[0190] In certain embodiments, the compound of the present disclosure is selected from: [ka] or a pharma- ceutically acceptable salt thereof.

[0191] In certain embodiments, the compound of the present disclosure is selected from: [ka] or a pharma- ceutically acceptable salt thereof.

[0192] Further embodiments 1. (Embodiment 1) In certain embodiments, the compound of the present disclosure is selected from: [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof. (In the formula, each n is independently 1, 2, or 3; each m is independently 0, 1, 2, or 3; o is 0, 1, or 2; [ka] is either a single or double bond, Z is CH 2 , C(CH 2 ), or C(O), X 1 is S, O, and N(R 30 ), X 2 is a bond, N(R 30 ), and -ON(R 30 )- is selected from X 3 is N and C(R 17 ), X 4 is N and C(R 18 ), where X 3 and X 4 can be N, X 5 is C or Si, X 6 teeth, [ka] is selected from X 7 is O, S, N(R30 ), and CR 5 R 6 is selected from each X 8 and X 9 are O, S, and NR 30 , C.R. 9 R 10 , C.R. 5 R 6 and C.H. 2 where X is independently selected from 8 and X 9 cannot both be the same group, X 10 teeth, [ka] is selected from X 11 N and CR 1 is selected from X 12 N and CR 2 is selected from R 1 and R 2 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 R is independently selected from the group consisting of heterocycle, aryl, heteroaryl, cyano, and nitro, and is other than hydrogen, halogen, cyano, and nitro. 1 Groups and R 2 Each of the groups is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; R 3 and R 4 is hydrogen, CN, C(O)R 31 , -SR 30 , and -OR 30 are independently selected from Or, R 3 and R 4 Instead, combine and C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 and forming an oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from oxo; Each R 5 and R 6 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) 2 where R 5 Groups and R 6 The groups may be optionally replaced by a carbon-carbon double bond when they are on adjacent carbons; R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is hydrogen, halogen, C 1 ~C 6 Alkyl, C2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 R is independently selected from the group consisting of heterocycle, aryl, and heteroaryl, and is other than hydrogen and halogen. 7 Group, R 8 Group, R 9 Group, R 10 Group, R 11 Groups and R 12 Each of the groups is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; Or, R 7 and R 8 may be taken together with the carbons to which they are attached to form a 3- to 6-membered carbocyclic spiro ring or a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; Or, R 7 and R 8 together with the carbons to which they are attached, [ka] or may form a carbonyl; Or, R 9 and R 10 may be joined together with the atom to which they are attached to form a 3- to 6-membered carbocyclic spiro ring or a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; Or, R 9 and R 10 together with the atoms to which they are attached, [ka] or may form a carbonyl; Or, R 11 and R 12 may be taken together with the carbons to which they are attached to form a 3- to 6-membered carbocyclic spiro ring or a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; Or, R 11 and R 12 together with the carbons to which they are attached, [ka] or may form a carbonyl; Or, R 7 and R 9 together with the atoms to which they are attached form a 3- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; or Or, R 9 and R 11 together with the atoms to which they are attached form a 3- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; or Or, R 7 and R 11form one or two carbon bridges together with the atoms to which they are attached, Each R 13 is hydrogen or C 1 ~C 6 independently selected from alkyl, R 14 , R 15 , and R 16 is hydrogen, halogen, SF 5 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -C 1 ~C 6 Alkyl-aryl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 R is independently selected from the group consisting of heterocycle, aryl, heteroaryl, cyano, and nitro, and is other than hydrogen, halogen, cyano, and nitro. 14 , R 15 , and R 16 Each of the groups is SF 5 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halogen, C 1 -C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; R 17 and R 18 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) 2 are independently selected from Or, R 17 and R 18 form a double bond with the carbon to which they are attached, R 19 and R 20 is hydrogen, C 1 ~C 6 Alkyl, C 5 ~C 10 Bicyclic carbocycle, C 4 ~C 6 Heterocycle, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -N(R 30 ) 2 , -(CH 2 ) n -R 33 , and [ka] are independently selected from R 21 is C 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkyl, -OC 1 ~C 6 is selected from alkyl, aryl, -O-aryl, heteroaryl, or -O-heteroaryl; R 21 Each of the groups is SF 5 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; R 22 -C 1 ~C 6 Alkyl-R 23 , -C 2 ~C 6 Alkenyl-R 23 , -C 2 ~C 6 Alkynyl-R 23 and bicyclic cycloalkyl-R 23 Selected from R 22 Each of the C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; R 23 is hydrogen, sugar, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , and -S(O) 2 R31 is selected from Each R 25 is hydrogen, SF 5 , halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 R is independently selected from the group consisting of heterocycle, aryl, heteroaryl, cyano, and nitro, and is other than hydrogen, halogen, cyano, and nitro. 25 Each of the groups is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; R 26 teeth, [ka] is selected from R 27 teeth, [ka] [ka] is selected from R 29 is a halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, and heteroaryl; R other than hydrogen and halogen; 29 Each of the groups is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; Each R 30 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, aryl, heteroaryl, heterocycle, and C(O)R 31 are independently selected from Each R 31 is hydrogen, C1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 32 , -SR 32 , -N(R 32 ) 2 , heterocycle, aryl, and heteroaryl; Each R 32 is hydrogen, C 1 ~C 6 Alkyl, and C 1 ~C 6 haloalkyl; Each R 33 is hydrogen, guanidine, heteroaryl, aryl, -C 6 H 5 -OR 30 ;-OR 30 , -SR 30 , -SeR 30 , -N(R 30 ) 2 , and -C(O ) R 31 are independently selected from R 34 teeth, [ka] is selected from R 35 is C 3 ~C 10 Alkyl or C 3 ~C 10 haloalkyl; wherein for compounds of formula I and formula II, at least one of the following is satisfied: aX 3 is C(R 17 ) and X 4 is C(R 18 ) is; bR 17 is a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R30 ) 2 Selected from; cX 5 is Si; dZ is C(CH 2 ) is; eZ is CH 2 is; fR 7 and R 8 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; gR 9 and R 10 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; hR 11 and R 12 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; iR 7 and R 9 together with the atoms to which they are attached form a 3- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; R 8 or R 10 is not hydrogen; jR 9 and R 11 together with the atoms to which they are attached form a 3- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; R 10 or R 12 is not hydrogen; kR 7 and R 11 form one or two carbon bridges together with the atoms to which they are attached; lX 6 teeth, [ka] Selected from; mR 3 and R 4 At least one of the groups is CN, -SR 30 or C(O)R 31 is; or nR 3 and R 4 is combined with C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 forming an oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from, and oxo; wherein for compounds of formula X and formula XI, at least one of the following is satisfied: aX 3 is C(R 17 ) and X 4 is C(R 18 ) is; bR 17 is a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) 2 Selected from; cX5 is Si; dZ is C(CH 2 ) is; eZ is CH 2 is; fR 7 and R 8 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; gR 9 and R 10 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; hR 9 and R 11 together with the atoms to which they are attached form a 3- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; R 10 is not hydrogen; iR 11 and R 12 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; jR 7 and R 9together with the atoms to which they are attached form a 3- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; R 10 is not hydrogen; kR 7 and R 11 form one or two carbon bridges together with the atoms to which they are attached; lR 22 must contain at least three ORs. 30 substituted with a group; mR 23 is a sugar; nR 3 and R 4 At least one of the groups is CN, -SR 30 or C(O)R 31 is; or oR 3 and R 4 is combined with C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 forming an oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from, and oxo; wherein for the compound of formula XIV, at least one of the following is satisfied: aX 1 is O or N(R 30 ) is; bR 14 is not hydrogen; cR 1 is not hydrogen; dR 2 is not hydrogen; eR 3 is not hydrogen, or fR 4 is not hydrogen).

[0193] 2. The compound is [ka] The compound according to embodiment 1, selected from: or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof.

[0194] 3. The compound has the formula: [ka] The compound according to embodiment 1, or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof.

[0195] 4.Formula: [ka] The compound according to embodiment 1, or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof.

[0196] 5. The compound of embodiment 1, selected from: [ka] [ka] [ka] [ka] [ka] (In the formula, R 21 is C 1 ~C 6 Alkyl and -OC 1 ~C6 alkyl, Each R 25 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 R is independently selected from the group consisting of heterocycle, aryl, heteroaryl, cyano, and nitro, and is other than hydrogen, halogen, cyano, and nitro. 1 and R 2 Each of the groups is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; R 14 , R 15 , and R 16 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -C1 ~C 6 Alkyl-aryl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 R is independently selected from the group consisting of heterocycle, aryl, heteroaryl, cyano, and nitro, and is other than hydrogen, halogen, cyano, and nitro. 14 , R 15 , and R 16 Each of the groups is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, and nitro).

[0197] 6. In certain embodiments, the compound of the present disclosure is selected from: [ka] [ka] [ka] or a pharma- ceutically acceptable salt, isotopic analog, prodrug, or isolated isomer thereof. (In the formula, each n is independently 1, 2, or 3; each m is independently 0, 1, 2, or 3; o is 0, 1, or 2; [ka] is either a single or double bond, Z is CH 2 , C(CH 2 ), or C(O), X 1 is S, O, and N(R 30 ), X 2 is a bond, N(R 30 ), and -ON(R 30 )- is selected from X 3 is N and C(R 17 ), X 4 is N and C(R 18 ), where X 3 and X 4 can be N, X 5 is C or Si, X 6 teeth, [ka] is selected from X 7 is O, S, N(R 30 ), and CR 5 R 6 is selected from each X 8 and X 9 are O, S, and NR 30 , C.R. 9 R 10 , C.R. 5 R 6 and C.H. 2 where X is independently selected from 8 and X9 cannot both be the same group, X 11 N and CR 1 is selected from X 12 N and CR 2 is selected from R 1 and R 2 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 R is independently selected from the group consisting of heterocycle, aryl, heteroaryl, cyano, and nitro, and is other than hydrogen, halogen, cyano, and nitro. 1 Groups and R 2 Each of the groups is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; R 3 and R 4 is hydrogen, C(O)R 31 , -SR 30 , and -OR30 are independently selected from Or, R 3 and R 4 Instead, combine and C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 and forming an oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from oxo; Each R 5 and R 6 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) 2 where R 5 Groups and R 6 The groups may be optionally replaced by a carbon-carbon double bond when they are on adjacent carbons; R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 R is independently selected from the group consisting of heterocycle, aryl, and heteroaryl, and is other than hydrogen and halogen. 7 Group, R 8 Group, R 9 Group, R 10 Group, R11 Groups and R 12 Each of the groups is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; Or, R 7 and R 8 together with the carbons to which they are attached, may form a 3- to 6-membered carbocyclic spiro ring or a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; Or, R 7 and R 8 together with the carbons to which they are attached, [ka] or may form a carbonyl; Or, R 9 and R 10 together with the atoms to which they are attached, may form a 3- to 6-membered carbocyclic spiro ring or a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; Or, R 9 and R 10 together with the atoms to which they are attached, [ka] or may form a carbonyl; Or, R 11 and R 12 may be taken together with the carbons to which they are attached to form a 3- to 6-membered carbocyclic spiro ring or a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; Or, R 11 and R 12 together with the carbons to which they are attached, [ka] or may form a carbonyl; Or, R 7 and R 9 together with the atoms to which they are attached form a 4- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; or Or, R 9 and R 11 together with the atom to which they are attached form a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; or Or, R 7 and R 11 form one or two carbon bridges together with the atoms to which they are attached, Each R 13 is hydrogen or C 1 ~C 6 independently selected from alkyl, R 14 , R 15 , and R 16 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -C1 ~C 6 Alkyl-aryl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 R is independently selected from the group consisting of heterocycle, aryl, heteroaryl, cyano, and nitro, and is other than hydrogen, halogen, cyano, and nitro. 14 , R 15 , and R 16 Each of the groups is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; R 17 and R 18 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) 2 are independently selected from Or, R 17 and R 18 form a double bond with the carbon to which they are attached, R 19 and R 20 is hydrogen, C 1 ~C 6 Alkyl, C 5 ~C10 Bicyclic carbocycle, C 4 ~C 6 Heterocycle, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -N(R 30 ) 2 , -(CH 2 ) n -R 33 , and [ka] are independently selected from R 21 is C 1 ~C 6 Alkyl and -OC 1 ~C 6 alkyl, R 22 -C 1 ~C 6 Alkyl-R 23 , -C 2 ~C 6 Alkenyl-R 23 , -C 2 ~C 6 Alkynyl-R 23 and bicyclic cycloalkyl-R 23 Selected from R 22 Each of the C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; R 23is hydrogen, sugar, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , and -S(O) 2 R 31 is selected from Each R 25 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 R is independently selected from the group consisting of heterocycle, aryl, heteroaryl, cyano, and nitro, and is other than hydrogen, halogen, cyano, and nitro. 1 and R 2 Each of the groups is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; R 26 teeth, [ka] [ka] is selected from R 27 teeth, [ka] is selected from Each R 30 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, aryl, heteroaryl, heterocycle, and C(O)R 31 are independently selected from Each R 31 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 32 , -SR 32 , -N(R 32 ) 2 , heterocycle, aryl, and heteroaryl; Each R 32 is hydrogen, C 1 ~C 6 Alkyl, and C 1 ~C 6 haloalkyl; Each R 33 is hydrogen, guanidine, heteroaryl, aryl, -C 6 H 5 -OR 30 ;-OR 30 , -SR 30 , -SeR 30 , -N(R 30 ) 2 , -C(O)R 31 are independently selected from wherein for compounds of formula I and formula II, at least one of the following is satisfied: aX 3 is C(R17 ) and X 4 is C(R 18 ) is; bR 17 is a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) 2 Selected from; cX 5 is Si; dZ is C(CH 2 ) is; eZ is CH 2 is; fR 7 and R 8 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; gR 9 and R 10 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; hR 11 and R 12 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; iR 7 and R 9 Together with the atoms to which they are attached, 4~ forming an 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; R 10 or R 12 is not hydrogen; jR 9 and R 11 Together with the atoms to which they are attached, 4~ forming an 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; R 8 or R 10 is not hydrogen; kR 7 and R 11 form one or two carbon bridges together with the atoms to which they are attached; lX 6 teeth, [ka] Selected from; mR 3 and R 4 At least one of the following is -SR 30 or C(O)R 31 is; or nR 3 and R 4 is combined with C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 forming an oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from, and oxo; wherein for compounds of formula X and formula XI, at least one of the following is satisfied: aX 3 is C(R 17 ) and X 4is C(R 18 ) is; bR 17 is a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 , and -N(R 30 ) 2 Selected from; cX 5 is Si; dZ is C(CH 2 ) is; eZ is CH 2 is; fR 7 and R 8 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; gR 9 and R 10 together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; hR 9 and R 11 Together with the atoms to which they are attached, 4~ forming an 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; R 10 is not hydrogen; iR 11 and R 12together with the carbons to which they are attached form a 3- to 6-membered carbocyclic spiro ring, a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; [ka] , or form a carbonyl; jR 7 and R 9 together with the atoms to which they are attached form a 4- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; R 10 is not hydrogen; kR 7 and R 11 form one or two carbon bridges together with the atoms to which they are attached; lR 22 must contain at least three ORs. 30 substituted with a group; mR 23 is a sugar; nR 3 and R 4 At least one of the following is -SR 30 or C(O)R 31 is; or oR 3 and R 4 is combined with C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 forming an oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from, and oxo; wherein for the compound of formula XIV, at least one of the following is satisfied: aX 1 is O or N(R 30 ) is; bR 14 is not hydrogen; cR 1 is not hydrogen; dR 2 is not hydrogen; eR 3 is not hydrogen; or fR 4 is not hydrogen).

[0198] 7. The compound according to any one of embodiments 1 to 6, wherein n is 1.

[0199] 8. The compound of any one of embodiments 1-7, wherein each m is independently 0 or 1.

[0200] 9. The compound according to any one of embodiments 1-8, wherein Z is C(O).

[0201] 10.X 1 The compound of any one of embodiments 1-9, wherein is S.

[0202] 11.X 2 The compound of any one of embodiments 1-10, wherein is a bond.

[0203] 12.X 3 C(R 17 12. The compound of any one of embodiments 1-11, wherein

[0204] 13.X 4 The compound of any one of embodiments 1-12, wherein is N.

[0205] 14.X 5 The compound of any one of embodiments 1-13, wherein

[0206] 15.X 6 but [ka] The compound of any one of embodiments 1-14, wherein

[0207] 16.X 7The compound of any one of embodiments 1-15, wherein

[0208] 17.X 7 CR 5 R 6 The compound of any one of embodiments 1-15, wherein

[0209] 18.X 7 The compound of any one of embodiments 1-15, wherein is S.

[0210] 19.X 7 N(R 30 16. The compound of any one of embodiments 1-15, wherein

[0211] 20.X 8 is CH and X 9 The compound of any one of embodiments 1-19, wherein is N.

[0212] 21.X 8 is CH and X 9 The compound of any one of embodiments 1-19, wherein is N.

[0213] 22.X 11 and X 12 The compound of any one of embodiments 1-21, wherein both are CH.

[0214] 23.X 11 and X 12 and the other is N.

[0215] 24.R 1 and R 2 is hydrogen, halogen, -OR 30 , -SR 30 , -N(R 30 ) 2 , and C 1 ~C 6 The compound of any one of embodiments 1-23, wherein:

[0216] 25.R 1 and R 2 is hydrogen, halogen, and C 1 ~C 6 The compound of any one of embodiments 1-23, wherein:

[0217] 26.R 1 and R 2 The compound of any one of embodiments 1-23, wherein are both hydrogen.

[0218] 27.R 3 and R 4 The compound of any one of embodiments 1-26, wherein are both hydrogen.

[0219] 28.R 3 is hydrogen and R 4 The compound of any one of embodiments 1-26, wherein is hydroxyl.

[0220] 29.R 3 and R 4 But, it combines to form C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OR 30 The compound of any one of embodiments 1-26, which forms an oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from:

[0221] 30.R 5 and R 6 The compound of any one of embodiments 1-29, wherein are both hydrogen.

[0222] 31.R 7 The compound of any one of embodiments 1-30, wherein is hydrogen.

[0223] 32.R 9 The compound of any one of embodiments 1-31, wherein is hydrogen.

[0224] 33.R 7 and R 11 The compound of any one of embodiments 1-30, wherein:

[0225] 34.R 7 and R 11 The compound of any one of embodiments 1-30, wherein:

[0226] 35.R 11 The compound of any one of embodiments 1-31, wherein is hydrogen.

[0227] 36.R 9 and R 11 The compound of any one of embodiments 1-31, wherein:

[0228] 37.R 9 and R 11 The compound of any one of embodiments 1-31, wherein:

[0229] 38.R 10 The compound of any one of embodiments 1-35, wherein is hydrogen.

[0230] 39.R 10 But halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , and -S(O) 2 R 31 The compound according to any one of embodiments 1 to 37, selected from:

[0231] 40.R 10 is selected from aryl and heteroaryl, each of which is 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 38. The compound of any one of embodiments 1-37, optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro.

[0232] 41.R 9 and R 10 The compound of any one of embodiments 1-31, wherein:

[0233] 42.R 9 and R 10 The compound of any one of embodiments 1-31, wherein:

[0234] 43.R 9 and R 10 The compound of any one of embodiments 1-31, wherein:

[0235] 44.R 10 The compound of any one of embodiments 1-40, wherein is methyl.

[0236] 45.R 12 The compound of any one of embodiments 1-44, wherein is hydrogen.

[0237] 46.R 8 The compound of any one of embodiments 1-45, wherein is hydrogen.

[0238] 47.R 13 The compound of any one of embodiments 1-46, wherein is hydrogen.

[0239] 48.R 13 C 1 ~C 6 The compound according to any one of embodiments 1-46, wherein is alkyl.

[0240] 49.R 14 C 1 ~C 6 The compound of any one of embodiments 1-48, wherein is alkyl.

[0241] 50.R 14 The compound of any one of embodiments 1-48, wherein is hydrogen.

[0242] 51.R 14 The compound of any one of embodiments 1-48, wherein is halogen.

[0243] 52.R 14 The compound of any one of embodiments 1-48, wherein is haloalkyl.

[0244] 53.R 14 OR 30 The compound of any one of embodiments 1-48, wherein

[0245] 54.R 14 The compound of any one of embodiments 1-48, wherein is -O-phenyl.

[0246] 55.R 15 C 1 ~C 6 The compound of any one of embodiments 1-54, wherein is alkyl.

[0247] 56.R15 The compound of any one of embodiments 1-54, wherein is hydrogen.

[0248] 57.R 15 The compound of any one of embodiments 1-54, wherein is halogen.

[0249] 58.R 15 The compound of any one of embodiments 1-54, wherein is haloalkyl.

[0250] 59.R 15 OR 30 The compound of any one of embodiments 1-54, wherein

[0251] 60.R 15 The compound of any one of embodiments 1-54, wherein is -O-phenyl.

[0252] 61.R 16 C 1 ~C 6 The compound of any one of embodiments 1-60, wherein is alkyl.

[0253] 62.R 16 The compound of any one of embodiments 1-60, wherein is hydrogen.

[0254] 63.R 16 The compound of any one of embodiments 1-60, wherein is halogen.

[0255] 64.R 16 The compound of any one of embodiments 1-60, wherein is haloalkyl.

[0256] 65.R 16 OR 30 The compound of any one of embodiments 1-60, wherein

[0257] 66.R 16 The compound of any one of embodiments 1-60, wherein is -O-phenyl.

[0258] 67.R 17 The compound of any one of embodiments 1-66, wherein is hydrogen.

[0259] 68.R 18 The compound of any one of embodiments 1-67, wherein is hydrogen.

[0260] 69.R 19 The compound of any one of embodiments 1-68, wherein is hydrogen.

[0261] 70.R 19 But, C 1 ~C 6 Alkyl, C 5 ~C 10 Bicyclic carbocycle, C 4 ~C 6 Heterocycle, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -N(R 30 ) 2 , -(CH 2 ) n -R 33 , and [ka] The compound according to any one of embodiments 1-68, selected from:

[0262] 71.R 20 The compound of any one of embodiments 1-70, wherein is hydrogen.

[0263] 72.R 20 But, C 1 ~C 6 Alkyl, C 5 ~C 10 Bicyclic carbocycle, C 4 ~C 6 Heterocycle, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -N(R 30 ) 2 , -(CH2 ) n -R 33 , and [ka] The compound according to any one of embodiments 1 to 70, selected from:

[0264] 73.R 20 Ga-(CH 2 ) n -R 33 The compound of any one of embodiments 1-70, wherein

[0265] 74.R 21 C 1 ~C 6 The compound according to any one of embodiments 1-73, wherein the compound is haloalkyl.

[0266] 75.R 21 Ga-OC 1 ~C 6 The compound according to any one of embodiments 1-73, wherein the compound is haloalkyl.

[0267] 76.R 21 But SF 5 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, and nitro.

[0268] 77.R 21 But SF 5 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 -C 6 Alkynyl, halogen, C 1 -C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro.

[0269] 78.R 21 The compound of any one of embodiments 76-77, wherein is unsubstituted.

[0270] 79.R 21 is substituted with at least one halogen group.

[0271] 80.R 21 But there is at least one C 1 ~C 6 The compound of any one of embodiments 76-77, which is substituted with an alkyl group.

[0272] 81.R 21 The compound of any one of embodiments 76-77, wherein is substituted with one fluoro group.

[0273] 82.R 21 is substituted with one methyl group.

[0274] 83.R 22 But, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; 1 ~C 6 Alkyl-R 23 The compound of any one of embodiments 1-82, wherein

[0275] 84.R 22 But, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; 3 ~C 6 Alkyl-R 23 The compound of any one of embodiments 1-82, wherein

[0276] 85.R 22 But, C1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 bicyclic cycloalkyl-R optionally substituted with 1, 2, 3, or 4 substituents independently selected from heterocycle, aryl, heteroaryl, cyano, and nitro; 23 The compound of any one of embodiments 1-82, wherein

[0277] 86.R 23 The compound of any one of embodiments 1-85, wherein is hydrogen.

[0278] 87.R 23 The compound of any one of embodiments 1-85, wherein is a sugar.

[0279] 88.R 23 -OR 30 The compound of any one of embodiments 1-85, wherein

[0280] 89.R 23 But, SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , or -S(O) 2 R 31 The compound of any one of embodiments 1-85, wherein

[0281] 90.R 25 C 1 ~C 6 The compound of any one of embodiments 1-89, wherein is alkyl.

[0282] 91.R 25 The compound of any one of embodiments 1-89, wherein is hydrogen.

[0283] 92.R 25 The compound of any one of embodiments 1-89, wherein is halogen.

[0284] 93.R 25 The compound of any one of embodiments 1-89, wherein is haloalkyl.

[0285] 94.R 25 OR 30 The compound of any one of embodiments 1-89, wherein

[0286] 95.R 25 The compound of any one of embodiments 1-89, wherein is -O-phenyl.

[0287] 96.R 25 SF 5 The compound of any one of embodiments 1-89, wherein

[0288] 97.R 26 but [ka] The compound of any one of embodiments 1-96, wherein

[0289] 98.R 26 but, [ka] The compound according to any one of embodiments 1 to 96, selected from:

[0290] 99.R 26 but [ka] The compound of any one of embodiments 1-96, wherein

[0291] 100.R 26 but [ka] The compound of any one of embodiments 1-96, wherein

[0292] 101.R 26 but [ka] The compound of any one of embodiments 1-96, wherein

[0293] 102.R 26 but [ka] The compound according to any one of embodiments 1 to 96, selected from:

[0294] 103.R 27 but [ka] The compound of any one of embodiments 1-102, wherein

[0295] 104.R 27 but [ka] The compound of any one of embodiments 1-102, wherein

[0296] 105.R 27 but [ka] The compound of any one of embodiments 1-102, wherein

[0297] 106.R 30 The compound of any one of embodiments 1-105, wherein is hydrogen.

[0298] 107.R 30 C 1 ~C 6 The compound according to any one of embodiments 1-105, wherein is alkyl.

[0299] 108.R 30 The compound of any one of embodiments 1-105, wherein is methyl.

[0300] 109.R 30 C 1 ~C 6 The compound according to any one of embodiments 1-105, which is haloalkyl.

[0301] 110.R 30 CF 3 The compound of any one of embodiments 1-105, wherein

[0302] 111.R 30 C(O)R 31 The compound of any one of embodiments 1-105, wherein

[0303] 112.R 31 The compound of any one of embodiments 1-111, wherein is hydrogen.

[0304] 113.R 31 C 1 ~C 6 The compound of any one of embodiments 1-111, wherein is alkyl.

[0305] 114.R 31 The compound of any one of embodiments 1-111, wherein is methyl.

[0306] 115.R 31 C 1 ~C 6 The compound according to any one of embodiments 1-111, wherein the compound is haloalkyl.

[0307] 116.R 31 CF 3 The compound of any one of embodiments 1-111, wherein

[0308] 117.R 31 -OR 32 The compound of any one of embodiments 1-111, wherein

[0309] 118.R 31 -N(R 32 ) 2 The compound of any one of embodiments 1-111, wherein

[0310] 119.R 32 The compound of any one of embodiments 1-118, wherein is hydrogen.

[0311] 120.R 32 C 1 ~C 6 The compound according to any one of embodiments 1-118, wherein is alkyl.

[0312] 121.R 33 The compound of any one of embodiments 1-120, wherein is hydrogen.

[0313] 122.R 33 is hydrogen, guanidine, heteroaryl, aryl, -C 6 H 5 -OR 30 , -OR 30 , -SR 30 , -SeR 30 , -N(R 30 ) 2 , and -C(O)R 31 The compound of any one of embodiments 1-120, independently selected from:

[0314] 123.R 33 The compound of any one of embodiments 1-120, wherein is guanidine.

[0315] 124.R 33 is hydrogen, guanidine, heteroaryl, aryl, -C 6 H 5 -OR 30 , -OR 30 , -SR 30 , -SeR 30 , -N(R 30 ) 2 , and -C(O)R 31 The compound of any one of embodiments 1-120, independently selected from:

[0316] 125. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0317] 126. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0318] 127. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0319] 128. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0320] 129. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0321] 130. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0322] 131. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0323] 132. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0324] 133. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0325] 134. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0326] 135. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0327] 136. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0328] 137. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0329] 138. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0330] 139. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0331] 140. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0332] 141. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0333] 142. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0334] 143. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0335] 144. A compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0336] 145. In certain embodiments, the compound of the present disclosure is selected from: [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0337] 146. In certain embodiments, the compound of the present disclosure is selected from: [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0338] 147. In certain embodiments, the compound of the present disclosure is selected from: [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0339] 148. In certain embodiments, a pharmaceutical composition is provided comprising any one of the compounds according to embodiments 1-147 and a pharma- ceutically acceptable carrier.

[0340] 149. In certain embodiments, a method for treating a complement-mediated disorder is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described in any one of embodiments 1-148 or a pharmaceutical composition thereof, or a pharma- ceutically acceptable salt thereof.

[0341] 150. The method of embodiment 149, wherein the subject is a human.

[0342] 151. The method of embodiment 149 or 150, wherein the disorder is mediated by C1s.

[0343] 152. The method of any one of embodiments 149-151, wherein the disorder is C3 glomerulopathy.

[0344] 153. The method of any one of embodiments 149-151, wherein the disorder is an ophthalmic disorder.

[0345] 154. The method of any one of embodiments 149-151, wherein the disorder is age-related macular degeneration (AMD).

[0346] 155. The method of any one of embodiments 149-151, wherein the disorder is paroxysmal nocturnal hemoglobinuria (PNH).

[0347] 156. The method according to any one of embodiments 149-151, wherein the disorder is C3 glomerulonephritis.

[0348] 157. The method according to any one of embodiments 149-151, wherein the disorder is dense deposit disease.

[0349] 158. The method according to any one of embodiments 149-151, wherein the disorder is angioedema.

[0350] 159. The method according to any one of embodiments 149-151, wherein the disorder is hereditary angioedema.

[0351] 160. The method of any one of embodiments 149-151, wherein the disorder is autoimmune hemolytic anemia.

[0352] 161. The method of any one of embodiments 149-151, wherein the disorder is cold agglutinin disease.

[0353] 162. The method according to any one of embodiments 149-151, wherein the disorder is transplant rejection.

[0354] 163. The method of any one of embodiments 149-151, wherein the disorder is selected from hereditary angioedema type 1, hereditary angioedema type 2, trauma, inflammation, sepsis, multiple organ dysfunction syndrome, endotoxemia, end stage renal disease, renal failure, delayed graft function, ischemia-reperfusion injury, neuromyelitis optica, common variable immunodeficiency, antibody-mediated rejection, graft rejection, asthma, allergic asthma, angioneurotic edema, acute ACE-induced angioedema, renal transplantation, and acute kidney injury.

[0355] 164. In a particular embodiment, there is provided a compound or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 147 or a pharmaceutical composition according to embodiment 148 for use in the treatment of a complement-mediated disorder.

[0356] 165. The compound or composition for use according to embodiment 164, wherein the subject is a human.

[0357] 166. The compound or composition for use according to embodiment 164 or 165, wherein the disorder is mediated by C1s.

[0358] 167. The compound or composition for use according to any one of embodiments 164-166, wherein the disorder is C3 glomerulopathy.

[0359] 168. The compound or composition for use according to any one of embodiments 164 to 166, wherein the disorder is an ophthalmological disorder.

[0360] 169. The compound or composition for use according to any one of embodiments 164 to 166, wherein the disorder is age-related macular degeneration (AMD).

[0361] 170. The compound or composition for use according to any one of embodiments 164-166, wherein the disorder is paroxysmal nocturnal hemoglobinuria (PNH).

[0362] 171. The compound or composition for use according to any one of embodiments 164-166, wherein the disorder is C3 glomerulonephritis.

[0363] 172. The compound or composition for use according to any one of embodiments 164-166, wherein the disorder is dense deposit disease.

[0364] 173. The compound or composition for use according to any one of embodiments 164-166, wherein the disorder is angioedema.

[0365] 174. The compound or composition for use according to any one of embodiments 164-166, wherein the disorder is hereditary angioedema.

[0366] 175. The compound or composition for use according to any one of embodiments 164-166, wherein the disorder is autoimmune hemolytic anemia.

[0367] 176. The compound or composition for use according to any one of embodiments 164-166, wherein the disorder is cold agglutinin disease.

[0368] 177. The compound or composition for use according to any one of embodiments 164-166, wherein the disorder is transplant rejection.

[0369] 178. The compound or composition for use according to any one of embodiments 164-166, wherein the disorder is selected from hereditary angioedema type 1, hereditary angioedema type 2, trauma, inflammation, sepsis, multiple organ dysfunction syndrome, endotoxemia, end stage renal disease, renal failure, delayed graft function, ischemia-reperfusion injury, neuromyelitis optica, common variable immunodeficiency, antibody mediated rejection, graft rejection, asthma, allergic asthma, angioneurotic edema, acute ACE-induced angioedema, renal transplantation, and acute kidney injury.

[0370] 179. In certain embodiments, there is provided the use of a compound according to any one of embodiments 1 to 147, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a complement-mediated disorder.

[0371] 180. The use according to embodiment 179, wherein the subject is a human.

[0372] 181. The use according to embodiment 179 or 180, wherein the disorder is mediated by C1s.

[0373] 182. The use according to any one of embodiments 179-181, wherein the disorder is C3 glomerulopathy.

[0374] 183. The use according to any one of embodiments 179 to 181, wherein the disorder is an ophthalmological disorder.

[0375] 184. The use according to any one of embodiments 179 to 181, wherein the disorder is age-related macular degeneration (AMD).

[0376] 185. The use according to any one of embodiments 179 to 181, wherein the disorder is paroxysmal nocturnal hemoglobinuria (PNH).

[0377] 186. The use according to any one of embodiments 179-181, wherein the disorder is C3 glomerulonephritis.

[0378] 187. The use according to any one of embodiments 179-181, wherein the disorder is dense deposit disease.

[0379] 188. The use according to any one of embodiments 179 to 181, wherein the disorder is angioedema.

[0380] 189. The use according to any one of embodiments 179 to 181, wherein the disorder is hereditary angioedema.

[0381] 190. The use according to any one of embodiments 179-181, wherein the disorder is autoimmune hemolytic anemia.

[0382] 191. The use according to any one of embodiments 179-181, wherein the disorder is cold agglutinin disease.

[0383] 192. The use according to any one of embodiments 179 to 181, wherein the disorder is transplant rejection.

[0384] 193. The use according to any one of embodiments 179 to 181, wherein the disorder is selected from hereditary angioedema type 1, hereditary angioedema type 2, trauma, inflammation, sepsis, multiple organ dysfunction syndrome, endotoxemia, end stage renal disease, renal failure, delayed graft function, ischemia-reperfusion injury, neuromyelitis optica, common variable immunodeficiency, antibody-mediated rejection, graft rejection, asthma, allergic asthma, angioneurotic edema, acute ACE-induced angioedema, renal transplantation, and acute kidney injury.

[0385] Pharmaceutical Preparations The active compounds described herein can be administered as pure chemicals to a host in need thereof, but are more typically administered to a host, typically a human, in need of such treatment as a pharmaceutical composition comprising an effective amount of an active compound described herein or a pharma- ceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof. Thus, in one embodiment, the present disclosure provides a pharmaceutical composition comprising an effective amount of a compound or a pharma- ceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, together with at least one pharma- ceutically acceptable carrier, for any of the uses described herein. The pharmaceutical composition may contain the compound or salt as the only active agent, or, in alternative embodiments, the compound and at least one additional active agent.

[0386] An effective amount of the active compound described herein, or the active compound described herein used in combination with another active agent, or alternately, or prior to, in combination with, or subsequent to, can be used in an amount sufficient to (a) inhibit the progression of a disorder mediated by the complement pathway, including an inflammatory disorder, an immune disorder, including autoimmunity, or a complement-related disorder, (b) cause the regression of an inflammatory disorder, an immune disorder, including autoimmunity, or a complement-related disorder, (c) cause the cure of an inflammatory disorder, an immune disorder, including autoimmunity, or a complement-related disorder, or to inhibit or prevent the onset of an inflammatory disorder, an immune disorder, including autoimmunity, or a complement-related disorder. Thus, an effective amount of the active compound described herein, or a salt or composition thereof, provides a sufficient amount of the active agent to provide a clinical benefit when administered to a patient.

[0387] The precise amount of an active compound or pharmaceutical composition described herein delivered to a host, typically a human, in need thereof will be determined by a health care provider to achieve the desired clinical benefit.

[0388] In certain embodiments, the pharmaceutical composition is in a unit dosage form containing from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of active compound, and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent. Examples are dosage forms containing at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 900, 1000, 1100, 1200, 1250, 1300, 1400, 1500, or 1600 mg of active compound, or a salt, N-oxide, isotopic analog, or prodrug thereof. In one embodiment, the dosage form has at least about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 200 mg, 400 mg, 500 mg, 600 mg, 1000 mg, 1200 mg, or 1600 mg of active compound, N-oxide, isotopic analog, prodrug, or salt thereof. The amount of active compound in the dosage form is calculated without considering salt. The dosage form can be administered as needed, for example, once a day (qd), twice a day (bid), three times a day (tid), four times a day (qid), once every other day (Q2d), once every other day (Q3d), or any dosing schedule that results in the treatment of the disorders described herein.

[0389] The compounds disclosed herein or used as described herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, via implants, including ocular implants, transdermally, via buccal administration, rectally, as ophthalmic solutions, as injections, including intraocular injections, intravenously, intra-aortically, intracranially, subdermally, intraperitoneally, subcutaneously, nasally, sublingually, intrathecally, or rectally, or by other means, in dosage unit formulations containing conventional pharma- ceutically acceptable carriers. For intraocular delivery, the compounds may be administered as desired, for example, as a solution, suspension, or other formulation, via intravitreal, intrastromal, intracameral, sub-Tenon, subretinal, retrobulbar, peribulbar, suprachoroidal, subchoroidal, choroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, pericornal, or lacrimal injection, or through a mucus, mucin, or mucosal barrier, in an immediate or controlled release manner, or in an intraocular device, injection, or topical formulation, e.g., a solution or suspension provided as an eye drop.

[0390] The pharmaceutical composition may be formulated into any pharma- ceutically useful form, for example, an aerosol, cream, gel, gel capsule, pill, microparticle, nanoparticle, injection or infusion solution, capsule, tablet, syrup, transdermal patch, subcutaneous patch, dry powder, inhalation formulation, medical device, suppository, buccal or sublingual formulation, parenteral formulation, or ophthalmic solution or suspension. Some dosage forms, such as tablets and capsules, are divided into unit doses of suitable size containing an appropriate amount of the active ingredient, for example, an effective amount of the active ingredient to achieve a desired purpose.

[0391] Pharmaceutical compositions suitable for administration as contemplated herein and methods for preparing such compositions are known in the art. Examples of known techniques include, for example, U.S. Patent Nos. 4,983,593, 5,013,557, 5,456,923, 5,576,025, 5,723,269, 5,858,411, 6,254,889, 6,303,148, 6,395,302, 6,497,903, 7,060,296, 7,078,057, 7,102 ... Nos. 404,828, 8,202,912, 8,257,741, 8,263,128, 8,337,899, 8,431,159, 9,028,870, 9,060,938, 9,211,261, 9,265,731, 9,358,478, and 9,387,252, which are incorporated herein by reference.

[0392] The pharmaceutical compositions contemplated herein may optionally include a carrier. The carrier must be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to the patient being treated. The carrier may be inert or may have pharmaceutical benefits of its own. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. Types of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, fillers, flavoring agents, glidants, lubricants, pH adjusters, preservatives, stabilizers, surfactants, solubilizers, tableting agents, and wetting agents. Some carriers may be listed in more than one category, for example, vegetable oils may be used as lubricants in some formulations and as diluents in others. Exemplary pharmaceutically acceptable carriers include sugar, starch, cellulose, powdered tragacanth, malt, gelatin, talc, and vegetable oils.

[0393] Examples of other matrix materials, fillers, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch. Examples of surfactants include sodium lauryl sulfate and polysorbate 80.

[0394] Examples of drug complexing or solubilizing agents include polyethylene glycol, caffeine, xanthene, gentisic acid, and cyclodextrin.

[0395] Examples of disintegrants include sodium starch glycolate, sodium alginate, sodium carboxymethylcellulose, methylcellulose, colloidal silicon dioxide, and croscarmellose sodium.

[0396] Examples of binders include methylcellulose, microcrystalline cellulose, starch, and gums such as guar gum and tragacanth.

[0397] Examples of lubricants include magnesium stearate and calcium stearate.

[0398] Examples of pH adjusters include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, and the like; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, and the like; and buffers that generally contain a mixture of an acid and its salt. The pharmaceutical composition may also contain other optional active agents that do not substantially interfere with the activity of the compounds of the present disclosure.

[0399] In certain embodiments, the pharmaceutical composition for administration further comprises a compound or salt of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, and optionally, a phosphoglyceride; a phosphatidylcholine; a dipalmitoylphosphatidylcholine (DPPC); a dioleoylphosphatidylethanolamine (DOPE); a dioleoyloxypropyltriethylammonium (DOTMA); a dioleoylphosphatidylcholine; a cholesterol. ;cholesterol esters;diacylglycerol;diacylglycerol succinate;diphosphatidylglycerol (DPPG);hexanedecanol;aliphatic alcohols such as polyethylene glycol (PEG);polyoxyethylene-9-lauryl ether;surface active fatty acids such as palmitic acid or oleic acid;fatty acids;fatty acid monoglycerides;fatty acid diglycerides;fatty acid amides;sorbitan trioleate (SPAN® 85) glycocholate;sorbitan monolaurate (SPAN® 20);polysorbate 20 ( TWEEN® 20; Polysorbate 60 (TWEEN® 60); Polysorbate 65 (TWEEN® 65); Polysorbate 80 (TWEEN® 80); Polysorbate 85 (TWEEN® 85); Polyoxyethylene monostearate; Surfactin; Poloxamer; Sorbitan fatty acid esters such as sorbitan trioleate; Lecithin; Lysolecithin; Phosphatidylserine; Phosphatidylinositol; Sphingomyelin; Phosphatidylethanolamine (cephalin); Cardiac Olipin;Phosphatidic acid;Cerebrosides;Dicetyl phosphate;Dipalmitoyl phosphatidylglycerol;Stearylamine;Dodecylamine;Hexadecyl-amine;Acetyl palmitate;Glycerol ricinoleate;Hexadecyl stearate;Isopropyl myristate;Tyloxapol;Poly(ethylene glycol) 5000-phosphatidylethanolamine;Poly(ethylene glycol) 400-monostearate;Phospholipids;Synthetic and / or natural detergents with high surface active properties;Deoxycholate;Cyclodextrin;chaotropic salts; ion pairing agents; glucose, fructose, galactose, ribose, lactose, sucrose, maltose, trehalose, cellobiose, mannose, xylose, arabinose, glucuronic acid, galacturonic acid, mannuronic acid, glucosamine, galactosamine, and neuraminic acid;Pullulan, cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextran, glycogen, hydroxyethyl starch, carrageenan, glycon, amylose, chitosan, N,O-carboxymethyl chitosan, algin and alginic acid, starch, chitin, inulin, konjac, glucomannan, pustulan, heparin, hyaluronic acid, curdlan, and xanthan, mannitol, sorbitol, xylitol, erythritol, maltitol, and lactitol, Pluronic® polymers, polyethylene, polycarbonates (e.g., poly(1,3-dioxane-2-one)), polyanhydrides (e.g., For example, poly(sebacic anhydride), polypropyl fumarate, polyamides (e.g., polycaprolactam), polyacetals, polyethers, polyesters (e.g., polylactides, polyglycolides, polylactide-co-glycolides, polycaprolactones, polyhydroxy acids (e.g., poly((β-hydroxyalkanoates))), poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polyureas, polystyrenes, and polyamines, polylysine, polylysine-PEG copolymers, and poly(ethyleneimine), poly(ethyleneimine)-PEG copolymers, glycerol monocaprylocaprate, propylene glycol, vitamin E including one or more of TPGS (also known as d-α-tocopheryl polyethylene glycol 1000 succinate), gelatin, titanium dioxide, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO / PPO), polyethylene glycol (PEG), sodium carboxymethylcellulose (NaCMC), and hydroxypropyl methylcellulose acetate succinate (HPMCAS);

[0400] In some embodiments, pharmaceutical preparations may contain polymers for controlled delivery of the described compounds, including, but not limited to, Pluronic® polymers, polyesters (e.g., polylactic acid, poly(lactic-co-glycolic acid), polycaprolactone, polyvalerolactone, poly(1,3-dioxan-2-one)); polyanhydrides (e.g., poly(sebacic anhydride)); polyethers (e.g., polyethylene glycol); polyurethanes; polymethacrylates; polyacrylates; and polycyanoacrylates.

[0401] In some embodiments, the polymer may be modified with acyclic polyacetals derived from polyethylene glycol (PEG), carbohydrates, and / or polysaccharides. See, e.g., Papisov, 2001, ACS Symposium Series, 786:301, which is incorporated herein by reference.

[0402] The compounds of the present disclosure may be formulated as particles. In one embodiment, the particles are or include microparticles. In an alternative embodiment, the particles are or include nanoparticles.

[0403] In additional alternative embodiments, the common techniques for preparing particles include, but are not limited to, solvent evaporation, solvent removal, spray drying, phase inversion, coacervation, and cold casting.Suitable methods for particle formulation are briefly described herein.Pharmaceutically acceptable excipients, including pH adjusters, disintegrants, preservatives, and antioxidants, can be optionally incorporated into particles during particle formation.

[0404] In one embodiment, the particles are obtained by a solvent evaporation method. In this method, a compound described herein (or a polymer matrix and one or more compounds described herein) is dissolved in a volatile organic solvent such as methylene chloride. The organic solution containing the compound described herein is then suspended in an aqueous solution containing a surfactant such as poly(vinyl alcohol). The resulting emulsion is stirred until most of the organic solvent evaporates, leaving solid nanoparticles or microparticles. The resulting nanoparticles or microparticles are washed with water and dried overnight in a freeze dryer (under vacuum, with or without heat). Nanoparticles of different sizes and morphologies can be obtained by this method.

[0405] Pharmaceutical compositions containing labile polymers, such as certain polyanhydrides, may be degraded during the manufacturing process by the presence of water. For these polymers, the particles may be made using methods carried out in completely or substantially anhydrous organic solvents.

[0406] Solvent removal can also be used to prepare particles from hydrolytically unstable compounds. In this method, the compound (or the polymer matrix and one or more compounds) is dispersed or dissolved in a volatile organic solvent, such as methylene chloride. This mixture is then suspended by stirring in an organic oil (such as silicon oil) to form an emulsion. Solid particles are formed from the emulsion, which can then be separated from the supernatant. The external morphology of the spheres produced by this technique depends largely on the identity of the drug.

[0407] In one embodiment, the active compound described herein is administered to a patient in need thereof as particles formed by solvent removal. In another embodiment, the present disclosure provides particles formed by solvent removal, comprising a compound of the present disclosure and one or more pharma- ceutically acceptable excipients as defined herein. In another embodiment, the particles formed by solvent removal comprise a compound of the present disclosure and an additional therapeutic agent. In a further embodiment, the particles formed by solvent removal comprise a compound of the present disclosure, an additional therapeutic agent, and one or more pharma- ceutically acceptable excipients. In another embodiment, any of the described particles formed by solvent removal can be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment, the particles formed from solvent removal are formulated into a tablet, but the tablet is not coated.

[0408] In one embodiment, the particles are obtained by spray drying. In this method, the compound (or the polymer matrix and one or more compounds) is dissolved in an organic solvent such as methylene chloride. The solution is pumped through an atomizing nozzle driven by a compressed gas flow, and the resulting aerosol is suspended in a heated air cyclone, where the solvent evaporates from the microdroplets to form particles. Using this method, microparticles and nanoparticles can be obtained.

[0409] In one embodiment, the active compounds described herein are administered to a patient in need thereof as a spray-dried dispersion (SDD). In another embodiment, the present disclosure provides a spray-dried dispersion (SDD) comprising a compound of the present disclosure and one or more pharma- ceutically acceptable excipients as defined herein. In another embodiment, the SDD comprises a compound of the present disclosure and an additional therapeutic agent. In a further embodiment, the SDD comprises a compound of the present disclosure, an additional therapeutic agent, and one or more pharma- ceutically acceptable excipients. In another embodiment, any of the spray-dried dispersions described can be coated to form a coated tablet. In an alternative embodiment, the spray-dried dispersion is formulated into a tablet, but the tablet is not coated.

[0410] Particles can be formed from the active compounds described herein using phase inversion method.In this method, the compound (or polymer matrix and one or more active compounds) is dissolved in a suitable solvent, and the solution is poured into a strong non-solvent, and the compound spontaneously forms microparticles or nanoparticles under favorable conditions.Using this method, nanoparticles of a wide range of sizes can be made, including nanoparticles to microparticles, typically with a narrow particle size distribution.

[0411] In one embodiment, the active compound described herein is administered to a patient in need thereof as a particle formed by phase inversion. In another embodiment, the present disclosure provides a particle formed by phase inversion comprising a compound of the present disclosure and one or more pharma- ceutically acceptable excipients as defined herein. In another embodiment, the particle formed by phase inversion comprises a compound of the present disclosure and an additional therapeutic agent. In a further embodiment, the particle formed by phase inversion comprises a compound of the present disclosure, an additional therapeutic agent, and one or more pharma- ceutically acceptable excipients. In another embodiment, any of the described particles formed by phase inversion can be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment, the particle formed by phase inversion is formulated into a tablet, but the tablet is not coated.

[0412] The technique of particle formation using coacervation is known in the art and described, for example, in GB-B-929406, GB-B-929401, and U.S. Pat. Nos. 3,266,987, 4,794,000, and 4,460,563. Coacervation involves the separation of a compound (or a polymer matrix and one or more compounds) solution into two immiscible liquid phases. One phase is a high-density coacervate phase that contains a high concentration of the compound, and the second phase contains a low concentration of the compound. Within the high-density coacervate phase, the compound forms nano- or micro-scale droplets that harden into particles. Coacervation can be induced by temperature change, addition of a non-solvent or addition of a micro-salt (simple coacervation), or addition of another polymer that forms an interpolymer complex (complex coacervation).

[0413] In one embodiment, the active compound described herein is administered to a patient in need thereof as particles formed by coacervation. In another embodiment, the present disclosure provides particles formed by coacervation comprising a compound of the present disclosure and one or more pharma- ceutically acceptable excipients as defined herein. In another embodiment, the particles formed by coacervation comprise a compound of the present disclosure and an additional therapeutic agent. In a further embodiment, the particles formed by coacervation comprise a compound of the present disclosure, an additional therapeutic agent, and one or more pharma- ceutically acceptable excipients. In another embodiment, any of the described particles formed by coacervation can be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment, the particles formed from coacervation are formulated into a tablet, but the tablet is not coated.

[0414] A method for cryogenic casting of controlled release microspheres is described in U.S. Patent No. 5,019,400 to Gombotz et al. In this method, the compound is dissolved in a solvent. This mixture is then sprayed into a vessel containing a liquid non-solvent at a temperature below the freezing point of the drug solution, freezing droplets of the compound. When the compound droplets and non-solvent are warmed, the solvent in the droplets melts and is extracted into the non-solvent, hardening the microspheres.

[0415] In one embodiment, the compound of the present disclosure is administered to a patient in need thereof as a particle formed by cold casting. In another embodiment, the present disclosure provides a particle formed by cold casting, comprising a compound of the present disclosure and one or more pharma- ceutically acceptable excipients as defined herein. In another embodiment, the particle formed by cold casting comprises a compound of the present disclosure and an additional therapeutic agent. In a further embodiment, the particle formed by cold casting comprises a compound of the present disclosure, an additional therapeutic agent, and one or more pharma- ceutically acceptable excipients. In another embodiment, any of the described particles formed by cold casting can be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment, the particle formed from cold casting is formulated into a tablet, but the tablet is not coated.

[0416] In one aspect of the present disclosure, an effective amount of the active compounds described herein are incorporated into nanoparticles, for example, for convenience of delivery and / or sustained release delivery. The use of nanoscale materials allows for alteration of fundamental physical properties such as solubility, diffusivity, blood circulation half-life, drug release characteristics, and / or immunogenicity. Many nanoparticle-based therapeutic and diagnostic agents have been developed for the treatment of cancer, diabetes, pain, asthma, allergies, and infectious diseases. These nanoscale agents may provide more effective and / or more convenient routes of administration, reduce therapeutic toxicity, extend product life cycles, and ultimately reduce healthcare costs. As therapeutic delivery systems, nanoparticles allow for targeted delivery and controlled release.

[0417] Furthermore, nanoparticle-based compound delivery can be used to reduce dosing frequency by releasing compounds at a sustained rate, to deliver drugs in a targeted manner to minimize systemic side effects, or to deliver two or more drugs simultaneously for combination therapy to create synergistic effects and suppress drug resistance. Many nanotechnology-based therapeutic products have been approved for clinical use. Among these products, liposomal drugs and polymer-based conjugates account for a large proportion of the products. See Zhang, L., et al., Nanoparticles in Medicine: Therapeutic Applications and Developments, Clin. Pharm. and Ther., 83(5):761-769, 2008.

[0418] Methods for making nanoparticles are known in the art (see, e.g., Muller, RH, et al., Solid lipid nanoparticles (SLN) for controlled drug delivery-a review of the state of the art, Eur. H. Pharm. Biopharm., 50:161-177, 2000; US 8,691,750 to Consien et al.; WO 2012 / 145801 to Kanwar; US 8,580,311 to Armes, S. et al.; Petros, RA and DeSimone, JM, Strategies in the design of nanoparticles for therapeutic applications, Nature Reviews / Drug See Discovery, vol. 9:615-627, 2010; US8,465,775; US8,444,899; US8,420,124; US8,263,129; US8,158,728; 8,268,446; Pellegrino et al., 2005, Small, 1:48; Murray et al., 2000, Ann. Rev. Mat. Sci., 30:545; and Trindade et al., 2001, Chem. Mat., 13:3843, all of which are incorporated herein by reference. Additional methods are described in the literature (e.g., Doubrow, Ed., "Microcapsules and Nanoparticles in Medicine and Pharmacy," CRC Press, Boca Raton, 1992; Mathiowitz et al., 1987, J. Control. Release, 5:13; Mathiowitz et al., 1987, Reactive Polymers, 6:275; and Mathiowitz et al., 1988, J. Appl. Polymer Sci., 35:755; U.S. Patent Nos. 5,578,325 and 6,007,845; P. Paolicelli et al., “Surface-modified PLGA-based Nanoparticles that can Efficiently Associate and Deliver Virus-like Particles” Nanomedicine. 5(6):843-853 (2010)), U.S. Patent No. 5,543,158 to Gref et al., or International Publication WO 2009 / 051837 by Von Andrian et al.; Zauner et al., 1998, Adv. Drug Del. Rev., 30:97; and Kabanov et al., 1995, Bioconjugate Chem., 6:7; (PEI; Boussif et al., 1995, Proc. Natl. Acad. Sci., USA, 1995, 92:7297), as well as poly(amidoamine) dendrimers (Kukowska-Latallo et al., 1999, Adv. Drug Del. Rev., 30:97). al.,1996,Proc.Natl.Acad.Sci.,USA,93:4897;Tang et al.,1996,Bioconjugate Chem.,7:703;and Haensler et al.,1993,Bioconjugate Chem.,4:372;Putnam et al.,1999,Macromolecules,32:3658;Barrera et al. al., 1993, J. Am. Chem. Soc., 115:11010; Kwon et al., 1989, Macromolecules, 22: 3250; Lim et al., 1999, J. Am. Chem. Soc., 121: 5633; and Zhou et al., 1990, Macromolecules, 23: 3399). Examples of these polyesters include poly(L-lactide-co-L-lysine) (Barrera et al., 1993, J. Am. Chem. Soc., 115:11010), poly(serine ester) (Zhou et al., 1990, Macromolecules, 23:3399), poly(4-hydroxy-L-proline ester) (Putnam et al., 1999, Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem. Soc., 121:5633), and びポリ(4-ヒドロキシ-L-プロリンエステル) (Putnam et al., 1999, Macromolecules, 32:3658; and びLim et al. al.,1999,J.Am.Chem.Soc.,121:5633;U.S. Patent No. 6,123,727;U.S. Patent No. 5,804,178;U.S. Patent No. 5,770,4 No. 17; U.S. Patent No. 5,736,372; U.S. Patent No. 5,716,404; U.S. Patent No. 6,095,148; U.S. Patent No. 5,837,752; U.S. Patent No. 5,902 ,599; U.S. Patent No. 5,696,175; U.S. Patent No. 5,514,378; U.S. Patent No. 5,512,600; U.S. Patent No. 5,399,665; U.S. Patent No. 5,0 19,379; U.S. Patent No. 5,010,167; U.S. Patent No. 4,806,621; U.S. Patent No. 4,638,045; and U.S. Patent No. 4,946,929; Wang et al.,2001,J.Am.Chem.Soc.,123:9480;Lim et al. al., 2001, J. Am. Chem. Soc., 123: 2460; Langer, 2000, Acc. Chem. Res., 33: 94; Langer, 1999, J. Control. Release, 62: 7; Uhrich et al., 1999, Chem. Rev., 99: 3181; Concise Encyclopedia of Polymer Science and Polymeric Amines and Ammonium Salts,Ed.by Goethals,Pergamon Press,1980;Principles of Polymerization by Odian,John Wiley & Sons,Fourth Edition,2004;Contemporary Polymer Chemistry by Allcock et al.,Prentice-Hall,1981;Deming et al., 1997, Nature, 390:386; Japan Patent No. 6,506,577, Japan Patent No. 6,632,922, Japan Patent No. 6,686,446, and Japan Patent No. 6,818,732; C. Astete et al., “Synthesis and characterization of PLGA nanoparticles” J. Biomater. Sci. Polymer Edn, Vol. 17, No. 3, pp. 247-289 (2006); K. Avgoustakis “Pegylated Poly(Lactide) and Poly(Lactide-Co-Glycolide) Nanoparticles: Preparation, Properties and Possible Applications in Drug Delivery”Current Drug Delivery 1:321-333(2004);C.Reis et al.,“Nanoencapsulation I.Methods for preparation of drug-loaded polymeric nanoparticles”Nanomedicine 2:8-21(2006);P.Paolicelli et al.,“Surface-modified PLGA-based Nanoparticles that can Efficiently Associate and Deliver Virus-like Particles” Nanomedicine. 5(6):843-853 (2010); and U.S. Pat. No. 6,632,671 to Unger (October 14, 2003), all of which are incorporated herein by reference.

[0419] In one embodiment, the polymer particles are from about 0.1 nm to about 10,000 nm, from about 1 nm to about 1000 nm, from about 10 nm to 1000 nm, from about 1 to 100 nm, from about 1 to 10 nm, from about 1 to 50 nm, from about 100 nm to 800 nm, from about 400 nm to 600 nm, or from about 500 nm. In one embodiment, the microparticles are less than about 0.1 nm, 0.5 nm, 1.0 nm, 5.0 nm, 10 nm, 25 nm, 50 nm, 75 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, 1000 nm, 1250 nm, 1500 nm, 1750 nm, or 2000 nm. In some embodiments, the compounds described herein can be covalently attached to nanoparticles, such as polystyrene particles, PLGA particles, PLA particles, or other polymers used in nanoparticles.

[0420] The pharmaceutical compositions according to the present disclosure may be formulated for oral administration. These compositions may contain any amount of active compound that achieves the desired result, for example, 0.1 to 99% by weight (wt.%) of the compound, usually at least about 5 wt.% of the compound. Some embodiments contain at least about 10%, 15%, 20%, 25 wt.% to about 50 wt.% or about 5 wt.% to about 75 wt.% of the compound.

[0421] Pharmaceutical compositions suitable for rectal administration are typically presented as unit-dose suppositories. These may be prepared by mixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[0422] Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers that may be used include petrolatum, lanolin, polyethylene glycols, alcohols, transdermal penetration enhancers, and combinations of two or more of these.

[0423] Pharmaceutical compositions suitable for transdermal administration may be presented as separate patches adapted to remain in intimate contact with the epidermis of recipient for extended periods of time. Pharmaceutical compositions suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3(6):318(1986)), typically taking the form of an aqueous solution of active compound, optionally buffered. In one embodiment, a microneedle patch or device is provided for delivering drugs through or into biological tissue, particularly the skin. The microneedle patch or device can deliver drugs through or into the skin or other tissue barrier at clinically relevant rates, with little or no damage, pain, or irritation to said tissue.

[0424] Pharmaceutical compositions suitable for pulmonary administration can be delivered by a wide range of passive breath-driven and active power-driven single / multiple dose dry powder inhalers (DPIs).The most commonly used devices for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers.Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers.The selection of a suitable pulmonary delivery device depends on parameters such as the nature of the drug and its formulation, the site of action, and the pathophysiology of the lungs.

[0425] Further non-limiting examples of devices and methods for inhalation drug delivery include, for example, US 7,383,837 (titled "Inhalation Device") (SmithKline Beecham Corporation); WO / 2006 / 033584 (titled "Powder Inhaler") (Glaxo SmithKline Pharmaceuticals SA); WO / 2005 / 044186 (titled "Inhalable Pharmaceutical Formulations Employing Desiccating Agents and Methods of Administering the Same") (Glaxo Group Ltd and SmithKline Beecham Corporation); US 9,095,670 (titled "Inhalation Device and Method of Dispensing Medicament"), US 8,205,611 (titled "Dry Powder Inhaler") (Astrazeneca AB); WO / 2013 / 038170 (titled "Inhaler") (Astrazeneca AB and Astrazeneca UK Ltd.); US / 2014 / 0352690 (titled "Inhalation Device with Feedback System"), US8,910,625 and US / 2015 / 0165137 (titled "Inhalation Device for Use in Aerosol Therapy") (Vectura GmbH);US6,948,496 (titled "Inhalers"), US / 2005 / 0152849 (titled "Powders Comprising Anti-adherent Materials for Use in Dry Powder Inhalers"), US6,582,678, US8,137,657, US / 2003 / 0202944, and US / 2010 / 0330188 (titled "Carrier Particles for Use in Dry Powder Inhalers"), US6,221,338 (titled "Method of Producing Particles for Use in Dry Powder Inhalers"), US6,989,155 (titled "Powders"), US / 2007 / 0043030 (titled "Pharmaceutical Compositions for Treating Premature Ejaculation by Pulmonary Inhalers") US7,845,349 (titled "Inhaler"), US / 2012 / 0114709 and US8,101,160 (titled "Formulations for Use in Inhaler Devices"), US / 2013 / 0287854 (titled "Compositions and Uses"), US / 2014 / 0037737 and US8,580,306 (titled "Particles for Use in a Pharmaceutical Composition"), US / 2015 / 0174343 (titled "Mixing Channel for an Inhalation Device"), US7,744,855 and US / 2010 / 0285142 (titled "Method of Making Particles for Use in a Pharmaceutical US 7,541,022, US / 2009 / 0269412, and US / 2015 / 0050350 (entitled "Pharmaceutical Formulations for Dry Powder Inhalers") (Vectura Limited).

[0426] Many methods and devices for ocular drug delivery are known in the art. Non-limiting examples are described in the following patents and patent applications (which are hereby incorporated by reference in their entireties): US 8,192,408 (entitled "Ocular trocar assembly") (Psivida U.S., Inc.); US 7,585,517 (entitled "Transcleral delivery") (Macusight, Inc.); US 5,710,182 and US 5,795,913 (entitled "Ophthalmic composition") (Santen OY); US 8,663,639 (entitled "Formulations for treating ocular diseases and conditions"), US 8,486,960 (entitled "Formulations and methods for vascular permeability-related diseases or conditions"), US 8,367,097 and US 8,927,005 (entitled "Liquid formulations for treatment of diseases or conditions"), US 7,455,855 (entitled "Delivering substance and drug delivery system using the WO / 2011 / 050365 (titled "Conformable Therapeutic Shield For Vision and Pain") and WO / 2009 / 145842 (titled "Therapeutic Device for Pain Management and Vision") (Forsight Labs, LLC); US9,066,779 and US8,623,395 (titled "Implantable therapeutic device"), WO / 2014 / 160884 (titled "Ophthalmic Implant for Delivering TherapeuticUS8,399,006, US8,277,830, US8,795,712, US8,808,727, US8,298,578, and WO / 2010 / 088548 (titled "Posterior segment drug delivery"), WO / 2014 / 152959 and US20140276482 (titled "Systems for Sustained Intraocular Delivery of Low Solubility Compounds from a Port Delivery System Implant"), US8,905,963 and US9,033,911 (titled "Injector apparatus and method for drug delivery"), WO / 2015 / 057554 (titled "Formulations and Methods for Increasing or Reducing US 8,715,712 and US 8,939,948 (titled "Ocular insert apparatus and methods"), WO / 2013 / 116061 (titled "Insertion and Removal Methods and Apparatus for Therapeutic Devices"), WO / 2014 / 066775 (titled "Ophthalmic System for Sustained Release of Drug to the Eye"), WO / 2015 / 085234 and WO / 2012 / 019176 (titled "Implantable Therapeutic Device"), WO / 2012 / 065006 (titled "Methods and Apparatus to determine Porous Structures for Drug Delivery"), WO / 2010 / 141729 (titled "Anterior Segment Drug Delivery"), WO / 2011 / 050327 (titled "Corneal Denervation for WO / 2013 / 022801 (title: Small Moleculeand WO / 2012 / 019047 (titled "Subconjunctival Implant for Posterior Segment Drug Delivery"), WO / 2012 / 068549 (titled "Therapeutic Agent Formulations for Implanted Devices"), WO / 2012 / 019139 (titled "Combined Delivery Methods and Apparatus"), WO / 2013 / 040426 (titled "Ocular Insert Apparatus and Methods"), WO / 2012 / 019136 (titled "Injector Apparatus and Method for Drug Delivery"), and WO / 2013 / 040247 (titled "Fluid Exchange Apparatus and Methods") (ForSight Vision4, Inc.).

[0427] Further non-limiting examples of methods for delivering active compounds include those disclosed in WO / 2015 / 085251 (entitled "Intracameral Implant for Treatment of an Ocular Condition") (Envisia Therapeutics, Inc.); WO / 2011 / 008737 (entitled "Engineered Aerosol Particles, and Associated Methods"), WO / 2013 / 082111 (entitled "Geometrically Engineered Particles and Methods for Modulating Macrophage or Immune Responses"), WO / 2009 / 132265 (entitled "Degradable compounds and methods of use thereof, particularly with particle replication in non-wetting templates"), WO / 2010 / 099321 (entitled "Interventional drug delivery system and associated methods"), WO / 2008 / 100304 (entitled "Polymer particle composites having high fidelity order, size, and shape"). WO / 2007 / 024323 (titled "Nanoparticle fabrication methods, systems, and materials") (Liquidia Technologies, Inc. and the University of North Carolina at Chapel Hill); WO / 2010 / 009087 (titled "Iontophoretic Delivery of a Controlled-Release Formulation in the Eye") (Liquidia Technologies, Inc. and Eyegate Pharmaceuticals, Inc.) and WO / 2009 / 132206 (titled "Compositions and Methods for Intracellular Delivery and Release of Cargo"), WO / 2007 / 133808 (titled "Nano-particles for cosmetic applications"), WO / 2007 / 056561 (titled "Medical devices, materials, and methods"), WO / 2010 / 065748 (titled "Method for producing patterned materials"), and WO / 2007 / 081876 (titled "Nanostructured surfaces for biomedical / biomaterial applications and processes thereof") (Liquidia Technologies, Inc.).

[0428] Further non-limiting examples of methods and devices for ocular drug delivery include, for example, WO2011 / 106702 and US8,889,193 (titled "Sustained delivery of therapeutic agents to an eye compartment"), WO2013 / 138343 and US8,962,577 (titled "Controlled release formulations for the delivery of HIF-1 inhibitors"), WO / 2013 / 138346 and US2013 / 0272994 (titled "Non-Linear Multiblock Copolymer-Drug Conjugates for the Delivery of Active Agents"), WO2005 / 072710 and US8,957,US2013 / 0164343 (titled "Compositions and Methods for Enhancing Transport Through Mucous"), WO2012 / 061703, US2012 / 0121718, and US2013 / 0236556 (titled "Compositions and Methods Relating to Reduced Mucoadhesion"), WO2012 / 039979 and US2013 / 0183244 (titled "Rapid Diffusion of Large Polymeric Nanoparticles in the Mammalian Brain"), WO2012 / 109363 and US2013 / 0323313 (titled "Mucus WO2013 / 090804 and US2014 / 0329913 (titled "Nanoparticles with enhanced mucosal penetration or decreased inflammation"), WO2013 / 110028 (titled "Nanoparticle formulations with enhanced mucosal penetration"), WO2013 / 166498 and US2015 / 0086484 (titled "Lipid-based drug carriers for rapid penetration through mucus linings") (The Johns Hopkins University); WO2013 / 166385 (titled "Pharmaceutical Nanoparticles Showing Improved Mucosal Transport"), US2013 / 0323179 (titled "Nanocrystals, Compositions,and Methods that Aid Particle Transport in Mucus" (The Johns Hopkins University and Kala Pharmaceuticals, Inc.); WO / 2015 / 066444 (titled "Compositions and methods for ophthalmic and / or other applications"), WO / 2014 / 020210 and WO / 2013 / 166408 (titled "Pharmaceutical nanoparticles showing improved mucosal transport") (Kala Pharmaceuticals, Inc.); US9,022,970 (titled "Ophthalmic injection device including dosage control device"), WO / 2011 / 153349 (titled "Ophthalmic compositions comprising pbo-peo-pbo block copolymers"), WO / 2011 / 140203 (titled "Stabilized ophthalmic galactomannan formulations"), WO / 2011 / 068955 (titled "Ophthalmic emulsion”, WO / 2011 / 037908 (titled “Injectable aqueous ophthalmic composition and method of use therefor”), US2007 / 0149593 (titled “Pharmaceutical Formulation for Delivery of Receptor Tyrosine Kinase Inhibiting (RTKi) Compounds to the Eye”), and US8,632,809 (titled “Water insoluble polymer matrix for drug delivery”) (Alcon, Inc.).

[0429] Further non-limiting examples of drug delivery devices and methods include, for example, US 2009 / 0203709 (titled "Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor") (Abbott Laboratories); US 2005 / 0009910 (titled "Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of a prodrug); US 20130071349 (titled "Biodegradable polymers for lowering intraocular pressure"); US 8,481,069 (titled "Tyrosine kinase microspheres"); US 8,465,778 (titled "Method of making tyrosine kinase microspheres"); US 8,409,607 (titled "Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods"); US 8,512,738 and US2014 / 0031408 (title: "Biodegradable intravitreal tyrosine kinase implants"), US2014 / 0294986 (title: "Microsphere Drug Delivery System for Sustained Intraocular Release"), US8,911,768 (title: "Methods For Treating Retinopathy With Extended Therapeutic Effect") (Allergan, Inc.); US6,495,164 (title: "Preparation of injectable suspensions having improved injectability") (Alkermes Controlled Therapeutics, Inc.; WO2014 / 047439 (titled "Biodegradable Microcapsules Containing Filling Material") (Akina, Inc.); WO2010 / 132664 (titled "Compositions And Methods For Drug Delivery") (Baxter International Inc. Baxter Healthcare SA); US2012 / 0052041 (titled "Polymeric nanoparticles with enhanced drug loading and methods of use thereof") (The Brigham and Women's Hospital, Inc.); US2014 / 0178475, US2014 / 0248358, and US20140249158 (titled "Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same") (BIND Therapeutics, Inc.); US5,869,103 (titled "Polymer microparticles for drug delivery”)(Danbiosyst UK Ltd.); US8628801 (titled "Pegylated Nanoparticles") (Universidad de Navarra); US2014 / 0107025 (titled "Ocular drug delivery system") (Jade Therapeutics, LLC); US6,287,588 (titled "Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof"), US6,589,549 (titled "Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles") (Macromed, Inc.); US6,007,845 and US5,578,325 (titled "Nanoparticles and microparticles of non-linear hydrophilichydrophobic multiblock copolymers") (Massachusetts Institute of Technology); US2004 / 0234611, US2008 / 0305172, US2012 / 0269894, and US20130122064 (titled "Ophthalmic depot formulations for periocular or subconjunctival administration (Novartis Ag); US6,413,539 (titled "Block polymer") (Poly-Med, Inc.); US2007 / 0071756 (titled "Delivery of an agent to ameliorate inflammation") (Peyman); US20080166411 (titled "Injectable Depot Formulations And Methods For Providing Sustained Release Of Poorly Soluble Drugs Comprising Nanoparticles") (Pfizer, Inc.); US6,706,289 (titled "Methods and compositions for enhanced delivery of bioactive molecules") (PR Pharmaceuticals, Inc.); and US8,663,674 (titled "Microparticle containing matrices for drug delivery") (Surmodics).

[0430] Use of Active Compounds for the Treatment of Selected Disorders In one embodiment, an effective amount of an active compound or salt thereof or composition described herein is used to treat a medical disorder that is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade), including a complement-associated disorder or an alternative complement pathway-associated disorder, a cellular disorder or abnormality that adversely affects the ability of a cell to participate in or respond to normal complement activity, or an undesirable complement-mediated response to a medical treatment, such as surgery or other medical procedure or administration of a pharmaceutical or biopharmaceutical, a blood transfusion, or administration of other allogeneic tissue or bodily fluid.

[0431] A complement-mediated disease or disorder is one in which the amount or activity of complement causes the disease or disorder in an individual.

[0432] In some embodiments, the complement-mediated disease or disorder is selected from the group consisting of an autoimmune disease, a cancer, a blood disease, an infectious disease, an inflammatory disease, an ischemia-reperfusion injury, a neurodegenerative disease, a neurodegenerative disorder, an eye disease, a kidney disease, a transplant rejection, a vascular disease, and a vasculitic disease.

[0433] In some embodiments, the complement-mediated disease or disorder is an autoimmune disease. In some embodiments, the complement-mediated disease or disorder is cancer.

[0434] In some embodiments, the complement-mediated disease or disorder is an infectious disease.

[0435] In some embodiments, the complement-mediated disease or disorder is an inflammatory disease.

[0436] In some embodiments, the complement-mediated disease or disorder is a hematological disease.

[0437] In some embodiments, the complement-mediated disease or disorder is ischemia-reperfusion injury.

[0438] In some embodiments, the complement-mediated disease or disorder is an eye disease, hi some embodiments, the complement-mediated disease or disorder is a renal disease.

[0439] In some embodiments, the complement-mediated disease or disorder is transplant rejection.

[0440] In some embodiments, the complement-mediated disease or disorder is antibody-mediated graft rejection.

[0441] In some embodiments, the complement-mediated disease or disorder is a vascular disease.

[0442] In some embodiments, the complement-mediated disease or disorder is a vasculitic disorder.

[0443] In some embodiments, the complement-mediated disease or disorder is a neurodegenerative disease or disorder.

[0444] In some embodiments, the complement-mediated disease is a neurodegenerative disease.

[0445] In some embodiments, the complement-mediated disorder is a neurodegenerative disorder. In some embodiments, the complement-mediated disease or disorder is a tauopathy.

[0446] In certain embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat a medical disorder of the central nervous system (CNS) or peripheral nervous system disorder involving complement activation. In an embodiment, the CNS disorder is ischemia-reperfusion injury or acquired brain or spinal cord injury, including, but not limited to, stroke, traumatic brain injury (TBI) and spinal cord injury (SCI).

[0447] In an embodiment, the disorder is a neurodegenerative disorder. In an embodiment, the disorder is a neuroinflammatory disorder.

[0448] In certain embodiments, the active compounds described herein, or pharma- ceutically acceptable salts thereof, are used to treat Alzheimer's disease (AD). AD has two hallmarks: amyloid-β (Aβ) plaques and neurofibrillary tangles containing abnormally phosphorylated tau. Recent studies have implicated complement in the development of AD; for example, genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the genes encoding the complement proteins clusterin (CLU) and CR1 (CR1) that are associated with risk of late-onset AD. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., 04 March 2019. Biomarker studies have also identified complement proteins and activation products in plasma and / or CSF to distinguish AD from controls and predict risk of progression to AD. (Ibid.)

[0449] In certain embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat certain forms of frontotemporal dementia, including, but not limited to, Pick's disease, sporadic frontotemporal dementia, and frontotemporal dementia with parkinsonism linked to chromosome 17, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and subacute sclerosing panencephalitis.

[0450] In certain embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat multiple sclerosis (MS). Multiple sclerosis (MS) is the most common cause of neurological disability in young adults in the Northern European Caucasian population, with a lifetime risk of approximately 1 in 400. C3 has been found to be deposited in the brains of MS patients. T-cell clones (TCCs) have been found to be associated with capillary endothelial cells, primarily within plaques and adjacent white matter. Areas of active myelin destruction are localized to C activation, and TCCs are deposited exclusively in such areas. C3d has been shown to be deposited in association with short segments of destroyed myelin in plaques with low-grade active demyelination, providing evidence of C's contribution to disease progression and acute inflammation. See Ingram et al., Complement in multiple sclerosis: its role in disease and potential as a biomarker. Clin Exp Immunol. 2009 Feb;155(2):128-39.

[0451] In certain embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat neuromyelitis optica (NMO). Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that primarily affects the optic nerve and spinal cord. Traditionally considered a variant of MS, it has recently been redefined according to new criteria using a combination of phenotypic subtyping and a newly developed disease biomarker, NMO immunoglobulin G (IgG), which has been reported to have a sensitivity of 58-76% and a specificity of 85-99% for NMO. NMO patients have higher levels of C3a and anti-C1q antibodies than healthy controls. C3a levels correlated with disease activity, neuropathy, and aquaporin-4 IgG. Nytrova et al.,Complement activation in patients with neuromyelitis optica.J Neuroimmunol.2014 Sep 15;274(1-2):185-91.

[0452] In certain embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat amyotrophic lateral sclerosis (ALS). ALS is caused by the progressive loss of upper and lower (alpha) motor neurons, resulting in degeneration of neuromuscular junctions in the peripheral nervous system, progressive muscle weakness, atrophy, spasticity, respiratory failure, and ultimately paralysis and death. Recent studies have shown increased C1q protein in the motor cortex and spinal cord of ALS postmortem tissue; C3 activation fragments and TCC in areas of pathology; C4d and TCC staining of degenerated neurons and glia in ALS motor cortex and spinal cord, and upregulation of C5aR1 in areas of pathology. C3d and C4d have been found in oligodendroglia and degenerated neurites surrounded by CR4-positive microglia in the spinal cord and motor cortex, and C1q, C3, and TCC have been shown to be present in the motor endplates of intercostal muscles of ALS donors even at early stages of the disease. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., 04 March 2019.

[0453] In certain embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat Parkinson's disease (PD). PD is characterized by the loss of dopaminergic neurons in the substantia nigra and the deposition of α-synuclein protein, forming Lewy bodies, which are pathological hallmarks of the disease. Patients exhibit resting tremor, bradykinesia, and rigidity. Complement activation has been associated with α-synuclein and Lewy bodies in Parkinson's disease, and in vitro studies have shown that the disease-associated splice variant α-synuclein 112, but not the full-length α-synuclein protein, triggers complement activation. In vivo, C3d, C4d, C7, and C9 localization in Lewy bodies has been reported. More recently, deposition of iC3b and C9 in Lewy bodies and melanized neurons has been reported, and iC3b immunoreactivity has been shown to increase with normal aging and is further elevated in PD compared to age-matched controls. Furthermore, a correlation has been shown between the ratio of C3 / Aβ42 or FH / Aβ42 in the CSF and the severity of motor and cognitive symptoms of Parkinson's disease. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., 04 March 2019. In some embodiments, the subject being treated suffers from Parkinson's disease with dementia (PDD).

[0454] In certain embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat Huntington's disease (HD). HD is an autosomal dominant genetic neurodegenerative disease characterized by progressive motor symptoms, psychiatric disorders, and dementia. HD is caused by an expansion of a three base pair (CAG) repeat in exon 1 of the HTT gene (39-121 repeats vs. normal range 8-39 repeats), which translates into a polyglutamine sequence at the N-terminus of the protein. This leads to polyglutamine length-dependent misfolding and accumulation of huntingtin protein in the striatum and cortex (layers 3, 5, and 6), followed by neuronal loss in these regions, which extends to the hippocampus. Neurons, astrocytes, and myelin sheaths in the caudate and striatum in HD have been shown to be immunoreactive for C1q, C4, C3, and neoepitopes of iC3b and TCC. In the HD striatum, expression of mRNAs encoding the early complement components C1q (c-chain), C1r, C3, and C4, the complement regulators C1INH, clusterin, MCP, DAF, and CD59, and the complement receptors C3a and C5a has been shown to be elevated. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., 04 March 2019.

[0455] In certain embodiments, an effective amount of an active compound described herein, or a pharmacologic acceptable salt thereof, is administered to treat or prevent any of the following conditions: argyrophilic grain dementia, British amyloid angiopathy, cerebral amyloid angiopathy, Creutzfeldt-Jakob disease, dementia pugilistica, diffuse neurofibrillary tangle disease with calcification, Down's syndrome, frontotemporal lobar degeneration, Gerstmann-Sträussler-Scheinker disease, Hallervorden-Spatz disease, inclusion body myositis, multiple system atrophy, and / or myocardial infarction. It is used to treat myotonic dystrophy, myotonic dystrophy, Niemann-Pick disease type C, non-Guam motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, senile dementia with neurofibrillary tangles, multi-infarct dementia, ischemic stroke, chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), and stroke.

[0456] In certain embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat hereditary motor and sensory neuropathy (HMSN).

[0457] In some embodiments, the hereditary sensory neuropathy is Charcot-Marie-Tooth (CMT) disease.

[0458] In some embodiments, the HSMN is Charcot-Marie-Tooth disease type 1A or 1B.

[0459] In some embodiments, the HSMN is Charcot-Marie-Tooth type 2 disease.

[0460] In some embodiments, the HSMN is Dejerine-Sottas disease (Charcot-Marie-Tooth type 3).

[0461] In some embodiments, the HSMN is Refsum's disease.

[0462] In some embodiments, the HSMN is Charcot-Marie-Tooth with cone features. In some embodiments, the HSMN is Charcot-Marie-Tooth type 6. In some embodiments, the HSMN is HMSN+ retinitis pigmentosa.

[0463] In some embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat Churg-Strauss Syndrome.

[0464] In some embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat peripheral arterial disease (PAD).

[0465] In certain embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat myasthenia gravis associated with a CNS disorder.

[0466] In certain embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat dementia with Lewy bodies.

[0467] In certain embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat an individual suffering from a prion disease.

[0468] In certain embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat Behcet's disease.

[0469] In certain embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat congenital myasthenia.

[0470] In certain embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat subacute sclerosing panencephalitis (SSPE).

[0471] In certain embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat Guillain-Barre syndrome.

[0472] In certain embodiments, the CNS disorder to be treated is a demyelinating disease, including, but not limited to, demyelinating myelolytic diseases and demyelinating leukodystrophy diseases.

[0473] In certain embodiments, the disorder to be treated is a demyelinating myeloablative disease, including, but not limited to, multiple sclerosis, neuromyelitis optica, neuromyelitis optica spectrum disorder (NMOSD), idiopathic inflammatory demyelinating disease (IIDD), anti-NMDA receptor encephalitis, acute disseminated encephalomyelitis, anti-MOG autoimmune encephalomyelitis, chronic relapsing inflammatory optic neuritis (CRION), acute disseminated encephalomyelitis (ADEM), immune-mediated encephalomyelitis, progressive multifocal leukoencephalopathy (PML), McDonald positive multiple sclerosis, acute hemorrhagic leukoencephalitis, Rasmussen encephalitis, Marburg multiple sclerosis, pseudoswollen and tumescent multiple sclerosis, Barrow concentric sclerosis, diffuse myelinating sclerosis, sporadic sclerosis, multiple sclerosis with cavitary lesions, spinal cortical sclerosis, and idiopathic inflammatory disease. These include multiple myeloid multiple sclerosis (MCMS), atypical optic myeloid multiple sclerosis, pure myeloid multiple sclerosis, HLADRB3*02:02 multiple sclerosis, autoimmune GFAP astrocytopathy, chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barré syndrome, progressive inflammatory neuropathy, Lewis-Sumner syndrome, central peripheral combined demyelinating disease (CCPD), Bickerstaff brainstem encephalitis, Fisher syndrome, trigeminal neuralgia, NMDAR anti-NMDA receptor encephalitis, primary progressive MS (PPMS), OPA1 mutant multiple sclerosis, KIR4.1 multiple sclerosis, aquaporin-associated multiple sclerosis, chronic cerebrospinal venous insufficiency (CCSVI or CCVI), diffuse sclerosis, and Schilder's disease.

[0474] In certain embodiments, the disorder to be treated is a demyelinating leukodystrophy disease, including, but not limited to, myelitis, central pontine myelinolysis (CPM), extrapontine myelinolysis, tabes dorsalis, progressive multifocal leukoencephalopathy, leukoencephalopathy with disappearance of white matter, leukoencephalopathy with neuroaxonal spheroids, reversible posterior leukoencephalopathy syndrome, macrocephalic leukoencephalopathy with subcortical cysts, macrocephalic leukoencephalopathy with subcortical cysts1, hypertensive leukoencephalopathy, metachromatic leukodystrophy, Krabbe disease, Canavan disease, X-linked adrenoleukodystrophy, Alexander disease, cerebrotendinous xanthomatosis, Pelizaeus-Merzbacher disease, and Refsum disease.

[0475] In some embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat Buerger's disease, also known as thromboangiitis obliterans.

[0476] In some embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat giant cell arteritis.

[0477] In some embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat Raynaud's disease.

[0478] In certain embodiments, the disorder to be treated is a demyelinating disease of the peripheral nervous system, including, but not limited to, Guillain-Barre syndrome and its chronic counterparts, chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy, Charcot-Marie-Tooth disease and its counterparts, hereditary pressure sensitivity, copper deficiency associated conditions (peripheral neuropathy, myelopathy, and rarely optic neuropathy), and progressive inflammatory neuropathies.

[0479] In certain embodiments, the disorder to be treated is a neuroinflammatory disorder.In certain embodiments, the disorder to be treated includes, but is not limited to, cranial arteritis; giant cell arteritis; Holmes-Ardee syndrome; inclusion body myositis (IBM); meningitis; paraneoplastic neurological syndrome, such as but not limited to Lambert-Eaton myasthenic syndrome, stiff-man syndrome, encephalomyelitis (inflammation of the brain and spinal cord), myasthenia gravis, cerebellar degeneration, limbic and / or brainstem encephalitis, neuromyotonia, and opsoclonus (including eye movement) and sensory neuropathy; polymyositis; transverse myelitis; vasculitis, including temporal arteritis; arachnoiditis; Kinsbone syndrome or opsoclonus-myoclonus syndrome (OMS); or Saint Vitus Dance or Sydenham chorea (SD).

[0480] In some embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat transverse myelitis.

[0481] In certain aspects, the disorder to be treated is a peripheral neuropathy. In some embodiments, the peripheral neuropathy is a mononeuropathy. In some embodiments, the neuropathy is a polyneuropathy. In some embodiments, the polyneuropathy is a distal axonopathy, a diabetic neuropathy, a demyelinating polyneuropathy, a small fiber peripheral neuropathy, a mononeuritis multiplex, a polyneuritis, an autonomic neuropathy, or a neuritis.

[0482] In some embodiments, an effective amount of an active compound described herein, or a pharma- ceutically acceptable salt thereof, is used to treat an autoimmune vascular disease. In some embodiments, the autoimmune vascular disease is vasculitis. In some embodiments, vasculitis includes, but is not limited to, autoimmune inflammatory vasculitis, cutaneous small vessel vasculitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, Behcet's disease, Kawasaki disease, Buerger's disease, and "limited-type" granulomatosis with polyangiitis vasculitis.

[0483] In some embodiments, an active compound or salt or composition thereof described herein is used to treat arteritis, including, but not limited to, giant cell arteritis, Takayasu's arteritis, temporal arteritis, and polyarteritis nodosa.

[0484] In some embodiments, a method for the treatment of glomerulonephritis is provided. In some embodiments, the glomerulonephritis is membranoproliferative glomerulonephritis (MPGN). In some embodiments, the MPGN is MPGN type I. In some embodiments, the MPGN is MPGN type II. In some embodiments, the MPGN is MPGN type III. In some embodiments, the MPGN is C3 glomerulonephritis (C3G). In some embodiments, the MPGN is dense deposit disease (DDD). In some embodiments, the MPGN is a C4 deposition disorder.

[0485] In some embodiments, the glomerulonephritis is IC-MPGN. In some embodiments, the glomerulonephritis is membranous glomerulonephritis. In some embodiments, the glomerulonephritis is IgA nephropathy. In some embodiments, the glomerulonephritis is post-infectious glomerulonephritis. In some embodiments, the glomerulonephritis is rapidly progressive glomerulonephritis, for example, type I (Goodpasture's syndrome), type II, or type III rapidly progressive glomerulonephritis.

[0486] In some embodiments, methods are provided for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) comprising administration to a host of an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, or a pharma- ceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharma- ceutically acceptable composition.

[0487] In some embodiments, a method is provided for the treatment of hereditary angioedema (HAE), comprising administering to a host an effective amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, or a pharma- ceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharma- ceutically acceptable composition. Mutations in the SERPING1 gene result in hereditary angioedema type I and type II. Hereditary angioedema is a disorder characterized by repeated episodes of severe swelling (angioedema). The most common areas of the body where swelling occurs are the hands and feet, face, intestinal tract, and airways. The SERPING1 gene directs the production of the C1 inhibitor protein, which is important in controlling inflammation. C1 inhibitor blocks the activity of certain proteins that promote inflammation. Mutations causing hereditary angioedema type I result in low blood levels of C1 inhibitor, while mutations causing type II result in the production of abnormally functioning C1 inhibitor. In the absence of adequate levels of functional C1 inhibitor, excessive amounts of a protein fragment (peptide) called bradykinin are produced. Bradykinin promotes inflammation by increasing fluid leakage through blood vessel walls into body tissues. Excessive accumulation of fluid in body tissues results in the swelling episodes seen in individuals with hereditary angioedema types I and II.

[0488] In some embodiments, methods are provided for the treatment of cold agglutinin disease (CAD) comprising administering to a host an effective amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, or a pharma- ceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharma- ceutically acceptable composition. CAD is a rare autoimmune hemolytic condition with potentially severe acute and chronic consequences caused by C1 activation of the classical complement pathway.

[0489] In some embodiments, a method is provided for the treatment of atypical hemolytic uremic syndrome (aHUS), comprising administering to a host an effective amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, or a pharma- ceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharma- ceutically acceptable composition. Atypical hemolytic uremic syndrome is a disease that primarily affects kidney function. Atypical hemolytic uremic syndrome can occur at any age, causing abnormal blood clots (thrombi) to form in the small blood vessels of the kidney. These clots can cause serious medical problems when they restrict or block blood flow. Atypical hemolytic uremic syndrome is characterized by three major features related to abnormal clotting: hemolytic anemia, thrombocytopenia, and renal failure.

[0490] In another embodiment, a method is provided for the treatment of wet or dry age-related macular degeneration (AMD) in a host, comprising administering an effective amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, or a pharma- ceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharma- ceutically acceptable composition. In another embodiment, a method is provided for the treatment of rheumatoid arthritis in a host, comprising administering an effective amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, or a pharma- ceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharma- ceutically acceptable composition.

[0491] In another embodiment, a method is provided for treating multiple sclerosis in a host comprising administration of an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, or a pharma- ceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharma- ceutically acceptable composition.

[0492] The active compounds disclosed herein, or pharma- ceutically acceptable salts, prodrugs, isotopic analogs, N-oxides, or isolated isomers thereof, optionally in a pharma- ceutically acceptable composition, are also useful for administration in combination (in the same or different dosage forms) or alternation with a second pharmaceutical agent for use in ameliorating or reducing the side effects of the second pharmaceutical agent.

[0493] For example, in some embodiments, the active compounds may be used in combination with adoptive cell transfer therapy to reduce the inflammatory responses associated with such therapy, eg, cytokine-mediated responses such as cytokine response syndrome.

[0494] In some embodiments, adoptive cell transfer therapy is the use of chimeric antigen receptor T cells (CAR T) or dendritic cells to treat hematological or solid tumors, such as B-cell-related hematological cancers.

[0495] In some embodiments, the hematological or solid tumor is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), pancreatic cancer, glioblastoma, or a CD19-expressing cancer.

[0496] In some embodiments, the adoptive cell transfer therapy is a non-modified T cell therapy, in which the T cells have been activated and / or expanded against one or more viral or tumor antigens, hi some embodiments, the associated inflammatory response is a cytokine-mediated response.

[0497] In some embodiments, the second pharmaceutical agent is a cell transformed to express a protein, where the protein in the host is mutated or otherwise impaired in function. In some embodiments, the transformed cell comprises a CRISPR gene.

[0498] Another embodiment is provided which includes administering to a host an effective amount of an active compound, or a pharma- ceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharma- ceutically acceptable composition, to treat an ophthalmic, pulmonary, gastrointestinal, or other disorder.

[0499] Any of the compounds described herein (e.g., Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX) can be administered to the eye in any desired dosage form, including intravitreal, intrastromal, intracameral, subtenon, subretinal, retrobulbar, peribulbar, suprachoroidal, choroidal, subchoroidal, conjunctival, subconjunctival, episcleral, posterior juxtascleral, scleral, pericorneal, and lacrimal injection, or through mucus, mucin, or mucosal barriers, in an immediate or controlled release manner. In certain embodiments, the active compound contains a lipophilic group, such as a lipophilic acyl group, and is delivered to the eye in a polymeric drug delivery system, such as polylactide, polylactide-co-glycolide, polyglycolide, or other degradable polymer, or a combination thereof, or another type of lipophilic material for intraocular delivery. In some embodiments, lipophilic active molecules are more soluble in the polymer or other delivery system form than in ocular fluids.

[0500] In other embodiments of the present disclosure, the active compounds provided herein can be used to treat or prevent host disorders mediated by complement.For example, the present disclosure includes methods for treating or preventing complement-related disorders induced by antibody-antigen interactions, components of immune or autoimmune disorders, or ischemic disorders.The present disclosure also provides methods for reducing immune responses, including inflammatory or autoimmune responses, mediated or affected by the classical complement pathway.

[0501] In some embodiments, the disorder is selected from fatty liver and conditions resulting from fatty liver, such as non-alcoholic steatohepatitis (NASH), hepatitis, cirrhosis and liver failure. In some embodiments of the present disclosure, a method is provided for treating fatty liver disease in a host by administering an effective amount of an active compound or a salt or composition thereof described herein.

[0502] In another embodiment, the active compound or its salt or composition described herein is used to regulate immune response before or during surgery or other medical treatment.A non-limiting example is its use in connection with acute or chronic graft-versus-host disease, which is a common complication resulting from organ transplantation, allogeneic tissue transplantation, and may also result from blood transfusion.

[0503] In some embodiments, the disclosure provides a method of treating or preventing dermatomyositis by administering to a subject in need thereof an effective amount of an active compound or a salt or composition thereof described herein.

[0504] In some embodiments, the present disclosure provides a method of treating or preventing amyotrophic lateral sclerosis by administering to a subject in need thereof an effective amount of an active compound or a salt or composition thereof described herein.

[0505] In some embodiments, the disclosure provides a method of treating or preventing abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, or hemodialysis by administering to a subject in need thereof an effective amount of an active compound or a salt or composition thereof described herein.

[0506] In another embodiment, a method is provided for treating or preventing cytokine or inflammatory responses to administration of a pharmaceutical or biological agent (e.g., CAR T cell therapy or monoclonal antibody therapy) in a host by administering an effective amount of an active compound or a salt or composition thereof as described herein.Various types of cytokine or inflammatory responses can occur depending on a number of factors, such as administration of a biological agent.

[0507] In some embodiments, the cytokine response or inflammatory response is cytokine release syndrome. In some embodiments, the cytokine response or inflammatory response is tumor lysis syndrome (which also results in cytokine release). Symptoms of cytokine release syndrome range from fever, headache, and skin rash to bronchospasm, low blood pressure, and even cardiac arrest. Severe cytokine release syndrome is called cytokine storm and can be fatal.

[0508] Fatal cytokine storms have been observed in response to the infusion of some monoclonal antibody therapeutics. See Abramowicz D, et al. "Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients" Transplantation (1989) 47(4):606-8; Chatenoud L, et al. "In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids" Transplantation (1990) 49(4):697-702; and Lim LC, Koh LP, and Tan P. "Fatal cytokine release syndrome with chimeric anti-CD20 monoclonal antibody rituximab in a 71-year-old patient with chronic lymphocytic leukemia" J. Clin Oncol. (1999) 17(6):1962-3.

[0509] Also contemplated herein is the use of the active compounds described herein or salts or compositions thereof to mediate adverse immune responses in patients receiving bispecific T cell engagers (BiTEs). Bispecific T cell engagers are those in which T cells are induced to target and bind to specific antigens on the surface of cancer cells. For example, the BiTE blinatumomab (Amgen) has recently been approved as a second-line therapy for Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia. Blinatumomab is administered by continuous intravenous infusion in 4-week cycles. The use of BiTE agents has been associated with adverse immune responses, including cytokine release syndrome. The cytokines most significantly elevated in CRS associated with ACT include IL-10, IL-6, and IFN-γ (Klinger et al., Immuno pharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of Tcell-engaging CD19 / CD3-bispecific BiTE antibody blinatumomab. Blood (2012) 119:6226-6233).

[0510] In another embodiment, the disorder is episcleritis, idiopathic episcleritis, anterior scleritis, or posterior scleritis. In some embodiments, the disorder is idiopathic anterior uveitis, HLA-B27-associated uveitis, herpes simplex keratoconjunctivitis, Posner-Schlossman syndrome, Fuchs heterochromic cyclitis, or cytomegalovirus anterior uveitis.

[0511] In some embodiments, the disclosure provides a method of treating or preventing IC-MPGN by administering to a subject in need thereof an effective amount of an active compound described herein, or a salt or composition thereof.

[0512] In some embodiments, the disclosure provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of an active compound described herein, or a salt or composition thereof.

[0513] In some embodiments, the present disclosure provides a method of treating or preventing hereditary angioedema (HAE) by administering to a subject in need thereof an effective amount of an active compound or a salt or composition thereof described herein.

[0514] In some embodiments, the disclosure provides a method of treating or preventing cold agglutinin disease (CAD) by administering to a subject in need thereof an effective amount of an active compound or a salt or composition thereof described herein.

[0515] In some embodiments, the disclosure provides a method of treating or preventing atypical hemolytic syndrome (aHUS) by administering to a subject in need thereof an effective amount of an active compound or a salt or composition thereof described herein.

[0516] In some embodiments, the present disclosure provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound or a salt or composition thereof described herein.

[0517] In some embodiments, the disclosure provides a method of treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of an active compound or a salt or composition thereof described herein.

[0518] In some embodiments, the disclosure provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of an active compound or a salt or composition thereof described herein.

[0519] In some embodiments, the disclosure provides a method of treating or preventing myasthenia gravis by administering to a subject in need thereof an effective amount of an active compound or a salt or composition thereof described herein.

[0520] In some embodiments, the disclosure provides a method of treating or preventing atypical hemolytic uremic syndrome (aHUS) by administering to a subject in need thereof an effective amount of an active compound or a salt or composition thereof described herein.

[0521] In yet another embodiment, the disclosure provides a method of treating or preventing a disorder described below by administering to a subject in need thereof an effective amount of an active compound or a salt or composition thereof described herein: vitritis, sarcoidosis, syphilis, tuberculosis, or Lyme disease; retinal vasculitis, Eales' disease, tuberculosis, syphilis, or toxoplasmosis; neuroretinitis, viral retinitis, or acute retinal necrosis; varicella zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, lichen planus, or dengue-related disease (e.g., dengue hemorrhagic fever); masked syndrome, contact dermatitis, trauma-induced inflammation, UVB-induced inflammation, eczema, granuloma annulare, or acne.

[0522] In further embodiments, the disorder is acute myocardial infarction, aneurysm, cardiopulmonary bypass, dilated cardiomyopathy, complement activation during cardiopulmonary bypass surgery, coronary artery disease, restenosis after stent placement or percutaneous transluminal coronary angioplasty (PTCA); antibody-mediated graft rejection, anaphylactic shock, anaphylaxis, allograft, humoral and vascular graft rejection, graft dysfunction, graft-versus-host disease, Graves' disease, adverse drug reactions, or chronic graft vasculopathy; allergic bronchopulmonary aspergillosis, allergic neuritis, drug allergy, radiation-induced lung injury, eosinophilic pneumonia, radiographic contrast allergy, bronchiolitis obliterans, or interstitial pneumonia; parkinsonism dementia complex, sporadic frontotemporal dementia, 1 The present invention is selected from frontotemporal dementia parkinsonism linked to chromosome 7, frontotemporal lobar degeneration, senile dementia with neurofibrillary tangles, cerebral amyloid angiopathy, cerebrovascular disorders, certain forms of frontotemporal dementia, chronic traumatic encephalopathy (CTE), Parkinson's disease with dementia (PDD), argyrophilic grain dementia, dementia pugilistica, dementia with Lewy bodies (DLB), or multi-infarct dementia; Creutzfeldt-Jakob disease, Huntington's disease, multifocal motor neuropathy (MMN), prion protein cerebral amyloid angiopathy, polymyositis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, non-Guam motor neuron disease with neurofibrillary tangles, neuroregeneration, and diffuse neurofibrillary tangle disease with calcification.

[0523] In some embodiments, the disorder is atopic dermatitis, dermatitis, dermatomyositis bullous pemphigoid, scleroderma, scleroderma dermatomyositis, psoriatic arthritis, pemphigus vulgaris, discoid lupus erythematosus, cutaneous lupus, chilblain lupus erythematosus, or lupus erythematosus-lichen planus overlap syndrome; cryoglobulinemic vasculitis, mesenteric / intestinal vasculopathy, peripheral vascular disease, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), IL-2-induced vascular leak syndrome, or immune complex vasculitis; vascular Selected from: edema, thrombocytopenia (HELLP) syndrome, sickle cell disease, platelet refractory state, red blood cell casts, or typical or infectious hemolytic uraemic syndrome (tHUS); hematuria, hemorrhagic shock, drug-induced thrombocytopenia, autoimmune hemolytic anemia (AIHA), azotemia, vasculitis and / or lymphangitis, rotational atherectomy, or delayed hemolytic transfusion reaction; British amyloid angiopathy, Buerger's disease, bullous pemphigoid, C1q nephropathy, cancer, and fulminant antiphospholipid syndrome.

[0524] In another embodiment, the disorder is wet (exudative) AMD, dry (non-exudative) AMD, chorioretinal degeneration, choroidal neovascularization (CNV), choroiditis, loss of RPE function, blindness (including loss of vision or visual field), blindness due to AMD, retinal damage in response to light exposure, retinal degeneration, retinal detachment, retinal dysfunction, retinal neovascularization (RNV), retinopathy of prematurity, pathological myopia, or RPE degeneration; pseudophakic bullous keratopathy, symptomatic macula. Degeneration-related disorders, optic nerve degeneration, photoreceptor degeneration, cone degeneration, photoreceptor cell loss, pars planitis, scleritis, proliferative vitreoretinopathy, or ocular drusen formation; chronic urticaria, Churg-Strauss syndrome, cold agglutinin disease (CAD), corticobasal degeneration (CBD), cryoglobulinemia, cyclitis, damage to Bruch's membrane, Degos disease, diabetic vasculopathy, elevated liver enzymes, endotoxemia, epidermolysis bullosa, or epidermolysis bullosa acquisita; essential mixed type 2 cryoglobulinemia, excess blood urea nitrogen - BUN, focal segmental glomerulosclerosis, Gerstmann-Straussler-Scheinker disease, giant cell arteritis, gout, Hallervorden-Spatz disease, Hashimoto's disease, Henoch-Schönlein purpura nephritis, or abnormal urinary sediment; hepatitis, Hepatitis A, Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV), viral infections, more commonly, e.g. selected from Flaviviridae, Reoviridae, Coronaviridae, Poxviridae, Adenoviridae, Herpesviridae, Caliciviridae, Reoviridae, Picornaviridae, Togaviridae, Orthomyxoviridae, Rhabdoviridae, or Hepadnaviridae; Neisseria meningitidis, Shiga toxin E. coli associated hemolytic uremic syndrome (STEC-HUS), hemolytic uremic syndrome (HUS); Streptococcus, and post-streptococcal glomerulonephritis.

[0525] In further embodiments, the disorder is hyperlipidemia, hypertension, hypoalbuminemia, hypovolemic shock, hypocomplementemic urticarial vasculitis syndrome, hypophosphatasia, hypovolemic shock, idiopathic pneumonia syndrome, or idiopathic pulmonary fibrosis; inclusion body myositis, intestinal ischemia, iridocyclitis, iritis, juvenile chronic arthritis, Kawasaki disease (arteritis), or lipiduria; membranoproliferative glomerulonephritis (MPGN) I, microscopic polyangiitis, mixed cryoglobulinemia, molybdenum cofactor deficiency (MoCD) type A, pancreatitis, panniculitis, Pick's disease, polyarteritis nodosa (PAN), progressive subcortical gliosis, proteinuria, reduced glomerular filtration rate (GFR), or renal vascular disease; multiple organ failure, multiple system atrophy. spinal cord injury, spinal muscular atrophy, spondyloarthropathy, Reiter's syndrome, spontaneous abortion, recurrent abortion, pre-eclampsia, synucleinopathies, Takayasu's arteritis, postpartum thyroiditis, thyroiditis, type I cryoglobulinemia, type II mixed cryoglobulinemia, type III mixed cryoglobulinemia, ulcerative colitis, uremia, urticaria, venous gas embolism (VGE), or Wegener's granulomatosis; von Hippel-Lindau disease, ocular histoplasmosis, hard drusen, soft drusen, pigment clumping, and photoreceptor and / or retinal pigment epithelium (RPE) loss.

[0526] In some embodiments, an active compound or salt or composition described herein is used in the treatment of autoimmune oophoritis, endometriosis, autoimmune orchitis, Ord's thyroiditis, autoimmune enteropathy, celiac disease, Hashimoto's encephalopathy, antiphospholipid syndrome (APLS) (Hughes syndrome), aplastic anemia, autoimmune lymphoproliferative syndrome (Canal-Smith syndrome), autoimmune neutropenia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, steatohepatitis (Dercum's disease), adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, eosinophilic fasciitis, and the like. fibromyalgia, neuromyotonia (Isaacs disease), paraneoplastic degeneration, autoimmune inner ear disease, Meniere's disease, interstitial cystitis, autoimmune pancreatitis, Zika virus-related disorder, Chikungunya virus-related disorder, subacute myelopathy, Bacterial endocarditis (SBE), IgA nephropathy, IgA vasculitis, polymyalgia rheumatica, rheumatic vasculitis, alopecia areata, autoimmune progesterone dermatitis, dermatitis herpetiformis, erythema nodosum, pemphigoid of pregnancy, hidradenitis suppurativa, lichen sclerosus, linear immunoglobulin A disease (LAD), morphea, myositis, acute pityriasis lichenoides, vitiligo post-myocardial infarction syndrome (Dressler syndrome), post-pericardiotomy syndrome, autoimmune retinopathy, Cogan syndrome, Graves' ophthalmopathy, lignified conjunctivitis, Mooren's ulcer, opsoclonus-myoclonus syndrome, optic neuritis, retinocochlear cerebrovascular disease (Suzac syndrome), sympathetic ophthalmia , Tolosa-Hunt syndrome, interstitial lung disease, antisynthetase syndrome, Addison's disease, autoimmune polyendocrine syndrome (APS) type I, autoimmune polyendocrine syndrome (APS) type II, autoimmune polyendocrine syndrome (APS) type III, disseminated sclerosis (multiple sclerosis, pattern II), rapidly progressive glomerulonephritis (RPGN), juvenile rheumatoid arthritis, enthesitis-associated arthritis, reactive arthritis (Reiter's syndrome), autoimmune hepatitis or lupoid hepatitis, primary biliary cirrhosis (PBS), primary sclerosing cholangitis, microscopic colitis, latent lupus (undifferentiated connective tissue disease (UCTD)),The present invention is useful for treating or preventing a disorder selected from acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-n-methyl-D-aspartate receptor encephalitis, Barrow concentric sclerosis (Schilder's disease), Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, Ostrun's syndrome, pediatric autoimmune streptococcal associated neuropsychiatric disorder (PANDAS), progressive inflammatory neuropathy, restless legs syndrome, stiff person syndrome, Sydenham's syndrome, transverse myelitis, lupus vasculitis, leukocytoclastic vasculitis, microscopic polyangiitis, polymyositis, and ocular ischemia-reperfusion injury.

[0527] Examples of ocular disorders that may be treated in accordance with the compositions and methods disclosed herein include amebic keratitis, fungal keratitis, bacterial keratitis, viral keratitis, onchocercal keratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis, corneal dystrophic diseases, Fuchs endothelial dystrophy, Sjogren's syndrome, Stevens-Johnson syndrome, autoimmune dry eye disease, environmental dry eye disease, corneal neovascularization disease, and prognosis of corneal transplant rejection. prevention and treatment of autoimmune uveitis, infectious uveitis, posterior uveitis (including toxoplasmosis), panuveitis, inflammatory diseases of the vitreous or retina, prevention and treatment of endophthalmitis, macular edema, macular degeneration, age-related macular degeneration, proliferative and non-proliferative diabetic retinopathy, hypertensive retinopathy, autoimmune diseases of the retina, primary and metastatic intraocular melanoma, other intraocular metastatic tumors, open-angle glaucoma, angle-closure glaucoma, pigmentary glaucoma, and combinations thereof.

[0528] In further embodiments, the disorder is selected from glaucoma, diabetic retinopathy, bullous skin diseases (including bullous pemphigoid, pemphigus, and epidermolysis bullosa), ocular cicatricial pemphigoid, uveitis, adult macular degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, diabetic macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, scattershot retinitis-choroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ophthalmic pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, and retinal vein occlusion, and central retinal vein occlusion (CVRO).

[0529] In some embodiments, complement-mediated diseases include ophthalmological diseases (including early or neovascular age-related macular degeneration and geographic atrophy), autoimmune diseases (including arthritis, rheumatoid arthritis), respiratory diseases, and cardiovascular diseases. In other embodiments, the compounds of the present disclosure are suitable for use in the treatment of diseases and disorders associated with fatty acid metabolism, including obesity and other metabolic disorders.

[0530] Disorders that may be treated or prevented by the active compounds or salts or compositions thereof described herein include hereditary angioedema, capillary leak syndrome, hemolytic uremic syndrome (HUS), neuropathy, Guillain-Barre syndrome, diseases of the central nervous system and other neurodegenerative conditions, glomerulonephritis (including membranoproliferative glomerulonephritis), SLE nephritis, proliferative nephritis, liver fibrosis, tissue regeneration and neuroregeneration, or Barrachia-Simmons syndrome; the inflammatory effects of sepsis, systemic inflammatory response syndrome (SIRS), disorders of inappropriate or unwanted complement activation. injury, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation in autoimmune diseases, systemic lupus erythematosus (SLE), lupus nephritis, arthritis, immune complex disorders and autoimmune diseases, systemic lupus, or lupus erythematosus; ischemia / reperfusion injury (I / R injury), myocardial infarction, myocarditis, post-ischemic reperfusion state, balloon angioplasty, atherosclerosis, post-pump syndrome in cardiopulmonary or renal bypass, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, antiphospholipid syndrome, autoimmune heart disease, ischemia reperfusion injury, obesity, or diabetes; Alzheimer's dementia, stroke, schizophrenia, traumatic brain injury, trauma, Parkinson's disease, epilepsy, graft rejection, prevention of miscarriage, biomaterial reactions (e.g., in hemodialysis, implants), hyperacute allograft rejection, xenograft rejection, transplantation, psoriasis, burns, thermal injuries including burns or frostbite, or crush injuries; asthma, allergies, acute respiratory distress syndrome (ARDS), cystic fibrosis, adult respiratory distress syndrome, dyspnea, hemoptysis, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism These conditions also include, but are not limited to, lung cancer and infarction, pneumonia, fibrosing dust disease, inert dusts and inorganic substances (e.g., silicon, coal dust, beryllium, and asbestos), pulmonary fibrosis, organic dust disease, chemical injury (due to irritant gases and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., burns, frostbite), bronchoconstriction, hypersensitivity pneumonitis, parasitosis, Goodpasture's syndrome (anti-glomerular basement membrane nephritis), pulmonary vasculitis, microimmune vasculitis, and immune complex-associated inflammation.

[0531] In some embodiments, there is provided a method for treating sickle cell in a host comprising administration of an effective amount of an active compound, or a salt or composition thereof, as described herein.

[0532] In some embodiments, there is provided a method for treating immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), or idiopathic thrombocytopenic purpura (ITP) in a host comprising administration of an effective amount of an active compound or a salt or composition thereof described herein.

[0533] In some embodiments, there is provided a method for treating ANCA vasculitis in a host comprising administration of an effective amount of an active compound, or a salt or composition thereof, as described herein.

[0534] In some embodiments, there is provided a method for treating IgA nephropathy in a host comprising administration of an effective amount of an active compound or a salt or composition thereof described herein.

[0535] In some embodiments, there is provided a method for treating rapidly progressive glomerulonephritis (RPGN) in a host, comprising administration of an effective amount of an active compound or a salt or composition thereof described herein.

[0536] In some embodiments, there is provided a method for treating lupus nephritis in a host comprising administration of an effective amount of an active compound or a salt or composition thereof described herein.

[0537] In some embodiments, there is provided a method for treating hemorrhagic dengue fever in a host comprising administration of an effective amount of an active compound or a salt or composition thereof described herein.

[0538] In a further alternative embodiment, the active compound or its salt or composition described herein is used to treat autoimmune disorders. The complement pathway enhances the ability of antibodies and phagocytes to remove microorganisms and damaged cells from the body. It is a part of the innate immune system and is an essential process for healthy individuals. When the complement pathway is inhibited, the body's immune system response is reduced. Therefore, the objective of the present disclosure is to treat autoimmune disorders by administering an effective dose of the active compound or its salt or composition described herein to a subject in need thereof.

[0539] In some embodiments, the autoimmune disorder is caused by the activation of the complement system. In some embodiments, the autoimmune disorder is caused by the activation of the alternative complement pathway. In some embodiments, the autoimmune disorder is caused by the activation of the classical complement pathway. In another embodiment, the autoimmune disorder is caused by a mechanism that is not directly related to the complement system, such as hyperproliferation of T lymphocytes or overproduction of cytokines.

[0540] Non-limiting examples of autoimmune diseases include lupus, allograft rejection, autoimmune thyroid disease (such as Graves' disease and Hashimoto's thyroiditis), autoimmune uveoretinitis, giant cell arteritis, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, and terminal ileitis), diabetes, multiple sclerosis, pernicious anemia, psoriasis, rheumatoid arthritis, sarcoidosis, and scleroderma.

[0541] In some embodiments, the active compounds or salts or compositions described herein are used to treat lupus, non-limiting examples of which include lupus erythematosus, cutaneous lupus, discoid lupus erythematosus, chilblain lupus erythematosus, and lupus erythematosus-lichen planus overlap syndrome.

[0542] Lupus erythematosus is a general category of disease that includes both systemic and cutaneous disorders. Systemic forms of the disease can have systemic as well as cutaneous symptoms. However, there are also forms of the disease that are only cutaneous without systemic symptoms. For example, SLE is an inflammatory disorder of unknown etiology that occurs mainly in women and is characterized by joint symptoms, butterfly rash, recurrent pleurisy, pericarditis, generalized lymphadenopathy, splenomegaly, as well as CNS involvement and progressive renal failure. The serum of most patients (>98%) contains antinuclear antibodies, including anti-DNA antibodies. High titers of anti-DNA antibodies are essentially specific for SLE. The traditional treatment for this disease has been the administration of corticosteroids or immunosuppressants.

[0543] There are three forms of cutaneous lupus: chronic cutaneous lupus (also known as discoid lupus erythematosus or DLE), subacute cutaneous lupus, and acute cutaneous lupus. DLE is a disfiguring chronic disorder that primarily affects the skin, with sharply demarcated patches and plaques that exhibit erythema, keratinocytes, scaling, telangiectasias, and atrophy. The condition is often triggered by sun exposure, and the initial lesion is an erythematous, round, desquamating papule that is 5-10 mm in diameter and exhibits keratinocytes. DLE lesions most commonly appear on the cheeks, nose, scalp, and ears, but may be generalized over the upper trunk, extensor limbs, and oral mucosa. If left untreated, the central lesion atrophies and scars. Unlike SLE, antibodies to double-stranded DNA (e.g., DNA binding tests) are almost universally absent in DLE.

[0544] Diabetes refers to either type 1 or type 2 diabetes. In some embodiments, the active compound or its salt or composition described herein is provided in an amount effective to treat a patient with type 1 diabetes. In some embodiments, the active compound or its salt or composition described herein is provided in an amount effective to treat a patient with type 2 diabetes.

[0545] Type 1 diabetes is an autoimmune disease. Autoimmune diseases occur when the body's system for fighting infection (the immune system) attacks parts of the body. Then, in type 1 diabetes, the pancreas produces little or no insulin.

[0546] In some embodiments, the complement-mediated disease or disorder comprises graft rejection, hi some embodiments, the complement-mediated disease or disorder is antibody-mediated graft rejection.

[0547] In certain embodiments, the active compound or its salt or composition described herein is used to treat proliferative disorders, including but not limited to cancer.The target cancers suitable for administration of the active compound or its salt described herein include estrogen receptor positive cancer, HER negative advanced breast cancer, late metastatic breast cancer, liposarcoma, non-small cell lung cancer, liver cancer, ovarian cancer, glioblastoma, refractory solid tumors, retinoblastoma positive breast cancer and retinoblastoma positive endometrial cancer, vaginal cancer and ovarian cancer and lung cancer and bronchial cancer, adenocarcinoma of the colon, adenocarcinoma of the rectum, central nervous system germ cell tumor, teratoma, estrogen receptor negative breast cancer, estrogen receptor positive breast cancer, familial testicular germ cell tumor, HER2 negative breast cancer, HER2 positive breast cancer, male breast cancer, ovarian immature teratoma, ovarian mature teratoma, ovarian monodermal and highly restricted teratoma, progesterone receptor negative breast cancer, progesterone receptor positive breast cancer. cancer, recurrent breast cancer, recurrent colon cancer, recurrent extragonadal germ cell tumors, recurrent extragonadal nonseminomatous germ cell tumors, recurrent extragonadal seminoma, recurrent malignant testicular germ cell tumors, recurrent melanoma, recurrent ovarian germ cell tumors, recurrent rectal cancer, stage III extragonadal nonseminomatous germ cell tumors, stage III extragonadal seminoma, stage III malignant testicular germ cell tumors, stage III ovarian germ cell tumors, stage IV breast cancer, stage IV colon cancer, stage IV extragonadal nonseminomatous germ cell tumors, stage IV extragonadal seminoma, stage IV melanoma, stage IV ovarian germ cell tumors, stage IV rectal cancer, testicular immature teratoma, testicular mature teratoma. In certain embodiments, the target cancers include estrogen receptor positive breast cancer, HER2 negative advanced breast cancer, late stage metastatic breast cancer, liposarcoma, non-small cell lung cancer, liver cancer, ovarian cancer, glioblastoma, refractory solid tumors, retinoblastoma positive breast cancer and retinoblastoma positive endometrial cancer, vaginal and ovarian cancer and lung and bronchial cancer, metastatic colorectal cancer, metastatic melanoma with CDK4 mutation or amplification, or cisplatin resistant unresectable germ cell tumor, lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer,Prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, cancer of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, fibrosarcoma, myxosarcoma, chondrosarcoma, osteosarcoma, chordoma, malignant fibrous histiocytoma, hemangiosarcoma, angiosarcoma, lymphangiosarcoma, mesothelioma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma; epidermoid carcinoma, malignant skin adnexal tumor, adenocarcinoma, hepatoma, hepatocellular carcinoma, renal cell carcinoma, adrenal tumor, cholangiocarcinoma, transitional epithelial carcinoma, choriocarcinoma, seminoma, embryonal cell carcinoma, atypical glioma; glioblastoma multiforme, neuroblastoma, medulloblastoma, malignant meningioma, malignant schwannoma, neurofibrosarcoma, parathyroid carcinoma, medullary carcinoma of the thyroid, bronchial carcinoid, pheochromocytoma, islet cell carcinoma, malignant carcinoid, malignant paraganglioma, melanoma, Merkel cell neoplasm, phyllodes cystosarcoma, salivary carcinoma, thymic carcinoma, bladder carcinoma, and Wilms' tumor, blood disorders or hematological malignancies, including, but not limited to, bone marrow disorders, lymphatic disorders, leukemia, lymphoma, myelodysplastic syndromes ... cutaneous myeloplastic syndromes (MDS), myeloproliferative disorders (MPD), adipocyte disorders, and myelomas (e.g., multiple myeloma), among others, T-cell or NK-cell lymphomas, including, but not limited to, peripheral T-cell lymphoma; anaplastic large cell lymphomas, including, but not limited to, anaplastic lymphoma kinase (ALK)-positive, ALK-negative anaplastic large cell lymphoma, or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphomas, including, but not limited to, mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, cutaneous large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneous gamma-delta T-cell lymphoma; primary cutaneous small / medium cell CD4+ T-cell lymphoma, and lymphomatoid papulosis; adult T-cell leukemia / lymphoma (ATLL); blastic NK-cell lymphoma; enteropathic T-cell lymphoma; hepatosplenic gamma-delta T-cell lymphoma; lymphoblastic lymphoma; nasal NK / T-cell lymphoma; therapy-related T-cell lymphoma; e.g.These include lymphomas appearing after solid organ or bone marrow transplantation; T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia; chronic lymphoproliferative disorder of NK cells; aggressive NK-cell leukemia; systemic EBV+ T-cell lymphoproliferative disorder of children (associated with chronic active EBV infection); vaccinia bullosa-like lymphoma; adult T-cell leukemia / lymphoma; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; or subcutaneous panniculitis-like T-cell lymphoma.

[0548] In some embodiments, the methods described herein can be used to treat a host, e.g., a human, having lymphoma or a lymphocytic or myeloid proliferation disorder or abnormality. For example, the methods described herein can be administered to a host having Hodgkin's lymphoma or non-Hodgkin's lymphoma. For example, the host can be treated with a non-Hodgkin's lymphoma, such as, but not limited to: AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK cell lymphoma; Burkitt's lymphoma; Burkitt-like lymphoma (small non-cleaved cell lymphoma); chronic lymphocytic leukemia / small lymphocytic lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathic T-cell lymphoma; follicular lymphoma; hepatosplenic gamma delta T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; childhood lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; therapy-related T-cell lymphoma; or Waldenstrom's macroglobulinemia, Hodgkin lymphoma, including but not limited to: nodular sclerosing classical Hodgkin lymphoma (CHL); mixed cellularity CHL; lymphopenic CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin lymphoma; or nodular lymphocyte-predominant HL, certain B-cell lymphomas or proliferative disorders, including, but not limited to: multiple myeloma; diffuse large B-cell lymphoma; follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT); small cell lymphocytic lymphoma; mediastinal large B-cell lymphoma; nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; hairy cell leukemia; splenic lymphoma / leukemia, Unclassified;splenic diffuse red pulp small B-cell lymphoma;hairy cell leukemia-variant;lymphoplasmacytic lymphoma;heavy chain disease, e.g., alpha chain disease, gamma chain disease, mu chain disease;plasma cell myeloma;isolated plasmacytoma of bone;extraosseous plasmacytoma;primary cutaneous follicular center lymphoma;T-cell / histiocyte-rich large B-cell lymphoma;chronic inflammation-associated DLBCL;age-related Epstein-Barr virus (EBV)+ DLBCL;mediastinal (thymic) primary large B-cell lymphoma;primary cutaneous DLBCL, leg type;The patient may have ALK+ large B-cell lymphoma; plasmablastic lymphoma; HHV8-associated multicentric large B-cell lymphoma; Castleman's disease; unclassifiable B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma; or unclassifiable B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin's lymphoma, a leukemia, such as an acute or chronic leukemia of lymphocytic or myeloid origin, including but not limited to: acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); large granular lymphocytic leukemia; or adult T-cell chronic leukemia. In some embodiments, the patient is diagnosed with acute myeloid leukemia, e.g., anaplastic AML (M0); myeloblastic leukemia (M1; with / without minimal cellular maturation); myeloblastic leukemia (M2; with cellular maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant [M4E] with eosinophilia); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7), HPV-positive malignancies such as small cell lung cancer, retinoblastoma, cervical cancer, and certain head and neck cancers, Burkholderia glaucoma, and other cancers. certain classes of MYC amplified tumors, such as human lymphomas, and triple-negative breast cancers; certain classes of sarcomas, certain classes of non-small cell lung cancers, certain classes of melanomas, certain classes of pancreatic cancers, certain classes of leukemias, certain classes of lymphomas, certain classes of brain cancers, certain classes of colon cancers, certain classes of prostate cancers, certain classes of ovarian cancers, certain classes of uterine cancers, certain classes of thyroid cancers and other endocrine tissue cancers, certain classes of salivary gland cancers, certain classes of thymus cancers, certain classes of kidney cancers, certain classes of bladder cancers, and certain classes of testicular cancers;

[0549] In certain aspects, the active compounds or salts thereof described herein can be used to preserve or prevent damage to organs or blood products.For example, the active compounds or salts thereof described herein can be used to prevent damage to organs, tissues, cell preparations, or blood products harvested for transplantation.In some embodiments, the organ is the heart, kidney, pancreas, lung, liver, or intestine.In some embodiments, the tissue is derived from the cornea, bone, tendon, muscle, heart valve, nerve, artery or vein, or skin.In some embodiments, the blood product is whole blood, plasma, red blood cells, or reticulocytes.

[0550] In some embodiments, the active compound or salt or composition described herein prevents or delays the onset of at least one symptom of a complement-mediated disease or disorder in an individual. In some embodiments, the active compound or salt or composition described herein reduces or eliminates at least one symptom of a complement-mediated disease or disorder in an individual. Examples of symptoms include, but are not limited to, symptoms associated with autoimmune disease, cancer, blood disease, infectious disease, inflammatory disease, ischemia-reperfusion injury, neurodegenerative disease, neurodegenerative disorder, renal disease, transplant rejection, eye disease, vascular disease, or vasculitis disorder. The symptom can be a nervous system symptom, such as cognitive dysfunction, memory impairment, reduced motor function, and the like. The symptom can also be the activity of C1s protein in the cells, tissues, or body fluids of the individual. The symptom can be the degree of complement activation in the cells, tissues, or body fluids of the individual.

[0551] In some embodiments, administering an active compound or a salt thereof or a composition described herein to an individual modulates complement activation in the cells, tissues, or body fluids of the individual.In some embodiments, administering an active compound or a salt thereof or a composition described herein to an individual inhibits complement activation in the cells, tissues, or body fluids of the individual.For example, in some embodiments, an active compound or a salt thereof or a composition described herein, when administered in one or more doses as a monotherapy or combination therapy to an individual with a complement-mediated disease or disorder, inhibits complement activation in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to the complement activation in the individual before treatment with a compound described herein.

[0552] In some embodiments, the active compounds or salts or compositions described herein reduce C3 deposition on red blood cells, e.g., in some embodiments, the active compounds or salts or compositions described herein reduce deposition of C3b, iC3b, etc. on RBCs. In some embodiments, the active compounds or salts or compositions described herein inhibit complement-mediated red blood cell lysis.

[0553] In some embodiments, an active compound or a salt thereof or a composition described herein reduces C3 deposition on platelets, e.g., in some embodiments, an active compound or a salt thereof or a composition described herein reduces deposition of C3b, iC3b, etc. on platelets.

[0554] In some embodiments, administration of an active compound or salt thereof or composition described herein results in: (a) decreased complement activation; (b) improved cognitive function; (c) decreased neuronal loss; (d) reduced neuronal phospho-tau levels; (e) decreased glial cell activation; (f) decreased lymphocyte infiltration; (g) decreased macrophage infiltration; (h) decreased antibody deposition; (i) decreased glial cell loss; (j) decreased oligodendrocyte loss; (k) decreased dendritic cell infiltration; (l) decreased neutrophil infiltration; (m) decreased erythrocyte lysis; and (n) decreased erythrocyte phagocytosis. , (o) reduced platelet phagocytosis, (p) reduced platelet lysis, (q) improved graft survival, (r) reduced macrophage-mediated phagocytosis, (s) improved vision, (t) improved motor control, (u) improved thrombosis formation, (v) improved coagulation, (w) improved renal function, (x) reduced antibody-mediated complement activation, (y) reduced autoantibody-mediated complement activation, (z) improved anemia, (aa) reduced demyelination, (ab) reduced eosinophilia, (ac) reduced C3 deposition on red blood cells (e.g., reduced deposition of C3b, iC3b, etc. on RBCs), and (ad) reduced C3 deposition on platelets (e.g., reduced hematopoietin, erythrocytes, and / or erythrocytes). (a) reduced deposition of C3b, iC3b, etc. on platelets; (ae) reduced production of anaphylatoxin toxins; (af) reduced autoantibody-mediated blister formation; (ag) reduced autoantibody-induced pruritus; (ah) reduced autoantibody-induced lupus erythematosus; (ai) reduced autoantibody-mediated skin erosions; (aj) reduced destruction of red blood cells in transfusion reactions; (ak) reduced alloantibody-mediated lysis of red blood cells; (al) reduced hemolysis in transfusion reactions; (am) reduced alloantibody-mediated platelet lysis; (an) reduced platelet lysis in transfusion reactions; (ao) reduced mast cell activation; (ap) reduced mast cell histolytic activity. (aq) reduced vascular permeability, (ar) reduced edema, (as) reduced complement deposition on graft endothelium, (at) reduced anaphylatoxin production in graft endothelium, (au) reduced separation of the dermal-epidermal junction, (av) reduced anaphylatoxin production at the dermal-epidermal junction, (aw) reduced alloantibody-mediated complement activation in graft endothelium, (ax) reduced antibody-mediated neuromuscular junction loss, (ay) reduced complement activation at the neuromuscular junction, (az) reduced anaphylatoxin production at the neuromuscular junction, (ba) reduced complement deposition at the neuromuscular junction.(bb) reduced paralysis, (bc) reduced numbness, (bd) increased bladder control, (be) increased bowel control, (bf) reduced autoantibody associated mortality, and (bg) reduced autoantibody associated morbidity.

[0555] In some embodiments, an active compound or salt thereof or composition described herein, when administered in one or more doses as monotherapy or combination therapy to an individual having a complement-mediated disease or disorder, reduces the level or severity of the following outcomes: (a) complement activation, (b) cognitive decline, (c) neuronal loss, (d) neuronal phospho-tau levels, (e) glial cell activation, (f) lymphocyte infiltration, (g) macrophage infiltration, (h) antibody deposition, (i) glial cell loss, (j) oligodendrocyte loss, (k) dendritic cell infiltration, (l) neutrophil infiltration, (myocellular inflammation), (narrowing of the immune system, ... (i) effecting a reduction of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or greater than 90% in one or more of the following: (a) red blood cell infiltration; (b) red blood cell lysis; (c) red blood cell phagocytosis; (d) platelet phagocytosis; (e) platelet lysis; (f) graft rejection; (g) macrophage mediated phagocytosis; (h) macrophage mediated phagocytosis; (i) autoantibody mediated complement activation; (j) demyelination; (j) eosinophilia.

[0556] In some embodiments, an active compound or salt thereof or composition described herein, when administered in one or more doses as monotherapy or combination therapy to an individual having a complement-mediated disease or disorder, is effective to achieve at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or greater than 90% improvement in one or more of the following outcomes: a) cognitive function, b) graft survival, c) vision, d) motor control, e) clot formation, f) coagulation, g) renal function, and h) hematocrit (red blood cell count), compared to the level or degree of the outcome in the individual prior to treatment with the active compound.

[0557] In some embodiments, administering an active compound or a salt thereof or a composition described herein to an individual reduces complement activation in the individual. For example, in some embodiments, an active compound or a salt thereof, when administered in one or more doses as a monotherapy or combination therapy to an individual with a complement-mediated disease or disorder, reduces complement activation in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to the complement activation in the individual before treatment with the active compound or a salt thereof.

[0558] In some embodiments, administering the active compound or its salt or composition described herein improves cognitive function in an individual.For example, in some embodiments, when the active compound described herein is administered in one or more doses to an individual with complement-mediated disease or disorder as monotherapy or combination therapy, improves the cognitive function in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90% compared to the cognitive function in the individual before treatment with the active compound.

[0559] In some embodiments, administering the active compound or its salt or composition described herein reduces the rate of cognitive decline in an individual.For example, in some embodiments, when the active compound or its salt is administered in one or more doses to an individual with complement-mediated disease or disorder as a monotherapy or combination therapy, the rate of cognitive decline in the individual is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90% compared to the rate of cognitive decline in the individual before treatment with the active compound or its salt.

[0560] In some embodiments, administering the active compound or its salt or composition described herein to an individual reduces neuronal loss in the individual.For example, in some embodiments, when the active compound or its salt is administered in one or more doses to an individual with complement-mediated disease or disorder as a monotherapy or combination therapy, it reduces the neuronal loss in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to the neuronal loss in the individual before treatment with the active compound.

[0561] In some embodiments, administering the active compound or its salt or composition described herein to an individual reduces the phospho-tau level in the individual.For example, in some embodiments, the active compound or its salt, when administered in one or more doses as monotherapy or combination therapy to an individual with a complement-mediated disease or disorder, reduces the phospho-tau level in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to the phospho-tau level in the individual before treatment with the active compound or its salt.

[0562] In some embodiments, administering the active compound or its salt or composition described herein to an individual reduces the activation of glial cells in the individual.For example, in some embodiments, when the active compound or its salt is administered in one or more doses to an individual with a complement-mediated disease or disorder as a monotherapy or combination therapy, the glial activation in the individual is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to the activation of glial cells in the individual before treatment with the active compound or its salt.In some embodiments, the glial cells are astrocytes or microglia.

[0563] In some embodiments, administering an active compound or a salt thereof or a composition described herein to an individual reduces lymphocyte infiltration in the individual. For example, in some embodiments, the active compound or a salt thereof, when administered in one or more doses as a monotherapy or combination therapy to an individual with a complement-mediated disease or disorder, reduces lymphocyte infiltration in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to the lymphocyte infiltration in the individual before treatment with the active compound or a salt thereof.

[0564] In some embodiments, administering an active compound or a salt thereof or a composition described herein to an individual reduces macrophage infiltration in the individual. For example, in some embodiments, an active compound or a salt thereof, when administered in one or more doses as a monotherapy or combination therapy to an individual having a complement-mediated disease or disorder, reduces macrophage infiltration in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to macrophage infiltration in the individual before treatment with the active compound or a salt thereof.

[0565] In some embodiments, administering an active compound or a salt thereof or a composition described herein to an individual reduces antibody deposition in the individual. For example, in some embodiments, an active compound or a salt thereof, when administered in one or more doses as a monotherapy or combination therapy to an individual with a complement-mediated disease or disorder, reduces antibody deposition in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to antibody deposition in the individual before treatment with the active compound or a salt thereof.

[0566] In some embodiments, administering an active compound or a salt thereof or a composition described herein to an individual reduces anaphylatoxin (e.g., C3a, C4a, C5a) production in the individual. For example, in some embodiments, an active compound or a salt thereof, when administered in one or more doses as a monotherapy or combination therapy to an individual with a complement-mediated disease or disorder, reduces anaphylatoxin production in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to the level of anaphylatoxin production in the individual before treatment with the active compound or a salt thereof.

[0567] The present disclosure provides the use of an active compound of the present disclosure or a salt thereof, or a pharmaceutical composition comprising an active compound of the present disclosure or a salt thereof and a pharma- ceutically acceptable excipient, for treating an individual having a complement-mediated disease or disorder. In some embodiments, the present disclosure provides the use of an active compound of the present disclosure or a salt thereof, for treating an individual having a complement-mediated disease or disorder. In some embodiments, the present disclosure provides the use of a pharmaceutical composition comprising an active compound of the present disclosure or a salt thereof and a pharma- ceutically acceptable excipient, for treating an individual having a complement-mediated disease or disorder.

[0568] Combination therapy In one embodiment of the present disclosure, the active compound or its salt or composition described herein can be provided in combination with, or alternately, or prior to, in combination with, or successively with, at least one additional therapeutic agent in an effective amount for the treatment of, for example, the disorders listed herein.The non-limiting examples of the second active agent for such combination therapy are as described below.

[0569] In some embodiments, the active compounds described herein or their salts or compositions may be provided in combination or alternation with at least one additional inhibitor of the complement system or a second active compound having a different biological mechanism of action. In the following description and throughout this specification, when any term is used to refer to the active compounds described herein or their salts or compositions, it should be understood that unless otherwise specified or inconsistent with the context, it is considered to include pharma- ceutically acceptable salts, prodrugs, or compositions.

[0570] In non-limiting embodiments, an active compound or salt thereof or a composition described herein may be provided with a protease inhibitor, a soluble complement control agent, a therapeutic antibody (monoclonal or polyclonal), a complement component inhibitor, a receptor agonist, a chemotherapeutic agent, or a siRNA.

[0571] In other embodiments, the active compounds described herein are administered in combination or alternation with antibodies against tumor necrosis factor (TNF), such as, but not limited to, receptor fusion proteins, such as infliximab (REMICADE®), adalimumab (HUMIRA®), certolizumab (CIMZIA®), golimumab (SIMPONI®), or etanercept (ENBREL®). In some embodiments, the agent for combination therapy is a biosimilar of any of the agents listed above, including, but not limited to, REMISMA® (infliximab biosimilar), FLIXABI® (infliximab biosimilar), AMGEVITA® (adalimumab biosimilar), IMRALDI® (adalimumab biosimilar), CYTELZO® (adalimumab biosimilar), BENEPALI® (etanercept biosimilar), and ERELZI® (etanercept biosimilar).

[0572] In another embodiment, the active compounds described herein can be administered in combination or alternation with an anti-CD20 antibody, such as, but not limited to, rituximab (RITUXAN®), ofatumumab (ARZERRA®), tositumomab (BEXXAR®), obinutuzumab (GAZYVA®), ibritumomab (ZEVALIN®), ocrelizumab (OCREVUS®), or veltuzumab. In some embodiments, the agent for combination therapy is a biosimilar of any of the above agents, such as, but not limited to, TRUXIMA® (rituximab biosimilar).

[0573] In alternative embodiments, the active compounds described herein can be administered in combination or alternation with anti-IL6 antibodies, such as, but not limited to, tocilizumab (ACTEMRA®), siltuximab (SYLVANT®), sarilumab (KEVZARA®), sirumab, clazakizumab, bovalilizumab, olokizumab, and WBP216 (MEDI5117). In some embodiments, the agent for combination therapy is a biosimilar of any of the above agents, such as, but not limited to, BAT1806 (a tocilizumab biosimilar).

[0574] In alternative embodiments, the active compounds described herein can be administered in combination or alternation with IL17 inhibitors, such as, but not limited to, secukinumab (Cosentyx), ixekizumab (TALTZ®), brodalumab (SILIQ®), bimekizumab, ALX-0761, CJM112, CNTO6785, LY3074828, SCH-900117, and MSB0010841. In some embodiments, the agent for combination therapy is a biosimilar of any of the agents listed above.

[0575] In alternative embodiments, the active compounds described herein can be administered in combination or alternation with p40 (IL12 / IL23) inhibitors, such as, but not limited to, ustekinumab (STELARA®) and briakinumab (ABT874). In some embodiments, the agent for combination therapy is a biosimilar of any of the above agents, such as, but not limited to, FYB202 (ustekinumab biosimilar) and Neulara® (ustekinumab biosimilar).

[0576] In alternative embodiments, the active compounds described herein can be administered in combination or alternation with an IL23 inhibitor, such as, but not limited to, risankizumab (SKYRIZI®), tildrakizumab (ILUMYA®), guselkumab (TREMFYA®), mirakizumab, and brazikumab. In some embodiments, the agent for combination therapy is a biosimilar of any of the agents listed above.

[0577] In alternative embodiments, the active compounds described herein can be administered in combination or alternation with anti-interferon alpha antibodies, such as, but not limited to, sifalimumab, anifrolumab, and rontalizumab. In some embodiments, the agent for combination therapy is a biosimilar of any of the agents listed above.

[0578] In alternative embodiments, the active compounds described herein can be administered in combination or alternation with kinase inhibitors, such as, but not limited to, JAK1 / JAK3 inhibitors, such as, but not limited to, tofacitinib (XELJANZ®). In alternative embodiments, the active compounds described herein can be administered in combination or alternation with JAK1 / JAK2 inhibitors, such as, but not limited to, baracitinib (OLUMIANT®) and ruxolitinib (JAKAFI®).

[0579] In alternative embodiments, the active compounds described herein may be administered in combination or alternation with anti-VEGF agents, such as, but not limited to, aflibercept (EYLEA®; Regeneron Pharmaceuticals); ranibizumab (LUCENTIS®: Genentech and Novartis); pegaptanib (MACUGEN®; OSI Pharmaceuticals and Pfizer); bevacizumab (AVASTIN®; Genentech / Roche) and ziv-aflibercept (ZALTRAP®).

[0580] In alternative embodiments, the active compounds described herein may be administered in combination or alternation with tyrosine kinase inhibitors, including, but not limited to, lapatinib (TYKERB®), sunitinib (SUTENT®), axitinib (INLYTA®), pazopanib, sorafenib (NEXAVAR®), ponatinib (INCLUSIG®), regorafenib (STIVARGA®), cabozantinib (ABOMETYX®, COMETRIQ®), bendetanib (CAPRELSA®), ramucirumab (CYRAMZA®), lenvatinib (LENVIMA®), cediranib (RECENTIN®), anecoltan acetate, squalamine lactate, and corticosteroids.

[0581] In another embodiment, the active compounds described herein can be administered in combination or alternation with immune checkpoint inhibitors. Non-limiting examples of checkpoint inhibitors include anti-PD-1 or anti-PDL1 antibodies, such as nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.), atezolizumab (TECENTRIQ®), durvalumab (IMFINZI®), and KN035, or anti-CTLA4 antibodies such as ipilimumab (YERVOY®), tremelimumab, AGEN1884, and AGEN2041 (Agenus).

[0582] Non-limiting examples of active agents that can be used in combination with the active compounds described herein include, but are not limited to, the following: Protease inhibitors: plasma-derived C1-INH concentrates, e.g., CETOR® (Sanquin), BERINERT-P® (CSL Behring, Lev Pharma), HAEGARDA® (CSL Bering), CINRYZE®; recombinant human C1-inhibitors, e.g., RHUCIN®; ritonavir (NORVIR®, Abbvie, Inc.); Soluble complement regulators: soluble complement receptor 1 (TP10) (Avant Immunotherapeutics); sCR1-sLex / TP-20 (Avant Immunotherapeutics); MLN-2222 / CAB-2 (Millenium Pharmaceuticals); Mirococept (Inflazyme Pharmaceuticals); Therapeutic antibodies: eculizumab / SOLIRIS® (Alexion Pharmaceuticals); pexelizumab (Alexion Pharmaceuticals); ravulizumab / ULTOMIRIS® (Alexion Pharmaceuticals); BCD-148 (Biocad); ABP-959 (Amgen); SB-12 (Samsung Bioepsis); ofatumumab (Genmab A / S); TNX-234 (Tanox); TNX-558 (Tanox); TA106 (Taligen Therapeutics); neutratumab (G2 Therapies); anti-properdin (Novelmed Therapeutics); HuMax-CD38 (Genmab A / S); anti-properdin compounds from WO2018 / 140956 (Alexion Pharmaceuticals); Complement component inhibitors: compstatin / POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix); 4(1MEW)APL-1, APL-2 (Apellis); CP40 / AMY-101, PEG-Cp40 (Amyndas); eculizumab / SOLIRIS® (Alexion Pharmaceuticals); pexelizumab (Alexion Pharmaceuticals); ravulizumab / ULTOMIRIS® (Alexion Pharmaceuticals); Multi-targeted kinase inhibitors: sorafenib tosylate (NEXAVAR®); imatinib mesylate (GLEEVEC®); sunitinib malate (SUTENT®); ponatinib (ICLUSIG®); axitinib (INLYTA®); nintedanib (OFEV®); pazopanib HCl (VOTRIENT®); dovitinib (TKI-258, Oncology Ventures); gilteritinib (XOSPATA®); linifanib (ABT-869); crenolanib (CP-868596); masitinib (AB1010); tivozanib (FOTIVDA®); motesanib diphosphate (AMG-706); amuvatinib (MP-470); TSU-68 (SU6668, Orantinib); CP-673451; Ki8751; telatinib (BAY 57-9352); PP121; KRN 633; ​​MK-2461; tyrphostin (AG 1296); sennoside B; AZD2932; and trapidil; Anti-Factor H or Anti-Factor B Agents: Anti-FB siRNA (Alnylam); FCFD4514S (Genentech / Roche) SOMAmer for CFB and CFD (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6, NM8074 (Novelmed) and AMY-301 (Amyndas); Complement C3 or CAP C3 convertase targeting molecules: TT30 (CR2 / CFH) (Alexion); TT32 (CR2 / CR1) (Alexion Pharmaceuticals); nafamostat (FUT-175, Futhan) (Torri Pharmaceuticals); bicasiomab, NM9308 (Novelmed); CVF, HC-1496 (InCode) ALXN1102 / ALXN1103 (TT30) (Alexion Pharmaceuticals); rFH (Optherion); H17 C3 (C3b / iC3b) (EluSys Therapeutics; Mini-CFH (Amyndas) Myrococept (APT070); sCR1 (CDX-1135) (Celldex); CRIg / CFH; anti-CR3, anti-MASP2, anti-MASP3, anti-C1s, and anti-C1n molecules: CINRYZE® (Takeda); TNT003 (Bioverativ / Sanofi); BIVV009 (fka TNT009; Bioverativ / Sanofi); BIVV020 (Bioverativ / Sanofi); OMS721 (Omeros); and OMS906 (Omeros); Factor B and Factor Bb Inhibitors: IONIS-FB-LRx (Ionis Pharmaceuticals); such as those described in U.S. Patent Publication No. 20190071492 to Allergan, International Publication No. WO2017176651 to True North Therapeutics (now Sanofi), U.S. Patent No. 9,243,070 (Novelmed); NM8074 (Novelmed); and those further described below; Plasma kallikrein inhibitors: KALBITOR® and TAKHZYRO®; Bradykinin receptor antagonists: FIRAZYR®; Factor D inhibitors, as further described below; Receptor agonists: PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717 (Jerini); Other: recombinant human MBL (rhMBL; Enzon Pharmaceuticals); imide and glutarimide derivatives, e.g., thalidomide, lenalidomide, pomalidomide; Further non-limiting examples that may be used in combination or alternation with the active compounds described herein, or salts or compositions thereof, include:

[0583] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0584] In some embodiments, the drug for the combination therapy is a biosimilar of any of the drugs listed above.

[0585] In some embodiments, the active compounds or salts or compositions described herein may be provided with a compound that inhibits the enzyme that metabolizes the administered protease inhibitor. In some embodiments, the compound or salt may be provided with ritonavir.

[0586] In some embodiments, the active compound or salt or composition described herein may be provided in combination with a terminal complement inhibitor, such as a complement C5 inhibitor or a C5 convertase inhibitor. In another embodiment, the active compound or salt or composition described herein may be provided in combination with eculizumab, a monoclonal antibody directed against complement factor C5 and manufactured and marketed by Alexion Pharmaceuticals under the trade name SOLIRIS®. Eculizumab is approved by the US FDA for the treatment of PNH and aHUS. In another embodiment, the active compound or salt or composition described herein may be provided in combination with revulizumab, a monoclonal antibody directed against complement factor C5 and manufactured and marketed by Alexion Pharmaceuticals under the trade name ULTOMIRIS®. Revulizumab is approved by the US FDA for the treatment of PNH. Additional C5 and C5 convertase inhibitors include, but are not limited to, semdisirane (Alnylam); prozelimab (Regeneron); BCD-148 (Biocad); ABP-959 (Amgen); SB-12 (Samsung Bioepis Co., Ltd.); LFG316 (Novartis); Coversin (Nomacopan; Akari)); Zilcoplan (Ra Pharma); Clovalimab (SKY59; Roche / Chugai); and Muvodina (Adienne Pharma).

[0587] In some embodiments, the active compounds or salts or compositions described herein are provided in combination with an anti-inflammatory drug, an antibacterial agent, an anti-angiogenic agent, an immunosuppressant, an antibody, a steroid, an intraocular pressure reducing drug, or a combination thereof. Examples of such drugs include amikacin, anecoltan acetate, anthracenedione, anthracycline, an azole, amphotericin B, bevacizumab, camptothecin, cefuroxime, chloramphenicol, chlorhexidine, chlorhexidine digluconate, chlortrimazole, clotrimazole cephalosporin, corticosteroids, dexamethasone, desamethasone, econazole, ceftazidime, epipodophyllotoxin, cephalospor ... cin, fluconazole, flucytosine, fluoropyrimidine, fluoroquinoline, gatifloxacin, glycopeptide, imidazole, itraconazole, ivermectin, ketoconazole, levofloxacin, macrolide, miconazole, miconazole nitrate, moxifloxacin, natamycin, neomycin, nystatin, ofloxacin, polyhexamethylene biguanide, prednisolone, prednisolone acetate, pegaptani b, platinum analogs, polymyxin B, propamidine isethionate, pyrimidine nucleosides, ranibizumab, squalamine lactate, sulfonamides, triamcinolone, triamcinolone acetonide, triazoles, vancomycin, anti-vascular endothelial growth factor (VEGF) agents, VEGF antibodies, VEGF antibody fragments, vinca alkaloids, timolol, betaxolol, travoprost, latanoprost, bimatoprost, brimonidine, dorzolamide, These include acetazolamide, pilocarpine, ciprofloxacin, azithromycin, gentamicin, tobramycin, cefazolin, voriconazole, ganciclovir, cidofovir, foscarnet, diclofenac, nepafenac, ketorolac, ibuprofen, indomethacin, fluoromethalone, rimexolone, anecortave, cyclosporine, methotrexate, tacrolimus, anti-PDGFR molecules, and combinations thereof.

[0588] In some embodiments of the present disclosure, an active compound or salt thereof or composition described herein may be provided in combination or alternation with at least one immunosuppressant agent.Non-limiting examples of immunosuppressants include calcineurin inhibitors, such as cyclosporine or ascomycin, e.g., cyclosporine A (NEORAL®), FK506 (tacrolimus), pimecrolimus, mTOR inhibitors, such as rapamycin or its derivatives, e.g., sirolimus (RAPAMUNE®), everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, rapalogs, e.g., ridaforolimus, azathioprine, campath 1H, S1P receptor antagonists, Volume regulators, such as fingolimod or an analogue thereof, anti-IL-8 antibodies, mycophenolic acid or a salt thereof, such as the sodium salt, or a prodrug thereof, such as mycophenolate mofetil (CELLCEPT®), OKT3 (ORTHOCLONEOKT3®), prednisone, ATGAM®, Thymoglobulin®, brequinar sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus, leflunomide ARAVA®, CTLAI -Ig, anti-CD25, anti-IL2R, basiliximab (SIMULECT®), daclizumab (ZENAPAX®), misorubine, methotrexate, dexamethasone, ISAtx-247, SDZASM981 (pimecrolimus, ELIDEl®), CTLA4lg (abatacept), belatacept, LFA3lg, etanercept (sold as ENBREL® by Immunex), adalimumab (HUMIRA®), infliximab (REMICADE®), anti-LFA-1 It can be an antibody, natalizumab (ANTEGREN®), enlimomab, gabilimomab, antithymocyte immunoglobulin, siplizumab, alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, tocilizumab (Actemra), siltuximab (Sylvant), secukibumab (Cosentyx), ustekinumab (Stelara), risankizumab, sifalimumab, aspirin and ibuprofen.

[0589] Examples of anti-inflammatory agents include methotrexate, dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate, fluoromethalone acetate, fluoromethalone alcohol, loteprednol etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate, lodoxamide tromethamine, aspirin, ibuprofen, suprofen, piroxicam, meloxicam, flurbiprofen, naproxan, ketoprofen, tenoxicam, diclofenac sodium, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib, glucocorticoids, diclofenac, and any combination thereof. In some embodiments, an active compound or salt or composition described herein is combined with one or more nonsteroidal anti-inflammatory drugs (NSAIDs) selected from naproxen sodium (Anaprox), celecoxib (Celebrex), sulindac (Clinoril), oxaprozin (Daypro), salsalate (Disalcid), diflunisal (Dolobid), piroxicam (Feldene), indomethacin (Indocin), etodolac (Lodine), meloxicam (Mobic), naproxen (Naprosyn), nabumetone (Relafen), ketorolac tromethamine (Toradol), naproxen / esomeprazole (Vimovo), and diclofenac (Voltaren), and combinations thereof.

[0590] In some embodiments, the active compound or its salt or composition described herein is administered in combination or alternation with omega-3 fatty acid or peroxisome proliferator-activated receptor (PPAR) agonist. Omega-3 fatty acid is known to lower serum triglyceride by inhibiting DGAT and stimulating peroxisomal and mitochondrial beta-oxidation. Two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been found to have high affinity for both PPAR-α and PPAR-γ. Marine oils, such as fish oil, are excellent sources of EPA and DHA, which have been found to regulate lipid metabolism. Omega-3 fatty acid has been found to have beneficial effects on cardiovascular disease risk factors, particularly mild hypertension, hypertriglyceridemia, and coagulation factor VII phospholipid complex activity. Omega-3 fatty acids lower serum triglycerides, increase serum HDL cholesterol, lower systolic and diastolic blood pressure and heart rate, and reduce the activity of blood clotting factor VII-phospholipid complex. Moreover, omega-3 fatty acids appear to be well tolerated without any significant side effects. One form of such omega-3 fatty acids is a concentrate of omega-3 long-chain polyunsaturated fats derived from fish oil containing DHA and EPA, which is sold under the trade name OMACOR®. Such forms of omega-3 fatty acids are described, for example, in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594, the disclosures of which are incorporated herein by reference.

[0591] Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors related to retinoid, steroid, and thyroid hormone receptors. There are three distinct PPAR subtypes that are the products of different genes and are commonly called PPAR-alpha, PPAR-beta / delta (or simply delta) and PPAR-gamma. The general classes of drugs that stimulate peroxisome activity are known as PPAR agonists, e.g., PPAR-alpha agonists, PPAR-gamma agonists, and PPAR-delta agonists. Some drugs are combination PPAR agonists, such as alpha / gamma agonists, and some other drugs have dual agonist / antagonist activity. Fibrates, such as fenofibrate, bezafibrate, clofibrate, and gemfibrozil, are PPAR-α agonists and are used in patients to reduce triglyceride-rich lipoproteins, increase HDL, and reduce atherogenic dense LDL. Fibrates are typically administered orally to such patients. Fenofibrate, or 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester, has been known for many years as a medical active ingredient for its effectiveness in reducing blood triglyceride and cholesterol levels.

[0592] In some embodiments, the present disclosure provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound described herein or a salt or composition thereof in combination with an anti-VEGF agent. Non-limiting examples of anti-VEGF agents include aflibercept (EYLEA®; Regeneron Pharmaceuticals); ranibizumab (LUCENTIS®: Genentech and Novartis); pegaptanib (MACUGEN®; OSI Pharmaceuticals and Pfizer); bevacizumab (Avastin; Genentech / Roche); lapatinib (TYKERB®); sunitinib (SUTENT®); axitinib (INLYTA®); pazopanib; sorafenib (NEXAVAR®); ponatinib (INCLUSIG®); regorafenib (STIVARGA®); cabozantinib (Abometyx; COMETRIQ®); bendetanib (CAPRELSA®); ramucirumab (CYRAMZA®); lenvatinib (LENVIMA®); ziv-aflibercept (ZALTRAP (cediranib (RECENTIN®); anecoltan acetate, squalamine lactate, and corticosteroids, including but not limited to triamcinolone acetonide.

[0593] In some embodiments, the disclosure provides a method of treating or preventing age-related macular degeneration (AMD), comprising administering to a subject in need thereof an effective amount of an active compound described herein or a salt or composition thereof, in combination with a complement C5 inhibitor, such as those described herein and in the table above entitled Non-Limiting Examples of Possible Therapeutics, including, but not limited to, eculizumab (Alexion Pharmaceuticals); ravulizumab (Alexion Pharmaceuticals); LFG316 (Novartis / Morphosys); semdisirane, semdisirane / ALN-CC5 (Alnylam); ARC1005 (Novo Nordisk); coversin (Akari Therapeutics); mubodin (Adienne Pharma); RA101348 (Ra Pharma); SOBI002 (Swedish Orphan Biovitrum); SOMAmer (SomaLogic); Erdigna (Adienne Pharma); ARC1905 (Ophthotech); MEDI7814 (MedImmune); NOX-D19 (Noxxon); IFX-1, CaCP29 (InflaRx); PMX53, PMX205 (Cephalon, Teva); CCX168 (ChemoCentryx); ADC-1004 (Alligator Bioscience); and anti-C5aR-151, NN8209; anti-C5aR-215, NN8210 (Novo Nordisk); prozelimab (Regeneron); BCD-148 (Biocad); ABP-959 (Amgen); SB-12 (Samsung Bioepis Co., Ltd.); Zilcoplan (Ra Pharma); and clovalimab (SKY59; Roche / Chugal).

[0594] In some embodiments, the present disclosure provides a method for treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound described herein, or a salt or composition thereof, in combination with an anti-proparisin agent, such as, but not limited to, the anti-proparisin agents listed above, including NM9401 (Novelmed).

[0595] In some embodiments, the disclosure provides a method of treating or preventing age-related macular degeneration (AMD), comprising administering to a subject in need thereof an effective amount of an active compound described herein or a salt or composition thereof, or a combination thereof, such as a complement C3 inhibitor, such as a complement C3 inhibitor as described above, including but not limited to compstatin or a compstatin analog, such as compstatin / POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix); 4(1MEW) APL-1, APL-2 (Apellis); CP40 / AMY-101, PEG-Cp40 (Amyndas); Complement C3 or CAP C3 convertase targeting molecules: TT30 (CR2 / CFH) (Alexion); TT32 (CR2 / CR1) (Alexion Pharmaceuticals); Nafamostat (FUT-175, Futhan) (Torri Pharmaceuticals); Pharmaceuticals); bicatiomab, NM9308 (Novelmed); CVF, HC-1496 (InCode); ALXN1102 / ALXN1103 (TT30) (Alexion Pharmaceuticals); rFH (Optherion); H17 C3 (C3b / iC3b) (EluSys Therapeutics); Mini-CFH (Amyndas); myrococept (APT070); sCR1 (CDX-1135) (Celldex); and CRIg / CFH.

[0596] In some embodiments, the disclosure provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound described herein or a salt or composition thereof in combination with an anti-factor H or anti-factor B agent selected from anti-FB siRNA (Alnylam); FCFD4514S (Genentech / Roche) SOMAmers of CFB and CFD (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6 and AMY-301 (Amyndas).

[0597] In some embodiments, the present disclosure provides a method for treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound or a salt or composition thereof described herein in combination with an anti-MASP2, anti-C1s or anti-CR3 molecule, such as, but not limited to, Synlyse (ViroPharma / Baxter); TNT003 (True North); OMS721 (Omeros); OMS906 (Omeros); and Imprime PGG (Biothera).

[0598] In some embodiments, the disclosure provides a method of treating or preventing age-related macular degeneration (AMD), comprising administering to a subject in need thereof an effective amount of an active compound described herein, or a salt or composition thereof, to a subject in need thereof, a multi-targeted kinase inhibitor described herein, such as, but not limited to, sorafenib tosylate (NEXAVAR®); imatinib mesylate (GLEEVEC®); sunitinib malate (SUTENT®); ponatinib (ICLUSIG®); axitinib (INLYTA®); nintedanib (OFEV®); pazopanib HCl (VOTRIENT®); dovitinib (TKI-258, Oncology Ventures); gilteritinib (XOSPATA®); linifanib (ABT-869); crenolanib (CP-868596); masitinib (AB1010); tivozanib (FOTIVDA®); motesanib diphosphate (AMG-706); amuvatinib (MP-470); TSU-68 (SU6668, Orantinib); CP-673451; Ki8751; telatinib (BAY 57-9352); PP121; KRN 633; ​​MK-2461; tyrphostin (AG 1296); sennoside B; AZD2932; and trapidil.

[0599] In some embodiments, the disclosure provides a method of treating or preventing cold agglutinin disease (CAD), comprising administering to a subject in need thereof an effective amount of an active compound described herein or a salt or composition thereof, in combination with a complement C5 inhibitor, such as those described herein and in the table above entitled Non-Limiting Examples of Possible Therapeutic Agents for Combination Therapy, including, but not limited to, eculizumab (Alexion Pharmaceuticals); ravulizumab (Alexion Pharmaceuticals); LFG316 (Novartis / Morphosys); semdisirane, semdisirane / ALN-CC5 (Alnylam); ARC1005 (Novo Nordisk); coversin (Akari Therapeutics); mubodin (Adienne Pharma); RA101348 (Ra Pharma); SOBI002 (Swedish Orphan Biovitrum); SOMAmer (SomaLogic); Erdigna (Adienne Pharma); ARC1905 (Ophthotech); MEDI7814 (MedImmune); NOX-D19 (Noxxon); IFX-1, CaCP29 (InflaRx); PMX53, PMX205 (Cephalon, Teva); CCX168 (ChemoCentryx); ADC-1004 (Alligator Bioscience); and anti-C5aR-151, NN8209; anti-C5aR-215, NN8210 (Novo Nordisk); prozelimab (Regeneron); BCD-148 (Biocad); ABP-959 (Amgen); SB-12 (Samsung Bioepis Co., Ltd.); Zilcoplan (Ra Pharma); and clovalimab (SKY59; Roche / Chugal).

[0600] In some embodiments, the disclosure provides a method of treating or preventing cold agglutinin disease (CAD) by administering to a subject in need thereof an effective amount of an active compound described herein, or a salt or composition thereof, in combination with an anti-properdin agent, such as, but not limited to, the anti-properdin agents listed above, including NM9401 (Novelmed).

[0601] In some embodiments, the disclosure provides a method of treating or preventing cold agglutinin disease (CAD), comprising administering to a subject in need thereof an effective amount of an active compound described herein or a salt or composition thereof, or a combination thereof, including a complement C3 inhibitor, such as a complement C3 inhibitor as described above, including but not limited to compstatin or a compstatin analog, such as compstatin / POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix); 4(1MEW) APL-1, APL-2 (Apellis); CP40 / AMY-101, PEG-Cp40 (Amyndas); Complement C3 or CAP C3 convertase targeting molecules: TT30 (CR2 / CFH) (Alexion); TT32 (CR2 / CR1) (Alexion Pharmaceuticals); Nafamostat (FUT-175, Futhan) (Torri Pharmaceuticals); Pharmaceuticals); bicatiomab, NM9308 (Novelmed); CVF, HC-1496 (InCode); ALXN1102 / ALXN1103 (TT30) (Alexion Pharmaceuticals); rFH (Optherion); H17 C3 (C3b / iC3b) (EluSys Therapeutics); Mini-CFH (Amyndas); myrococept (APT070); sCR1 (CDX-1135) (Celldex); and CRIg / CFH.

[0602] In some embodiments, the disclosure provides a method of treating or preventing cold agglutinin disease (CAD) by administering to a subject in need thereof an effective amount of an active compound or salt or composition thereof described herein in combination with an anti-factor H or anti-factor B agent selected from IONIS-FB-LRx (Ionis Pharmaceuticals); anti-FB siRNA (Alnylam); FCFD4514S (Genentech / Roche) SOMAmer of CFB and CFD (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6 and AMY-301 (Amyndas).

[0603] In some embodiments, the disclosure provides a method of treating or preventing cold agglutinin disease (CAD) by administering to a subject in need thereof an effective amount of an active compound or a salt or composition thereof described herein in combination with an anti-MASP2, anti-C1s, or anti-C1n molecule, such as, but not limited to, Synlyse® (Takeda); Berinert® (Bering CSL), Ruconest® (Pharming), Haegarda® (Bering CSL); TNT003 (Bioverativ / Sanofi); BIVV009 (Bioverativ / Sanofi); BIVV020 (Bioverativ / Sanofi); OMS721 (Omeros); OMS906 (Omeros); and Imprime PGG (Biothera).

[0604] In some embodiments, the disclosure provides a method of treating or preventing cold agglutinin disease (CAD), comprising administering to a subject in need thereof an effective amount of an active compound described herein, or a salt or composition thereof, to a subject in need thereof, a multi-targeted kinase inhibitor described herein, such as, but not limited to, sorafenib tosylate (NEXAVAR®); imatinib mesylate (GLEEVEC®); sunitinib malate (SUTENT®); ponatinib (ICLUSIG®); axitinib (INLYTA®); nintedanib (OFEV®); pazopanib HCl (VOTRIENT®); dovitinib (TKI-258, Oncology Ventures); gilteritinib (XOSPATA®); linifanib (ABT-869); crenolanib (CP-868596); masitinib (AB1010); tivozanib (FOTIVDA®); motesanib diphosphate (AMG-706); amuvatinib (MP-470); TSU-68 (SU6668, Orantinib); CP-673451; Ki8751; telatinib (BAY 57-9352); PP121; KRN 633; ​​MK-2461; tyrphostin (AG 1296); sennoside B; AZD2932; and trapidil.

[0605] In some embodiments, the present disclosure provides a method for treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of an active compound described herein, or a salt or composition thereof, together with an additional inhibitor of the complement system or another active compound having a different biological mechanism of action. In another embodiment, the present disclosure provides a method for treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of an active compound described herein, or a salt or composition thereof, in combination or alternation with eculizumab or ravulizumab.

[0606] In another embodiment, the disclosure provides a method for treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of an active compound described herein, or a salt or composition thereof, in combination or alternation with CP40.

[0607] In some embodiments, the additional agent is PEGylated CP40. CP40 is a peptide inhibitor that exhibits strong binding affinity to C3b and inhibits hemolysis of paroxysmal nocturnal hemoglobinuria (PNH) red blood cells. In some embodiments, the additional agent is a complement component inhibitor, such as, but not limited to, compstatin / POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix); 4(1MEW) APL-1, APL-2 (Apellis); CP40 / AMY-101, PEG-Cp40 (Amyndas); PDGF inhibitors, such as, but not limited to, sorafenib tosylate; imatinib mesylate (STI571); sunitinib malate; ponatinib (AP24534); axitinib; imatinib (STI571); nintedanib (BIBF 1120); pazopanib HCl (GW786034 HCl); dovitinib (TKI-258, CHIR-258); linifanib (ABT-869); crenolanib (CP-868596); masitinib (AB1010); tivozanib (AV-951); motesanib diphosphate (AMG-706); amuvatinib (MP-470); TSU-68 (SU6668, Orantinib); CP-673451; Ki8751; telatinib; PP121; pazopanib; KRN 633; ​​dovitinib (TKI-258) dilactate; MK-2461; tyrphostin (AG 1296); dovitinib (TKI258) lactate; sennoside B; sunitinib; AZD2932; and trapidil; anti-factor H or anti-factor B agents, e.g., anti-FB siRNA (Alnylam); FCFD4514S (Genentech / Roche) CFB and CFD SOMAmers (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6 and AMY-301 (Amyndas); complement C3 or CAP C3 convertase targeting molecules, including but not limited to, TT30 (CR2 / CFH) (Alexion); TT32 (CR2 / CR1) (Alexion Pharmaceuticals); nafamostat (FUT-175, Futhan) (Torri Pharmaceuticals); bicatiomab, NM9308 (Novelmed);CVF, HC-1496 (InCode) ALXN1102 / ALXN1103 (TT30) (Alexion Pharmaceuticals); rFH (Optherion); H17 C3 (C3b / iC3b) (EluSys Therapeutics); Mini-CFH (Amyndas) Myrococept (APT070); sCR1 (CDX-1135) (Celldex); CRIg / CFH, anti-CR3, anti-MASP2, anti-C1, or anti-C1n molecules, including but not limited to, Synlyse (Takeda); TNT003 (True North); OMS721 (Omeros); OMS906 (Omeros); and Imprime PGG (Biothera).

[0608] In some embodiments, the disclosure provides a method of treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of a composition comprising an active compound as described herein, or a salt or composition thereof, in combination or alternation with an additional inhibitor of the complement system or an active agent that functions via a different mechanism of action.

[0609] In another embodiment, the present disclosure provides a method of treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of an active compound as described herein, or a salt or composition thereof, in combination or alternation with methotrexate.

[0610] In certain embodiments, an active compound or salt or composition thereof described herein is administered in combination or alternation with at least one additional therapeutic agent selected from the following: aspirin (ANACIN®, ASCRIPTIN®, BAYER salicylates, including ASPIRIN®, ECOTRIN®, and salsalate (MONO-GESIC®, SALGESIC®); nonsteroidal anti-inflammatory drugs (NSAIDs); nonselective inhibitors of the cyclooxygenase (COX-1 and COX-2) enzymes, including diclofenac (CATAFLAM®, VOLTAREN®), ibuprofen (ADVIL®, MOTRIN®), ketoprofen (ORUDIS®), naproxen (ALEVE®, NAPROSYN®), piroxicam (Feldene), etodolac (LODINE®), indomethacin, oxaprozin (DAYPRO®), nabumetone (RELAFEN®), and meloxicam (MOBIC®); selective cyclooxygenase inhibitors, including celecoxib (CELEBREX®). COX-2 inhibitors; disease-modifying antirheumatic drugs (DMARDs) including azathioprine (IMURAN®), cyclosporine (Sandimmune, NEORAL®), gold salts (RIDAURA®, SOLGANAL®, AUROLATE®, MYOCHRYSINE®), hydroxychloroquine (PLAQUENIL®), leflunomide (ARAVA®), methotrexate (RHEUMATREX®), penicillamine (CUPRIMINE®), and sulfasalazine (AZULFIDINE®); biologics including abatacept (ORENCIA®), etanercept (ENBREL®), infliximab (REMICADE®), adalimumab (HUMIRA®), and anakinra (KINERET®);Corticosteroids, including betamethasone (CELESTONE®, SOLUSPAN®), cortisone (CORTONE®), dexamethasone (DECADRON®), methylprednisolone (SOLUMEDROL®, DEPOMEDROL®), prednisolone (DELTA-CORTEF®), prednisone (DELTASONE®, ORASONE®), and triamcinolone (Aristocort); gold salts, including auranofin (RIDAURA®); aurothioglucose (SOLGANAL®); Aurolate; Myochrysine; or any combination thereof....

Claims

1. Formula (I): 【Chemical 400】 or a pharma- ceutically acceptable salt thereof. (In the formula, n is 1, Z is C(O); X １ is S, X ２ is a bond, X ３ is C(R １７ ) and X ４ is N, X ５ is C or Si, X ６ teeth, 【Chemistry 406】 and R １ and R ２ are both hydrogen, R ３ and R ４ is hydrogen, CN, and -OR ３０ and R ３０ is hydrogen, R ５ and R ６ are both hydrogen, R 7 to R 12 and X 5 are the following (1) to (5): (1) R ９ and R １０ may be joined together with the atoms to which they are attached to form a 3- to 6-membered carbocyclic spiro ring or a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; R ７ , R ８ , R １１ , and R １２ are hydrogen, and X ５ is C; (2) R ９ and R １０ together with the atoms to which they are attached, 【Chemistry 410】 or a carbonyl, and both R ３２ is hydrogen, each of R 7 , R 8 , R 11 , and R 12 is hydrogen, and X ５ is C; (3) R ９ and R １１ together with the atoms to which they are attached form a 3- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S; R １０ and R １２ One of the groups is hydrogen and the other is C １ -C ６ alkyl, each of R 7 , R 8 , R 11 , and R 12 is hydrogen, and X ５ is C; (4) R ７ and R １１ together with the atoms to which they are attached form a one or two carbon bridge, R ８ , R ９ , R １０ , and R １２ is hydrogen, and X ５ is C; (5) X ５ is Si, R ９ and R １０ Both are C １ -C ６ alkyl, and R ７ , R ８ , R １１ , and R １２ each of which is hydrogen; Either Each R １３ is hydrogen, R １４ , R １５ , and R １６ is hydrogen; halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, -C １ ~C ３ alkyl-phenyl; and -OR ３０ and R ３０ is aryl, R other than hydrogen and halogen １４ , R １５ , and R １６ Each of the groups is SF ５ , C １ -C ６ Alkyl, halogen, and C １ -C ６ optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; R １７ is hydrogen, and R １９ and R ２０ are both hydrogen).

2. R ３ and R ４ The compound of claim 1 , wherein both are hydrogen.

3. R ３ is hydrogen, R ４ The compound of claim 1 , wherein is hydroxyl.

4. R ９ and R １１ are linked together to form a 4- to 8-membered carbocyclic ring; R １０ is C １ ~C ６ alkyl, R １２ is hydrogen, and X ５ The compound according to any one of claims 1 to 3, wherein

5. R ９ and R １１ are linked to form a cyclopropyl ring, and R １０ The compound of claim 4 , wherein is methyl.

6. R ９ and R １０ are joined to form a 3- to 6-membered carbocyclic spiro ring or a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, and S; R ７ , R ８ , R １１ , and R １２ is hydrogen, and X ５ The compound according to any one of claims 1 to 3, wherein is C.

7. R ７ and R １１ are linked to form a one or two carbon bridge, R ８ , R ９ , R １０ , and R １２ is hydrogen, and X ５ The compound according to any one of claims 1 to 3, wherein is C.

8. R ９ and R １０ together with the atoms to which they are attached, 【Chemistry 497】 and both R ３２ is hydrogen and X ５ The compound according to any one of claims 1 to 3, wherein is C.

9. R ９ and R １０ together with the atom to which they are attached to form a carbonyl, and X ５ The compound according to any one of claims 1 to 3, wherein is C.

10. X ５ is Si, R ９ and R １０ are both C １ -C ６ alkyl, and R ７ , R ８ , R １１ , and R １２ The compound according to any one of claims 1 to 3, wherein each of is hydrogen.

11. R ９ and R １０ and R are both methyl.

12. 【Chemical 483】 【Chemistry 484】 【Chemistry 487】 【Chemistry 488】 【Chemistry 489】 【Chemistry 492】 【Chemistry 493】 A compound selected from or a pharma- ceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a pharma- ceutically acceptable carrier.

14. A composition comprising a compound according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition according to claim 13 for use in treating a complement-mediated disorder in a subject.

15. The composition for use according to claim 14, wherein the subject is a human; and / or the disorder is mediated by C1s.

16. 16. The composition for use according to claim 14 or 15, wherein the disorder is C3 glomerulopathy, an ophthalmological disorder, age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephritis, dense deposit disease, angioedema, hereditary angioedema, autoimmune hemolytic anemia, cold agglutinin disease or graft rejection.

17. 16. The composition for use according to claim 14 or 15, wherein the disorder is selected from hereditary angioedema type 1, hereditary angioedema type 2, trauma, inflammation, sepsis, multiple organ dysfunction syndrome, endotoxemia, end stage renal disease, renal failure, delayed graft function, ischemia-reperfusion injury, neuromyelitis optica, common variable immunodeficiency, antibody mediated rejection, graft rejection, asthma, allergic asthma, angioneurotic edema, acute ACE-induced angioedema, and acute kidney injury.

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