Pharmaceutical compounds for treating complement-mediated disorders

Abstract

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

Description

[0001] Statement of related applications

[0002] This application claims the benefits of U.S. Provisional Application No. 62 / 822,553, filed March 22, 2019, and U.S. Provisional Application No. 62 / 951,669, filed December 20, 2019. The full text of each of these applications is incorporated herein by reference for all purposes. Invention Field

[0003] This article provides pharmaceutical compounds for the treatment of medical conditions, such as complement-mediated conditions, including complement C1-mediated conditions. Background of the Invention

[0005] The complement system is part of the innate immune system, which cannot adapt to changes in the host's life processes but is recruited and utilized by the adaptive immune system. For example, it assists or complements the ability of antibodies and phagocytes to clear pathogens. This complex regulatory pathway allows for a rapid response to pathogenic objects while protecting host cells from damage. More than thirty proteins and protein fragments constitute the complement system. These proteins function through opsonization (enhancing the phagocytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cytolysis (disrupting the membranes of exogenous cells), and agglutination (aggregating and binding pathogens together).

[0006] The complement system has three pathways: the classical pathway, the alternative pathway, and the lectin pathway. The classical pathway is triggered by an antibody-antigen complex containing antibody isotypes IgG and IgM. The antibody-antigen complex binds to C1, and this initiates cleavage of C4 and C2 to produce C3 convertase, which then cleaves C3 into C3a and C3b. C3a interacts with its C3a receptor to recruit leukocytes, while C3b binds to C3 convertase to form C5 convertase. C5 convertase cleaves C5 into C5a and C5b. Similar to C3a, C5a interacts with its C5a receptor to recruit leukocytes, but C5b interacts with C6, C7, C8, and C8, and these proteins together form the cylindrical membrane attack complex (MAC), which causes cell swelling and rupture. These immune responses can be inhibited by preventing C1 from binding to the antibody-antigen complex.

[0007] Given the range of serious diseases mediated by dysfunction of the complement system, there is a clear medical need to provide pharmaceutically acceptable compounds, methods, compositions, and preparations for inhibiting the complement system in patients in need.

[0008] Therefore, one object of the present invention is to provide compounds, uses, compositions, combinations, and methods of preparation for treating conditions caused or aggravated by dysfunction of the complement system. Another object of the present invention is to provide compounds, uses, compositions, combinations, and methods of preparation for inhibiting C1s (complement 1 esterase) and thus treating conditions mediated by this enzyme. Summary of the Invention

[0009] This 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 their pharmaceutically acceptable salts, prodrugs, isotope analogs, N-oxides, or isolated isomers, optionally in pharmaceutically acceptable compositions. In one embodiment, the compounds, salts, or compositions thereof described herein are used to treat medical conditions that are inflammatory or immune symptoms, conditions mediated by complement cascades (including dysfunctional cascades), cellular conditions that adversely affect the ability of cells to participate in or respond to normal complement activity (including, for example, the classical complement pathway), or abnormal or undesirable complement-mediated responses to medical treatments (such as surgery or other medical procedures or administration of drugs or biological agents, blood transfusions, or administration of other allogeneic tissues or fluids).

[0010] These compounds can be used to treat medical conditions in a host (typically human) in need. The active compounds act as inhibitors of the classical complement pathway by inhibiting complement C1s. In one embodiment, a method of treating a condition mediated by complement activity is provided, comprising administering an effective amount, optionally in a pharmaceutically acceptable composition, 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 pharmaceutically acceptable salt, prodrug, isotope analog, N-oxide, or isolated isomer thereof, as described in more detail below.

[0011] In one embodiment, the condition is associated with the classical complement pathway, and the compound inhibits the classical pathway. In another embodiment, the condition is associated with the alternative complement cascade pathway. In a further embodiment, the condition is associated with the complement lectin pathway. Alternatively, the active compound, or its salt or prodrug, may act through a mechanism of action different from the complement cascade to treat the condition described herein. In yet another embodiment, the active compound and / or its salt or prodrug inhibit a combination of these pathways.

[0012] In another embodiment, a method is provided for treating a host (typically a human) suffering from a complement system-mediated condition, comprising administering prophylactic antibiotics or vaccines to reduce the likelihood of bacterial infection during treatment with one of the compounds described herein. In some embodiments, a prophylactic vaccine is administered to the host (typically a human) before, during, or after treatment with one of the compounds described herein. In some embodiments, prophylactic antibiotics are administered to the host (typically a human) before, during, or after treatment with one of the compounds described herein. In some embodiments, the infection is a meningococcal infection (e.g., sepsis and / or meningitis), an Aspergillus infection, or an infection caused by an encapsulated organism such as Streptococcus pneumoniae or Haemophilus influenzae type b (Hib), particularly in children. In other embodiments, a vaccine or antibiotic is administered to the patient after an infection has occurred due to or accompanied by suppression of the complement system.

[0013] In one aspect of this disclosure, compounds of formula I, II, III, IV, V, VI, VII, VIII, or IX are provided optionally in pharmaceutically acceptable carriers:

[0014]

[0015]

[0016] Or a pharmaceutically acceptable salt, isotope analog, prodrug, or isolated isomer thereof;

[0017] in:

[0018] Each n is independently 1, 2, or 3;

[0019] Each m is independently 0, 1, 2, or 3;

[0020] Is it a single bond or a double bond?

[0021] Z is CH2, C(CH2) or C(O);

[0022] X 1 Selected from S, O and N(R) 30 );

[0023] X 2 Selected from bond, N(R) 30 ) and -ON(R 30 )-;

[0024] X 3 Selected from N and C(R) 17 );

[0025] X 4 Selected from N and C(R) 18);

[0026] Where X 3 and X 4 Only one of them can be N;

[0027] X 5 It is C or Si;

[0028] X 6 Selected from

[0029] X 7 Selected from O, S, N(R) 30 ) and CR 5 R 6 ;

[0030] R 1 and R 2 Independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, heteroaryl, cyano, and nitro; R other than hydrogen, halogen, cyano, and nitro. 1 and R 2 Each of the groups may be optionally selected by one, two, three, or four independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0031] R 3 and R 4 Independently selected from hydrogen, C(O)R 31 -SR 30 and -OR 30 ;

[0032] Or R 3 and R 4 Independently selected from hydrogen, CN, C(O)R 31 -SR 30 and -OR 30 ;

[0033] Or rather R 3 and R 4 The combination forms an alkyl group, optionally composed of one, two, or three independently selected C1-C6 alkyl, C1-C6 haloalkyl, or -OR group. 30 Oxadiazoles substituted with oxo groups, for example, in this embodiment, It can be

[0034] Each R 5 and R 6 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR 30 and -N(R) 30 )2, where when R 5 and R 6 On adjacent carbon atoms, they can be optionally replaced by carbon-carbon double bonds, for example,

[0035] Optional includes

[0036] R 7 R 8 R 9 R 10 R 11 and R 12 Independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, and heteroaryl groups, except for hydrogen and halogens, of the R groups. 7 R 8 R 9 R 10 R 11 and R 12 Each of the groups may be optionally selected by one, two, three, or four independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0037] Or R7 and R 8 They can combine with the carbon atoms to which they are attached to form 3 to 6-membered carbon spirocycles or 4 to 6-membered heterocyclic spirocycles containing one or two independent heteroatoms selected from N, O and S;

[0038] Or R 7 and R 8 They can combine with the carbon atoms they are attached to form Or carbonyl;

[0039] Or R 9 and R 10 They can combine with the atoms they are attached to to form 3 to 6-membered carbon spirocycles or 4 to 6-membered heterocyclic spirocycles containing one or two independent heteroatoms selected from N, O and S;

[0040] Or R 9 and R 10 They can combine with the atoms they are connected to form Or carbonyl;

[0041] Or R 11 and R 12 They can combine with the carbon atoms to which they are attached to form 3 to 6-membered carbon spirocycles or 4 to 6-membered heterocyclic spirocycles containing one or two independent heteroatoms selected from N, O and S;

[0042] Or R 11 and R 12 They can combine with the carbon atoms they are attached to form Or carbonyl;

[0043] Or R 7 and R 9 Together with the atoms they are attached to, they form 3 to 8-membered carbon rings or 4 to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O and S;

[0044] Or R 9 and R 11 Together with the atoms they are attached to, they form 3 to 8-membered carbon rings or 4 to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O and S;

[0045] Or R 7 and R 11 Together with the atoms they are connected to, they form one or two carbon bridges, for example Can be selected as

[0046] Each R 13 Independently selected from hydrogen or C1-C6 alkyl;

[0047] R 14 R 15 and R16 Independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -C1-C6 alkyl-aryl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, heteroaryl, cyano, and nitro groups, except for hydrogen, halogen, cyano, and nitro groups, are all R groups. 14 R 15 and R 16 Each of the groups may be optionally selected by one, two, three, or four independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0048] Or R 14 R 15 and R 16 Independently selected from hydrogen, halogen, SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -C1-C6 alkyl-aryl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, heteroaryl, cyano, and nitro groups, except for hydrogen, halogen, cyano, and nitro groups, are all R groups. 14 R 15 and R 16 Each of the groups may be optionally selected by one, two, three, or four independently selected from SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0049] R 17 and R 18 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR 30 and -N(R) 30 )2;

[0050] Or R 17 and R 18 They combine with the carbon atoms they are attached to to form double bonds;

[0051] R 19 and R 20 Independently selected from hydrogen, C1-C6 alkyl, C5-C 10 Bicyclic carbocyclic rings, C4-C6 heterocycles, halogens, C1-C6 haloalkyl groups, -OR 30 -N(R) 30 2、-(CH2) n -R 33 and

[0052] R 21 Selected from C1-C6 alkyl and -O-C1-C6 alkyl;

[0053] Or R 21 The R is selected from C1-C6 haloalkyl, -O-C1-C6 haloalkyl, C1-C6 alkyl, -O-C1-C6 alkyl, aryl, -O-aryl, heteroaryl, or –O-heteroaryl. 21 Each of the groups may be optionally selected by one, two, three, or four independently selected from SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0054] Each R 30 Independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, heterocyclic and C(O)R 31 ;

[0055] Each R 31 Independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR 32 -SR 32 -N(R) 32 2. Heterocyclic, aryl, and heteroaryl compounds;

[0056] Each R 32 Independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;

[0057] Each R 33 Independently selected from hydrogen, guanidine, heteroaryl, aryl, -C6H5-OR 30 ;-OR 30 -SR 30 -SeR 30 -N(R) 30 )2 and -C(O)R 31 ,

[0058] For compounds of formulas I and II, at least one of the following conditions must be met:

[0059] aX 3 It is C(R) 17 ), and X 4 It is C(R) 18 );

[0060] bR 17 Selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and -OR 30 and -N(R) 30 )2;

[0061] cX 5 It is Si;

[0062] dZ is C(CH2);

[0063] eZ is CH2;

[0064] fR 7 and R 8 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0065] gR 9 and R 10 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0066] hR 11 and R 12 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0067] iR7 and R 9 Together with the atoms they are attached to, they form 3 to 8-membered carbon rings or 4 to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 10 Or R 12 It is not hydrogen;

[0068] jR 9 and R 11 Together with the atoms they are attached to, they form 3 to 8-membered carbon rings or 4 to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 8 Or R 10 It is not hydrogen;

[0069] kR 7 and R 11 Together with the atoms they are connected to, they form one or two carbon bridges;

[0070] lX 6 Selected from

[0071] mR 3 and R 4 At least one of them is CN or -SR 30 or C(O)R 31 ;or

[0072] nR 3 and R 4 The combination forms an alkyl group, optionally composed of one, two, or three independently selected C1-C6 alkyl, C1-C6 haloalkyl, or -OR group. 30 Oxadiazoles substituted with oxo groups.

[0073] In one embodiment, the compound of formula IX is:

[0074]

[0075] Or its pharmaceutically acceptable salt.

[0076] In another embodiment, the compound of formula IX is:

[0077]

[0078] Or its pharmaceutically acceptable salt.

[0079] In an alternative implementation, the compound of formula IX is

[0080]

[0081] Or its pharmaceutically acceptable salt.

[0082] On the other hand, the compounds disclosed herein have the formula X, XI, or XII:

[0083]

[0084] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0085] in:

[0086] R 22 Selected from -C1-C6 alkyl-R 23 -C2-C6 alkenyl-R 23 -C2-C6 ynyl-R 23 and bicyclic cycloalkyl-R 23 The R 22 Each of the following may be selected independently by one, two, three, or four from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0087] R 23 Selected from hydrogen, sugar, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 and -S(O)2R 31 ;and

[0088] All other variables are as defined in this document;

[0089] For compounds of formulas X and XI, at least one of the following conditions must be met:

[0090] aX 3 It is C(R) 17 ), and X 4 It is C(R) 18 );

[0091] bR 17 Selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and -OR 30 and -N(R) 30 )2;

[0092] cX 5It is Si;

[0093] dZ is C(CH2);

[0094] eZ is CH2;

[0095] fR 7 and R 8 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0096] gR 9 and R 10 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0097] hR 9 and R 11 Together with the atoms they are attached to, they form 3 to 8-membered carbon rings or 4 to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 10 It is not hydrogen;

[0098] iR 11 and R 12 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0099] jR 7 and R 9 Together with the atoms they are attached to, they form 3 to 8-membered carbon rings or 4 to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 10 It is not hydrogen;

[0100] kR 7 and R 11 Together with the atoms they are connected to, they form one or two carbon bridges;

[0101] lR 22 At least three ORs 30 Group substitution;

[0102] mR 23 It's sugar;

[0103] nR 3 and R 4 At least one of them is CN or -SR 30 or C(O)R 31 ;or

[0104] oR 3 and R 4 The combination forms an alkyl group, optionally composed of one, two, or three independently selected C1-C6 alkyl, C1-C6 haloalkyl, or -OR group. 30 Oxadiazoles substituted with oxo groups.

[0105] In one implementation, R 23 Selected from hydrogen, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 and -S(O)2R 31 .

[0106] In one embodiment, the compound of formula X is selected from:

[0107]

[0108] In one implementation, R 23 Selected from -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 and -S(O)2R 31 .

[0109] On the other hand, compounds of formula X, XI, or XII are selected from...

[0110]

[0111] Or a pharmaceutically acceptable salt, isotope analog, prodrug, or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier.

[0112] In an alternative embodiment, the compound of formula XII is

[0113]

[0114] Or its pharmaceutically acceptable salt.

[0115] On the other hand, the compounds disclosed herein have formula XIII:

[0116]

[0117] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0118] in:

[0119] X 7 Selected from O, S, N(R) 30 ) and CR 5 R 6 ;

[0120] o is 0, 1, or 2;

[0121] Each R 25 Independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, heteroaryl, cyano, and nitro; R other than hydrogen, halogen, cyano, and nitro. 25 Each of the groups may be optionally selected by one, two, three, or four independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution with heterocyclic, aryl, heteroaryl, cyano, and nitro groups; or

[0122] Each R 25 Independently selected from hydrogen, SF5, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, heteroaryl, cyano, and nitro; R other than hydrogen, halogen, cyano, and nitro. 25 Each of the groups may be optionally selected by one, two, three, or four independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0123] R 26 Selected from

[0124] Or R 26 Selected from

[0125] R 27 Selected from

[0126] Or R 27 yes

[0127] R 34 Selected from

[0128] X 11 Selected from N and CR 1 ;

[0129] X 12 Selected from N and CR 2 ;

[0130] Each of the other variables is as defined in this paper.

[0131] On the other hand, the compounds disclosed herein have formula XIV:

[0132]

[0133] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0134] The variables are as defined herein, and for compounds of formula XIV, at least one of the following conditions must be met:

[0135] aX 1 Is it O or N(R)? 30 );

[0136] bR 14 It is not hydrogen;

[0137] cR 1 It is not hydrogen;

[0138] dR 2 It is not hydrogen;

[0139] eR 3 Not hydrogen; or

[0140] fR 4 It's not hydrogen.

[0141] On the other hand, the compounds of formula XIII or XIV are selected from...

[0142]

[0143] Or a pharmaceutically acceptable salt, isotope analog, prodrug, or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier.

[0144] On the other hand, the compounds disclosed herein have the formula XV:

[0145]

[0146] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0147] in:

[0148] Each X 8 and X 9 Independently selected from O, S, NR 30 CR 9 R 10 CR 5 R 6 and CH2; where X 8 and X 9 They cannot all be the same group; and all other variables are as defined in this document.

[0149] In the alternative implementation plan, quilt Alternatively, for example in this implementation, formula The compound can be Replacement.

[0150] On the other hand, the compounds disclosed herein have formula XVI, XVII, or XVIII:

[0151]

[0152] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0153] in:

[0154] X 10 Selected from

[0155] R 35 Selected from C3-C 10 Alkyl or C3-C10 Halogenated alkyl groups; and

[0156] All other variables are as defined in this document.

[0157] On the other hand, the compounds disclosed herein have the formula XIX or the formula XX;

[0158]

[0159] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0160] in:

[0161] R 29 Selected from halogens, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C1-C6 haloalkyl groups, and -OR groups. 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, and heteroaryl groups, except for hydrogen and halogens, of the R groups. 29 Each of the groups may be optionally selected by one, two, three, or four independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups; and

[0162] All other variables are as defined in this document.

[0163] In the alternative implementation, R 29 It is hydrogen.

[0164] Pharmaceutical compositions comprising compounds or salts of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, and pharmaceutically acceptable carriers are also disclosed.

[0165] This disclosure therefore includes at least the following features:

[0166] a. The compound of the present disclosure or its pharmaceutically acceptable salt, prodrug, isotope analog, N-oxide or isolated isomer, optionally in a pharmaceutically acceptable composition;

[0167] b. Optionally, in pharmaceutically acceptable compositions, the disclosed compound or its pharmaceutically acceptable salt, prodrug, isotope analog, N-oxide, or isolated isomer, for the treatment or prevention of conditions including, but not limited to, fatty liver and the development of symptoms derived from fatty liver, such as nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, liver failure; dermatomyositis; amyotrophic lateral sclerosis; and responsive biological therapies (e.g., CARs). Cytokine or inflammatory responses associated with T-cell therapy; hereditary angioedema (HAE), chronic immune thrombocytopenic purpura (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 hemoglobinemia. Phlegm-heat (PNH), rheumatoid arthritis, multiple sclerosis, age-related macular degeneration (AMD), retinal degeneration, other ophthalmic diseases (e.g., geographic atrophy), respiratory or cardiovascular diseases; diseases 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 myeloid diseases, demyelinating leukocyte dystrophy, and neuroinflammatory diseases;

[0168] c. Pharmaceutically acceptable compositions of the compounds of this disclosure or their pharmaceutically acceptable salts, prodrugs, isotope analogs, N-oxides or isolated isomers in a pharmaceutically acceptable carrier;

[0169] d. The disclosed compound, or its pharmaceutically acceptable salt, prodrug, isotope analog, N-oxide or isolated isomer, optionally in a pharmaceutically acceptable composition, for the treatment or prevention of conditions mediated by the complement pathway, such as the classical complement pathway;

[0170] e. Use, optionally in a pharmaceutically acceptable composition, of a compound of the present disclosure as described herein, or a pharmaceutically acceptable salt, prodrug, isotope analog, N-oxide, or isolated isomer thereof, in the preparation of a medicament for the treatment or prevention of a condition, including but not limited to fatty liver and the development of conditions derived from fatty liver, such as nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, liver failure; dermatomyositis; amyotrophic lateral sclerosis; and responsive biological therapies (e.g., CARs). Cytokine or inflammatory responses associated with T-cell therapy; hereditary angioedema (HAE), chronic immune thrombocytopenic purpura (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 hemoglobinemia. Phlegm-heat (PNH), rheumatoid arthritis, multiple sclerosis, age-related macular degeneration (AMD), retinal degeneration, other ophthalmic diseases (e.g., geographic atrophy), respiratory or cardiovascular diseases; diseases 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 myeloid diseases, demyelinating leukocyte dystrophy, and neuroinflammatory diseases;

[0171] f. A method for preparing a medicament intended for the treatment or prevention of a condition or for the therapeutic use of a condition mediated by the classical complement pathway, characterized in that an embodiment of the present disclosure is used in the preparation.

[0172] g. Compounds or salts thereof as described herein in substantially pure form (e.g., at least 90% or 95%);

[0173] h. The compounds of this disclosure as described herein, or their pharmaceutically acceptable salts, prodrugs, isotope analogs, N-oxides, or isolated isomers, optionally in a carrier to form pharmaceutically acceptable compositions for the treatment of medical conditions as inflammatory or immune symptoms, conditions mediated by complement cascades (including dysfunctional cascades), cellular conditions that adversely affect the ability of cells to participate in or respond to normal complement activity, or abnormal or undesirable complement-mediated responses to medical treatments (such as surgery or other medical procedures or administration of drugs or biological agents, blood transfusions or other allogeneic tissue or fluid administration).

[0174] i. For each of (a) to (h) above and other aspects herein, every combination of parts and every active compound made therefrom or its use is covered and specifically and individually considered a disclosure, as such description is merely for convenience of space and is not intended to describe only the genus or even subgenus of this indication. Detailed Implementation

[0175] the term

[0176] 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 pertains.

[0177] Compounds of any kind described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates and other isomers, such as rotational isomers, as each is specifically described, unless otherwise indicated or otherwise excluded by the context.

[0178] The term "an" does not indicate a limitation on quantity, but rather that at least one of the mentioned items exists. The term "or" means "and / or". Unless otherwise indicated herein, the description of numerical ranges is intended only as a shorthand method for individually referring to each individual value falling within the range, and each individual value is incorporated into this specification as if it were individually described herein. The endpoints of all ranges are included within the range and can be combined independently. Unless otherwise indicated herein or otherwise obviously contradictory to the context, all methods described herein may be performed in a suitable order. Unless otherwise stated, the use of embodiments or exemplary language (e.g., "such as") is intended only as better illustration and does not constitute a limitation on the scope of the claimed invention.

[0179] This 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, having at least one desired atomic isotope substitution in an amount higher than the natural abundance of that isotope, i.e., enriched.

[0180] Examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as... 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 I. In one embodiment, the isotope-labeled compound can be used for metabolic studies (using...) 14 C) Reaction kinetic studies (using, for example) 2 H or 3 H) 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 for use in patients undergoing radiation therapy. Specifically, 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. The isotope-labeled compounds and their prodrugs disclosed herein can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents using the schemes or examples and preparation procedures disclosed below.

[0181] As a general example and not a limitation, isotopes of hydrogen include deuterium (…). 2 H) and tritium ( 3 H) can be optionally used anywhere in the structure to achieve the desired result. Alternatively, carbon isotopes, such as... 13 C and 14 C. In one embodiment, isotopic substitution involves replacing hydrogen with deuterium at one or more sites on the molecule to improve the properties of the drug, such as pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, deuterium can bind to carbon at the bond-breaking site during metabolism (α-deuterium kinetic isotope effect) or adjacent to or near the bond-breaking site (β-deuterium kinetic isotope effect).

[0182] Isotope substitution (e.g., deuterium substitution) can be partial or complete. Partial deuterium substitution means that at least one hydrogen atom is substituted with deuterium. In some embodiments, the isotope is enriched at 80%, 85%, 90%, 95%, or 99% or more at any site of interest. In one embodiment, deuterium is enriched at 80%, 85%, 90%, 95%, or 99% at the desired site. Unless otherwise stated, the enrichment at any point is above the natural abundance and, in one embodiment, sufficient to alter the detectability of the drug in the human body.

[0183] In one embodiment, the substitution of hydrogen atoms with deuterium atoms may be provided in any chemical formula of this disclosure. In one embodiment, the substitution of hydrogen atoms with deuterium atoms is carried out within any R group. In one embodiment, the R group is selected from R 1 R 2 R3 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 Any of the following. For example, when any R group is, or is substituted with, a methyl, ethyl, or methoxy group, the alkyl residue can be deuterated (in a non-limiting embodiment, CD3, CH2CD3, CD2CD3, CDH2, CD2H, CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In some other embodiments, the R group has an "'" or "a" indicator, which in one embodiment may be deuterated. In some other embodiments, the unsubstituted methylene carbon can be deuterated when two substituents of the central core ring combine to form a cyclopropyl ring.

[0184] The compounds of this disclosure can form solvates with solvents, including water. Therefore, in one embodiment, this disclosure includes a solvated form of the active compound. The term "solvate" refers to a molecular complex of a compound of this disclosure (including its salts) with one or more solvent molecules. Non-limiting examples of solvents include water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of this disclosure and water. Pharmaceutically acceptable solvates according to this disclosure include those in which the crystalline solvent can be isotopically substituted, such as D₂O, d₆-acetone, and d₆-DMSO. Solvates may be in liquid or solid form.

[0185] A hyphen ("-") not between two letters or symbols is used to indicate the connection point of a substituent. For example, -(C=O)NH2 is connected to the carbon atom of a ketone (C=O) group.

[0186] As used herein, the term "substituted" means that any one or more hydrogen atoms on a specified atom or group are partially substituted by a group selected from those indicated, provided that the normal valence state of the specified atom is not exceeded and the resulting compound is stable. For example, when the substituent is an oxo group (i.e., =O), both hydrogen atoms on the atom are substituted. For example, a pyridyl group substituted with an oxo group is a pyridinone. Combinations of substituents and / or variables are permitted, provided that such combinations produce stable compounds or useful synthetic intermediates.

[0187] A stable active compound is one that can be isolated and formulated into dosage forms with a shelf life of at least one month. An active compound is stable if its stable preparation intermediates or precursors do not degrade during the period required for the reaction or other use. The stable moiety or substituent does not degrade, react, or decompose during the period required for use. Non-limiting examples of unstable moieties are those with heteroatoms bonded in an unstable arrangement, as commonly known and confirmed by those skilled in the art.

[0188] Any suitable group may be present at a “substituted” or “optionally substituted” position to form a stable molecule and satisfy the desired purpose of this disclosure, and includes, but is not limited to, halogens (which may independently be F, Cl, Br, or I); cyano; hydroxyl; nitro; azide; alkanoyl (such as C2-C6 alkanoyl); formamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl, including those having one or more thioether bonds; alkylsulfinyl; alkylsulfonyl, including those having one or more sulfonyl bonds; aryl (e.g., phenyl, biphenyl, naphthyl, etc., each ring being substituted or unsubstituted); having, for example, 1 to 3 individual or fused rings and 6 to about 1 Arylalkyl groups with 4 or 18 ring carbon atoms, wherein benzyl is an exemplary arylalkyl group; arylalkoxy groups having 1 to 3 single or fused rings, wherein benzyloxy is an exemplary arylalkoxy group; or saturated or partially unsaturated heterocycles having 1 to 3 single or fused rings with one or more N, O, or S atoms, or heteroaryl groups having 1 to 3 single or fused rings with one or more N, O, or S atoms, such as 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. These groups may be further substituted, for example, with hydroxyl, alkyl, alkoxy, halogen, and amino groups. In some embodiments, “optionally substituted” includes one or more substituents independently selected from halogens, hydroxyl groups, amino groups, cyano groups, -CHO, -COOH, -CONH2, alkyl groups including C1-C6 alkyl groups, alkenyl groups including C2-C6 alkenyl groups, alkynyl groups including C2-C6 alkynyl groups, -C1-C6 alkoxy groups, alkanoyl groups including C2-C6 alkanoyl groups, (mono- and di-C1-C6 alkylamino)C0-C2 alkyl groups, haloalkyl groups including C1-C6 haloalkyl groups, hydroxyl C1-C6 alkyl groups, esters, carbamates, ureas, sulfonamides, -C1-C6 alkyl (heterocyclic), C1-C6 alkyl (heteroaryl), -C1-C6 alkyl (C3-C7 cycloalkyl), O-C1-C6 alkyl (C3-C7 cycloalkyl), B(OH)2, phosphate esters, phosphonates, and haloalkoxy groups including C1-C6 haloalkoxy groups.

[0189] "Alkyl" is a branched or straight-chain saturated hydrocarbon group. In one embodiment, the alkyl group contains 1 to about 12 carbon atoms, more generally 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one embodiment, the alkyl group contains 1 to about 8 carbon atoms. In some embodiments, the alkyl group is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges as used herein indicate that each member of the range is an alkyl group of a distinct kind. For example, the term C1-C6 alkyl as used herein refers to a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, and is intended to indicate that each of these is described as a distinct kind. For example, the term C1-C4 alkyl as used herein refers to a straight-chain or branched alkyl group having 1, 2, 3, or 4 carbon atoms, and is intended to indicate that each of these is described as a distinct kind. When C0-C n When alkyl groups are used in this article in combination with another group, such as (C 3- C7 cycloalkyl)C0-C4 alkyl or –C0-C4 alkyl (C3-C7 cycloalkyl), wherein the indicated group (in this case, cycloalkyl) is directly linked by a single covalent bond (C0 alkyl) or by an alkyl chain (in this case, 1, 2, 3, or 4 carbon atoms). Alkyl groups may also be linked via other groups such as heteroatoms, as in –O-C0-C4 alkyl (C3-C7 cycloalkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, and hexyl. Alkyl groups may optionally be independently substituted by one or more substituents described herein.

[0190] When using terms including "alkane," it should be understood that "cycloalkyl" or "carbocyclic" may be considered part of the definition unless the context explicitly excludes it. For example, but not limited to, the terms alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenyloxy, haloalkyl, etc., may all be considered to include cyclic forms of alkyl groups unless the context explicitly excludes them.

[0191] "Alkenyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, which may be located at a stable point along the chain. Non-limiting examples include C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, and C2-C4 alkenyl. The specified scope as used herein indicates that each member of the scope is an alkenyl group of a separate kind, as described above with respect to the alkyl portion. Examples of alkenyl groups include, but are not limited to, vinyl and propenyl groups. Alkenyl groups may optionally be substituted independently by one or more substituents as described herein.

[0192] "Alynyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, which can occur at any stable point along the chain, such as C2-C8 ynyl or C2-C6 ynyl. The specified ranges used herein denote each member of the range as an independent class of ynyl, as described above with respect to the alkyl portion. Examples of ynyl groups 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. An ynyl group may optionally be independently substituted by one or more substituents described herein.

[0193] "Haloalkyl" refers to a branched or straight-chain alkyl group that is substituted with one or more halogen atoms up to the maximum permissible number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl. Haloalkyl groups may optionally be substituted independently with one or more substituents described herein.

[0194] "Halogen" or "halogen" independently refers to any one of a fluorinated group, a chlorolated group, a brominated group, or an iodinated group.

[0195] "Aryl" refers to an aromatic group containing only carbon in one or more aromatic rings. In one embodiment, the aryl group contains 1 to 3 individual or fused rings and is 6 to 14 or 18 ring atoms without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion with a 4 to 7 or 5 to 7-membered saturated or partially unsaturated cyclic group optionally containing 1, 2 or 3 heteroatoms independently selected from N, O, B, P, Si and S to form, for example, 3,4-methylenedioxyphenyl. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, the aryl group is a side group. Examples of side rings are phenyl groups substituted with phenyl groups. Aryl groups may optionally be substituted independently with one or more substituents described herein.

[0196] The term "heterocyclic" refers to saturated and partially saturated cyclic groups containing heteroatoms, wherein the heteroatoms may be selected from N, S, and O. The term "heterocyclic" includes monocyclic 3-12-membered rings and bicyclic 5-16-membered ring systems (which may include fused, bridged, or spirobicyclic ring systems). It does not include rings containing -OO-, -OS-, or -SS- motifs. Examples of saturated heterocyclic groups include saturated 4- to 7-membered monocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolyl, imidazolyl, piperidinyl, pyrrololinyl, azacyclic butyl, piperazine, and pyrazolyl]; saturated 4- to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; and saturated 3- to 6-membered heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolyl]. Examples of partially saturated heterocyclic groups include, but are not limited to, dihydrothiophene, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolyl, imidazoyl, piperidinyl, pyrrololinyl, pyrazolyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazoyl, dihydrothiophene, 2,3-dihydro-benzo[1,4]dioxyl, indololinyl, isoyindololinyl, dihydrobenzothiophene, dihydrobenzofuranyl, isochromyl, chromanyl, 1,2-dihydroquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl. 1,2,3,4-Tetrahydro-quinolinyl, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxalkyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazolyl-6-yl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. "Bicyclic heterocycle" includes groups in which a heterocyclic group is fused to an aryl group, wherein the connecting point is a heterocycle. "Bicyclic heterocycle" also includes heterocyclic groups fused to a carbocyclic group. Examples include partially unsaturated fused heterocyclic groups containing 1 to 5 nitrogen atoms (e.g., 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. Heterocyclic groups may optionally be independently substituted by one or more substituents described herein.

[0197] Non-limiting examples of bicyclic heterocycles include:

[0198]

[0199] Unless otherwise described or clearly apparent from the context, the term "bicyclic heterocycle" includes cis and trans diastereomers. Non-limiting examples of chiral bicyclic heterocycles include:

[0200]

[0201] "Heteroaryl" refers to a stable monocyclic, bicyclic, or polycyclic aromatic ring containing 1 to 3, or in some embodiments 1, 2, or 3, heteroatoms selected from N, O, S, B, and P (and typically N, O, and S), with the remaining ring atom being carbon; or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7-membered aromatic ring, wherein the aromatic ring contains 1 to 3, or in some embodiments 1 to 2, heteroatoms selected from N, O, S, B, or P, with the remaining ring atom 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 typically has 5 or 6 ring atoms. In some embodiments, bicyclic heteroaryl is an 8 to 10-membered heteroaryl, i.e., a group containing 8 or 10 ring atoms, wherein one 5, 6, or 7-membered aromatic ring is fused to a second aromatic or non-aromatic ring, wherein the connecting point is an aromatic ring. When the total number of S and O atoms in a 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 does not exceed 2. In another embodiment, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. Examples of heteroaryl groups include, but are not limited to, pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cenolinyl, indazole, indolazinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purine, oxadiazolyl, triazolyl, thiazolyl, thiazolyl, furazonyl, benzofuranyl, benzobenzylthio, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphthidyl, tetrahydrofuranyl, and furanzopyridinyl. The heteroaryl group may be optionally and independently substituted by one or more substituents described herein.

[0202] "Dosage form" refers to the unit of administration of an active ingredient. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, balls, creams, ointments, suppositories, inhalable dosage forms, transdermal dosage forms, oral, sublingual, topical, gels, and mucosal dosage forms. "Dosage form" can also include implants, such as optical implants.

[0203] A “pharmaceutical composition” is a composition comprising at least one active agent and at least one other substance such as a pharmaceutically acceptable carrier. A “pharmaceutical combination” is a combination of at least two active agents that may be combined in a single dosage form or provided together in separate dosage forms, accompanied by instructions for use of the active agents to treat any of the conditions described herein.

[0204] "Pharmaceutically acceptable salts" are derivatives of the disclosed compounds, wherein the parent compound is modified by preparing its inorganic and organic pharmaceutically 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 using conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K) or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. These reactions are typically carried out in water, in an organic solvent, or in a mixture of both. Generally, non-aqueous media are typical where feasible, such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Salts of the compounds of the present invention further comprise solvates of the compound and the salt of the compound.

[0205] Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and so on. Pharmaceutically acceptable salts include salts acceptable for human consumption and, for example, quaternary ammonium salts of parent compounds formed from inorganic or organic acids. Examples of such salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids such as 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, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethanesulfonic acid, and HOOC-(CH2). 1-4 -COOH, etc., or salts prepared using different acids that produce the same counterion. A list of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., page 1418 (1985).

[0206] According to this disclosure, the term "carrier" used in pharmaceutical compositions / combinations refers to a diluent, excipient, or medium used to provide the active compound.

[0207] The terms "pharmaceuticalally acceptable excipient" and "pharmaceuticalally acceptable carrier" are used interchangeably and refer to excipients that can be used to prepare pharmaceutical compositions / combinations that are generally safe, acceptable for human consumption, and not biologically or otherwise unsuitable for administration to a host (typically a human). In one embodiment, an excipient acceptable for veterinary use is used. In another embodiment, an excipient acceptable for mammalian (particularly human) use is used.

[0208] "Patient," "host," or "subject" refers to a human or non-human animal that requires treatment or prevention of any condition specifically described herein, including but not limited to conditions treated by modulating the classical complement pathway or suffering from one of the compounds described herein. Typically, the host is a human. "Patient," "host," or "subject" also refers to, for example, mammals, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, birds, etc.

[0209] As used herein, “prodrug” means a compound that is converted into a parent drug when administered to a host in vivo. As used herein, the term “parent drug” means any chemical compound now 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 substance, including increasing the drug’s in vivo half-life. Prodrug strategies provide options for modulating the conditions under which the parent drug is produced in vivo. Non-limiting examples of prodrug strategies include the covalent connection of a removable group or a removable portion of a group, such as, but not limited to, acylation, phosphorylation, phosphonylation, aminophosphate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxyl derivatives, sulfonyl or sulfone derivatives, carbonylation or anhydrides, etc.

[0210] In one embodiment, for example, "providing a compound having at least one additional active agent" may mean that the compound and the additional active agent are provided simultaneously in a single dosage form, provided together in separate dosage forms, or provided in separate dosage forms for administration. In one embodiment, the compound is administered at intervals of a certain time period, which is within the time that both the compound and the at least one additional active agent are in the patient's bloodstream. In some embodiments, the compound and the additional active agent do not need to be prescribed to the patient by the same healthcare professional. In some embodiments, one or more additional active agents do not require a prescription. The compound or at least one additional active agent may be administered via any suitable route, such as oral tablets, oral capsules, oral solutions, inhalation, injection, suppositories, parenteral, sublingual, oral, intravenous, intra-aortic, transdermal, polymer-controlled delivery, non-polymer-controlled delivery, nanoparticles or microparticles, liposomes, and / or topical contact. In one embodiment, instructions for use as a combination therapy are provided on the drug label.

[0211] The term "therapeuticly effective amount" for the pharmaceutical compositions / combinations disclosed herein means an amount that effectively provides a therapeutic benefit when administered to a host, such as improvement of symptoms or reduction or attenuation of the disease itself. In one embodiment, the therapeutically effective amount is an amount sufficient to prevent a significant increase in or to significantly reduce detectable hemolysis levels in a patient's blood, serum, or tissues.

[0212] N-oxides

[0213] In some embodiments, any active compound may be provided to a patient in need 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 process. In yet another embodiment, the N-oxide is a metabolite of one of the active compounds described herein and may have independent activity. N-oxides can be formed by treating the compound of interest with an oxidizing agent such as a suitable peroxyacid or peroxide to generate an N-oxide compound. For example, a heteroaryl group (e.g., a pyridyl group) may be treated with an oxidizing agent such as sodium percarbonate under mild reaction conditions and in the presence of a rhenium-based catalyst to generate an N-oxide compound. Those skilled in the art will understand that appropriate protecting groups may be required for the chemical reaction. See Jain, SL et al., “Rhenium-Catalyzed Highly Efficient Oxidations of Tertiary Nitrogen Compounds to N-Oxides Using Sodium Percarbonate as Oxygen Source,” Synlett, 2261-2663, 2006.

[0214] In other aspects of this disclosure, any sulfur-containing active compound may be provided to a patient in need in its sulfoxide or sulfone form. In various embodiments, a sulfoxide or sulfone of the active compound or one of its precursors is used in the preparation. Sulfoxides in selected compounds as described herein can be oxidized using known methods to form sulfoxides. or sulfone For example, compound 1,3,5-triazo-2,4,6-triphosphazene-2,2,4,4,6,6-tetrachloride (TAPC) is an effective 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). Sulfides can also be oxidized in high yields by tantalum carbide-catalyzed oxidation with 30% hydrogen peroxide to sulfoxides. 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 using catalysts such as niobium carbide, see Kirihara, A. et al., “Tantalum Cardide 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 adducts are stable, inexpensive, and readily handled reagents 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). Those skilled in the art will understand that other heteroatoms, such as nitrogen, may need to be protected and then deprotected during the oxidation of the sulfur atom to produce the desired compound.

[0215] Implementation scheme of "alkyl"

[0216] In one embodiment, "alkyl" is C1-C 10 Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl.

[0217] In one implementation, "alkyl" has one carbon atom.

[0218] In one implementation, "alkyl" has two carbon atoms.

[0219] In one implementation, "alkyl" has three carbon atoms.

[0220] In one implementation, "alkyl" has four carbon atoms.

[0221] In one implementation, "alkyl" has five carbon atoms.

[0222] In one implementation, "alkyl" has six carbon atoms.

[0223] Non-limiting examples of "alkyl" include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0224] Other non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0225] Other non-limiting examples of "alkyl" include: sec-butyl, sec-pentyl, and sec-hexyl.

[0226] Other non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0227] Other non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and reactive pentyl.

[0228] Implementation scheme of "halogenated alkyl"

[0229] In one embodiment, "halogenated alkyl" is C1-C 10 Halogenated alkyl, C1-C9 halogenated alkyl, C1-C8 halogenated alkyl, C1-C7 halogenated alkyl, C1-C6 halogenated alkyl, C1-C5 halogenated alkyl, C1-C4 halogenated alkyl, C1-C3 halogenated alkyl and C1-C2 halogenated alkyl.

[0230] In one implementation, the "halogenated alkyl" has one carbon atom.

[0231] In one implementation, the "halogenated alkyl" has one carbon atom and one halogen.

[0232] In one implementation, the "halogenated alkyl" has one carbon atom and two halogens.

[0233] In one implementation, the "halogenated alkyl" has one carbon atom and three halogens.

[0234] In one implementation, the "halogenated alkyl" has two carbon atoms.

[0235] In one implementation, the "halogenated alkyl" has three carbon atoms.

[0236] In one implementation, the "halogenated alkyl" has four carbon atoms.

[0237] In one implementation, the "halogenated alkyl" has five carbons.

[0238] In one implementation, the "halogenated alkyl" has six carbons.

[0239] Non-limiting examples of “halogenated alkyl” include:

[0240] Other non-limiting examples of "haloalkyl" include:

[0241] Other non-limiting examples of "haloalkyl" include:

[0242] Other non-limiting examples of "haloalkyl" include:

[0243] Implementation plan for "Aryl"

[0244] In one implementation, "aryl" is a 6-carbon aromatic group (phenyl).

[0245] In one implementation, "aryl" is a 10-carbon aromatic group (naphthyl).

[0246] In one implementation, "aryl" means "substituted aryl".

[0247] Implementation plan of "hybrid aromatics"

[0248] In one implementation, "heteroaryl" is a 5-membered aromatic group containing 1, 2, or 3 nitrogen atoms.

[0249] Non-limiting examples of 5-membered "heteroaryl" compounds include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, isoxazole, oxazole, oxadiazole, oxtriazole, isothiazole, thiazole, thiazolium, and thiatriazole.

[0250] Other non-limiting examples of 5-yuan "hybrid aryl" compounds include:

[0251]

[0252] In one embodiment, "heteroaryl" is a 6-membered aromatic group (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl) containing 1, 2, or 3 nitrogen atoms.

[0253] Non-limiting examples of 6-membered "heteroaryl" compounds having one or two nitrogen atoms include:

[0254] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0255] Non-limiting examples of bicyclic "heteroaryl" compounds include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazol, benzoxazole, and benzothiazol.

[0256] Other non-limiting examples of bicyclic "heteroaryl" compounds include:

[0257]

[0258] Other non-limiting examples of bicyclic "heteroaryl" compounds include:

[0259]

[0260] Other non-limiting examples of bicyclic "heteroaryl" compounds include:

[0261]

[0262] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0263] Non-limiting examples of bicyclic "heteroaryl" compounds include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cyclophosphine, and naphthidine.

[0264] Other non-limiting examples of bicyclic "heteroaryl" compounds include:

[0265]

[0266] In an alternative implementation, the heteroaryl group is a tetrazolium.

[0267] "Cycloalkyl" implementation scheme

[0268] In one embodiment, "cycloalkyl" is a C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3-C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[0269] In one implementation, "cycloalkyl" has three carbon atoms.

[0270] In one implementation, "cycloalkyl" has four carbon atoms.

[0271] In one implementation, "cycloalkyl" has five carbons.

[0272] In one implementation, "cycloalkyl" has six carbons.

[0273] In one implementation, "cycloalkyl" has seven carbons.

[0274] In one implementation, "cycloalkyl" has eight carbons.

[0275] In one implementation, "cycloalkyl" has nine carbons.

[0276] In one implementation, "cycloalkyl" has ten carbon atoms.

[0277] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0278] Implementation plan of "heterocyclic"

[0279] In one implementation, a "heterocycle" refers to a cyclic ring having one nitrogen atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0280] In one implementation, a "heterocycle" refers to a cyclic ring having one nitrogen atom, one oxygen atom, and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0281] In one implementation, a "heterocycle" refers to a cyclic ring having two nitrogen atoms and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0282] In one implementation, a "heterocycle" refers to a cyclic ring having one oxygen atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0283] In one implementation, a "heterocycle" refers to a cyclic ring having one sulfur atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0284] Non-limiting examples of "heterocyclic" include aziridine, ethylene oxide, cyclothioethane, aziridine, 1,3-diazacyclobutane, oxocyclobutane, and thiocyclobutane.

[0285] Other non-limiting examples of "heterocyclic" compounds include pyrrolidine, 3-pyrrolidine, 2-pyrrolidine, pyrazolidine, and imidazoline.

[0286] Other non-limiting examples of "heterocyclic rings" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxothiocyclopentane, and 1,3-oxothiocyclopentane.

[0287] Other non-limiting examples of "heterocyclic" compounds include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiazide, 1,3-dithiazide, 1,4-dithiazide, morpholine, and thiomorpholine.

[0288] Non-limiting examples of "heterocycles" also include:

[0289]

[0290] Other non-limiting examples of "heterocycles" include:

[0291]

[0292] Other non-limiting examples of "heterocycles" include:

[0293]

[0294] Non-limiting examples of "heterocycles" also include:

[0295]

[0296] Non-limiting examples of "heterocycles" also include:

[0297]

[0298] Other non-limiting examples of "heterocycles" include:

[0299]

[0300] Other non-limiting examples of "heterocycles" include:

[0301]

[0302] The implementation plan for "sugar"

[0303] In one implementation, "sugar" refers to the formulas C3H5O3, C4H7O4, C5H9O5, and C6H 11 O6, C7H 13 O7 or C8H 15 Compounds of O8.

[0304] Non-limiting examples of sugar include

[0305] Other implementation schemes disclosed herein:

[0306] In one implementation scheme Selected from:

[0307]

[0308]

[0309] In one implementation scheme Selected from:

[0310]

[0311] In one implementation, R 22 Selected from

[0312] In one implementation, R 22 Selected from

[0313] In one implementation scheme Selected from

[0314] In one implementation scheme Selected from

[0315] In one implementation scheme Selected from

[0316] In another implementation, Selected from

[0317] In another implementation, Selected from

[0318] In another implementation, yes In another implementation, yes

[0319] In one implementation, R 26 Selected from

[0320] In one implementation, R 27 Selected from

[0321] In one implementation scheme Selected from

[0322] In one implementation, R 21 Selected from:

[0323]

[0324] On one hand, compounds of formula I are provided, which are selected from;

[0325]

[0326]

[0327] On one hand, compounds of formula I are provided, selected from:

[0328]

[0329]

[0330] On one hand, compounds of formula I are provided, selected from:

[0331]

[0332]

[0333] In one respect, the compounds disclosed herein are selected from:

[0334]

[0335]

[0336] In one respect, the compounds disclosed herein are selected from:

[0337]

[0338]

[0339] On one hand, compounds of formula I are provided, which are selected from:

[0340]

[0341]

[0342]

[0343] On one hand, compounds of formula I are provided, which are selected from:

[0344]

[0345]

[0346]

[0347] On one hand, compounds of formula I are provided, which are selected from:

[0348]

[0349]

[0350] On one hand, compounds of formula I are provided, which are selected from:

[0351]

[0352]

[0353] On one hand, compounds of formula I are provided, which are selected from:

[0354]

[0355]

[0356]

[0357] On one hand, compounds of formula IV are provided, selected from:

[0358]

[0359]

[0360] On one hand, compounds of formula V are provided, which are selected from:

[0361]

[0362]

[0363] On the other hand, the compounds of formula I are selected from:

[0364]

[0365]

[0366] Or a pharmaceutically acceptable salt, isotope analog, prodrug, or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier; wherein all variables are as defined herein.

[0367] On the other hand, the compounds of formula I are selected from:

[0368]

[0369] Or a pharmaceutically acceptable salt, isotope analog, prodrug, or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier; wherein all variables are as defined herein.

[0370] On the other hand, the compounds of formula I are selected from:

[0371]

[0372] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0373] in:

[0374] R 200 Selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and -OR 30 and -N(R) 30 ); and all other variables are as defined in this document.

[0375] On the other hand, the compounds of formula I are selected from:

[0376]

[0377] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0378] in:

[0379] Selected from 3- to 6-membered carbon cyclic rings and 4- to 6-membered heterocyclic rings containing one or two heteroatoms independently selected from N, O, and S; for example Optional

[0380] In the alternative implementation plan, Optionally selected by 1, 2, 3 or 4 independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR 30 and -N(R) 30 Substitution of )2 by substituents;

[0381] All other variables are as defined in this document.

[0382] On the other hand, the compounds of formula I are selected from:

[0383]

[0384] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0385] in:

[0386] It is a 3- to 8-membered carbon ring or a 4- to 8-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; for example, in one embodiment, Optional

[0387] In this respect, R 8 and R 10 At least one of them is not hydrogen; and

[0388] All other variables are as defined in this document.

[0389] On the other hand, the compounds of formula I are selected from:

[0390]

[0391] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0392] in:

[0393] It is a 3- to 8-membered carbon ring or a 4- to 8-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; for example, in one embodiment;

[0394] In this respect, R 10 and R 12 At least one of them is not hydrogen; and

[0395] All other variables are as defined in this document.

[0396] In alternative embodiments, the compounds disclosed herein are selected from:

[0397]

[0398] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0399] in:

[0400] It is a 3- to 8-membered carbon ring or a 4- to 8-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S, wherein One, two, three, or four of the following are selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and -OR groups. 30 and -N(R) 30 Substituents of )2; and

[0401] All other variables are as defined in this document.

[0402] On the other hand, the compounds of formula X are selected from:

[0403]

[0404]

[0405] Or a pharmaceutically acceptable salt, isotope analog, prodrug, or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier; wherein all variables are as defined herein.

[0406] On the other hand, the compounds of formula X are selected from:

[0407]

[0408] Or a pharmaceutically acceptable salt, isotope analog, prodrug, or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier; wherein all variables are as defined herein.

[0409] On the other hand, the compounds of formula X are selected from:

[0410]

[0411] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0412] in:

[0413] R 200 Selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and -OR 30 and -N(R) 30 ), and all other variables are as defined in this document.

[0414] On the other hand, the compounds of formula X are selected from:

[0415]

[0416]

[0417] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0418] in:

[0419] Selected from 3- to 6-membered carbon cyclic rings and 4- to 6-membered heterocyclic rings containing one or two heteroatoms independently selected from N, O, and S;

[0420] In the alternative implementation plan, Optionally selected by 1, 2, 3 or 4 independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR 30 and -N(R) 30 Substitution of )2 by substituents;

[0421] All other variables are as defined in this document.

[0422] On the other hand, the compounds of formula X are selected from:

[0423]

[0424] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0425] in:

[0426] It is a 3- to 8-membered carbon ring or a 4- to 8-membered heterocycle containing one or two heteroatoms independently selected from N, O and S;

[0427] In this respect, R 8 and R 10 At least one of them is not hydrogen; and

[0428] All other variables are as defined in this document.

[0429] On the other hand, the compounds of formula X are selected from:

[0430]

[0431] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0432] in:

[0433] It is a 3- to 8-membered carbon ring or a 4- to 8-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; for example, in one embodiment

[0434] In this respect, R 10 and R 12 At least one of them is not hydrogen; and

[0435] All other variables are as defined in this document.

[0436] In alternative embodiments, the compounds disclosed herein are selected from:

[0437]

[0438] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0439] in:

[0440] It is a 3- to 8-membered carbon ring or a 4- to 8-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S, wherein One, two, three, or four of the following are selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and -OR groups. 30 and -N(R) 30 Substituents of )2; and

[0441] All other variables are as defined in this document.

[0442] In one embodiment, the 3- to 8-membered carbon ring is a 4- to 8-membered carbon ring. In another embodiment, the 3- to 8-membered carbon ring is a 4- to 8-membered carbon ring.

[0443] In one implementation, R 7 and R 9 Together with the atoms they are attached to, they form 4 to 8-membered carbon rings or 4 to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O and S;

[0444] In one implementation, R 9 and R 11 Together with the atoms they are attached to, they form 4 to 8-membered carbon rings or 4 to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O and S;

[0445] In one implementation scheme It is a 4- to 8-membered carbon ring or a 4- to 8-membered heterocycle containing one or two heteroatoms independently selected from N, O and S;

[0446] On the other hand, the compounds of formula XIV are selected from:

[0447]

[0448] Or a pharmaceutically acceptable salt, isotope analog, prodrug, or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier; wherein all variables are as defined herein.

[0449] On the other hand, the compounds of formula XIV are selected from:

[0450]

[0451] Or a pharmaceutically acceptable salt, isotope analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

[0452] in:

[0453] R 201 Selected from halogens, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C1-C6 haloalkyl groups, and -OR groups. 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, and heteroaryl compounds, excluding halogens, of the R group. 201 Each of the groups may be optionally selected by one, two, three, or four independently selected from C1-C6 alkyl, C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups; and

[0454] All other variables are as defined in this document.

[0455] In some aspects of this disclosure, R 9 and R 11 Together with the atoms they are attached to, they form cyclopropane.

[0456] In one embodiment, the compounds disclosed herein are selected from:

[0457]

[0458]

[0459] as well as

[0460]

[0461] Or its pharmaceutically acceptable salt.

[0462] In some embodiments, the compounds disclosed herein are selected from:

[0463]

[0464]

[0465] Or its pharmaceutically acceptable salt.

[0466] In some embodiments, the compounds disclosed herein are selected from:

[0467]

[0468]

[0469] Or its pharmaceutically acceptable salt.

[0470] In some embodiments, the compounds disclosed herein are selected from:

[0471]

[0472]

[0473]

[0474] Or its pharmaceutically acceptable salt;

[0475] Each R 40 Independently selected from: SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, heteroaryl, cyano, and nitro groups.

[0476] In some embodiments, the compounds disclosed herein are selected from:

[0477]

[0478] Or its pharmaceutically acceptable salt.

[0479] In some embodiments, the compounds disclosed herein are selected from:

[0480]

[0481] Or its pharmaceutically acceptable salt.

[0482] Other implementation plans

[0483] 1. (Implementation Scheme 1) In some embodiments, the compounds disclosed herein are selected from:

[0484]

[0485]

[0486]

[0487]

[0488]

[0489] Or a pharmaceutically acceptable salt, isotope analog, prodrug, or isolated isomer thereof;

[0490] in:

[0491] Each n is independently 1, 2, or 3;

[0492] Each m is independently 0, 1, 2, or 3;

[0493] o is 0, 1, or 2;

[0494] Is it a single bond or a double bond?

[0495] Z is CH2, C(CH2) or C(O);

[0496] X 1 Selected from S, O and N(R) 30 );

[0497] X 2 Selected from bond, N(R) 30 ) and -ON(R 30 )-;

[0498] X 3 Selected from N and C(R) 17 );

[0499] X 4 Selected from N and C(R) 18 );

[0500] Where X 3 and X 4 Only one of them can be N;

[0501] X 5 It is C or Si;

[0502] X 6 Selected from

[0503] X 7 Selected from O, S, N(R) 30 ) and CR 5 R 6 ;

[0504] Each X 8and X 9 Independently selected from O, S, NR 30 CR 9 R 10 CR 5 R 6 and CH2; where X 8 and X 9 They cannot all be the same functional groups;

[0505] X 10 Selected from

[0506] X 11 Selected from N and CR 1 ;

[0507] X 12 Selected from N and CR 2 ;

[0508] R 1 and R 2 Independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, heteroaryl, cyano, and nitro; R other than hydrogen, halogen, cyano, and nitro. 1 and R 2 Each of the groups may be optionally selected by one, two, three, or four independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0509] R 3 and R 4 Independently selected from hydrogen, CN, C(O)R 31 -SR 30 and -OR 30 ;

[0510] Or rather R 3 and R 4The combination forms an alkyl group, optionally composed of one, two, or three independently selected C1-C6 alkyl, C1-C6 haloalkyl, or -OR group. 30 Oxadiazoles substituted with oxo groups;

[0511] Each R 5 and R 6 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR 30 and -N(R) 30 )2, where when R 5 and R 6 When carbon atoms are adjacent to each other, they can be arbitrarily replaced by carbon-carbon double bonds;

[0512] R 7 R 8 R 9 R 10 R 11 and R 12 Independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, and heteroaryl groups, except for hydrogen and halogens, of the R groups. 7 R 8 R 9 R 10 R 11 and R 12 The group is optionally selected by 1, 2, 3 or 4 independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0513] Or R 7 and R 8 They can combine with the carbon atoms to which they are attached to form 3 to 6-membered carbon spirocycles or 4 to 6-membered heterocyclic spirocycles containing one or two independent heteroatoms selected from N, O and S;

[0514] Or R 7 and R 8 They can combine with the carbon atoms they are attached to form Or carbonyl;

[0515] Or R 9 and R 10 They can combine with the atoms they are attached to to form 3 to 6-membered carbon spirocycles or 4 to 6-membered heterocyclic spirocycles containing one or two independent heteroatoms selected from N, O and S;

[0516] Or R 9 and R 10 They can combine with the atoms they are connected to form Or carbonyl;

[0517] Or R 11 and R 12 They can combine with the carbon atoms to which they are attached to form 3 to 6-membered carbon spirocycles or 4 to 6-membered heterocyclic spirocycles containing one or two independent heteroatoms selected from N, O and S;

[0518] Or R 11 and R 12 They can combine with the carbon atoms they are attached to form Or carbonyl;

[0519] Or R 7 and R 9 Together with the atoms they are attached to, they form 3 to 8-membered carbon rings or 4 to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O and S;

[0520] Or R 9 and R 11 Together with the atoms they are attached to, they form 3 to 8-membered carbon rings or 4 to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O and S;

[0521] Or R 7 and R 11 Together with the atoms they are connected to, they form one or two carbon bridges;

[0522] Each R 13 Independently selected from hydrogen or C1-C6 alkyl;

[0523] R 14 R 15 and R 16 Independently selected from hydrogen, halogen, SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -C1-C6 alkyl-aryl. -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R31 Heterocyclic, aryl, heteroaryl, cyano, and nitro groups, except for hydrogen, halogen, cyano, and nitro groups, are all R groups. 14 R 15 and R 16 Each of the groups may be optionally selected by one, two, three, or four independently selected from SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0524] R 17 and R 18 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR 30 and -N(R) 30 )2;

[0525] Or R 17 and R 18 They combine with the carbon atoms they are attached to to form double bonds;

[0526] R 19 and R 20 Independently selected from hydrogen, C1-C6 alkyl, C5-C 10 Bicyclic carbocyclic rings, C4-C6 heterocycles, halogens, C1-C6 haloalkyl groups, -OR 30 -N(R) 30 2、-(CH2) n -R 33 and

[0527] R 21 The R is selected from C1-C6 haloalkyl, -O-C1-C6 haloalkyl, C1-C6 alkyl, -O-C1-C6 alkyl, aryl, -O-aryl, heteroaryl, or –O-heteroaryl. 21 Each of the groups may be optionally selected by one, two, three, or four independently selected from SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0528] R 22 Selected from -C1-C6 alkyl-R 23 -C2-C6 alkenyl-R 23 -C2-C6 ynyl-R 23 and bicyclic cycloalkyl-R 23 The R 22 Each of the following may be selected independently by one, two, three, or four from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0529] R 23 Selected from hydrogen, sugar, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 and -S(O)2R 31 ;

[0530] Each R 25 Independently selected from hydrogen, SF5, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, heteroaryl, cyano, and nitro; R other than hydrogen, halogen, cyano, and nitro. 25 Each of the groups may be optionally selected by one, two, three, or four independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0531] R 26 Selected from

[0532] R 27 Selected from

[0533] R 29 Selected from halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, and heteroaryl groups, except for hydrogen and halogens, of the R groups. 29 Each of the groups may be optionally selected by one, two, three, or four independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution with heterocyclic, aryl, heteroaryl, cyano and nitro groups.

[0534] Each R 30 Independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, heterocyclic and C(O)R 31 ;

[0535] Each R 31 Independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR 32 -SR 32 -N(R) 32 2. Heterocyclic, aryl, and heteroaryl compounds;

[0536] Each R 32 Independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;

[0537] Each R 33 Independently selected from hydrogen, guanidine, heteroaryl, aryl, -C6H5-OR 30 ;-OR 30 -SR 30 -SeR 30 -N(R) 30)2 and -C(O)R 31 ;

[0538] R 34 Selected from

[0539] R 35 Selected from C3-C 10 Alkyl or C3-C 10 Halogenated alkyl groups;

[0540] For compounds of formulas I and II, at least one of the following conditions must be met:

[0541] aX 3 It is C(R) 17 ), and X 4 It is C(R) 18 );

[0542] bR 17 Selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and -OR 30 and -N(R) 30 )2;

[0543] cX 5 It is Si;

[0544] dZ is C(CH2);

[0545] eZ is CH2;

[0546] fR 7 and R 8 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0547] gR 9 and R 10 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0548] hR 11 and R 12 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0549] iR 7 and R 9Together with the atoms they are attached to, they form 3 to 8-membered carbon rings or 4 to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 8 or R 10 It is not hydrogen;

[0550] jR 9 and R 11 Together with the atoms they are attached to, they form 3 to 8-membered carbon rings or 4 to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 10 or R 12 It is not hydrogen;

[0551] kR 7 and R 11 Together with the atoms they are connected to, they form one or two carbon bridges;

[0552] lX 6 Selected from

[0553] mR 3 and R 4 At least one of them is CN or -SR 30 or C(O)R 31 ;or

[0554] nR 3 and R 4 The combination forms an alkyl group, optionally composed of one, two, or three independently selected C1-C6 alkyl, C1-C6 haloalkyl, or -OR group. 30 Oxadiazoles substituted with oxo groups;

[0555] For compounds of formulas X and XI, at least one of the following conditions must be met:

[0556] aX 3 It is C(R) 17 ), and X 4 It is C(R) 18 );

[0557] bR 17 Selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and -OR 30 and -N(R) 30 )2;

[0558] cX 5 It is Si;

[0559] dZ is C(CH2);

[0560] eZ is CH2;

[0561] fR 7 and R8 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0562] gR 9 and R 10 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0563] hR 9 and R 11 Together with the atoms they are attached to, they form 3 to 8-membered carbon rings or 4 to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 10 It is not hydrogen;

[0564] iR 11 and R 12 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0565] jR 7 and R 9 Together with the atoms they are attached to, they form 3 to 8-membered carbon rings or 4 to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 10 It is not hydrogen;

[0566] kR 7 and R 11 Together with the atoms they are connected to, they form one or two carbon bridges;

[0567] lR 22 At least three ORs 30 Group substitution;

[0568] mR 23 It's sugar;

[0569] nR 3 and R 4 At least one of them is CN or -SR 30 or C(O)R 31 ;or

[0570] oR 3 and R 4 The combination forms an alkyl group, optionally composed of one, two, or three independently selected C1-C6 alkyl, C1-C6 haloalkyl, or -OR group. 30 Oxadiazoles substituted with oxo groups;

[0571] For compounds of formula XIV, at least one of the following conditions must be met:

[0572] aX 1 Is it O or N(R)? 30 );

[0573] bR 14 It is not hydrogen;

[0574] cR 1 It is not hydrogen;

[0575] dR 2 It is not hydrogen;

[0576] eR 3 It is not hydrogen; or

[0577] fR 4 It's not hydrogen.

[0578] 2. The compound of embodiment 1, wherein the compound is selected from:

[0579]

[0580] Or a pharmaceutically acceptable salt, isotope analog, prodrug, or isolated isomer thereof.

[0581] 3. The compound of embodiment 1, wherein the compound has the following formula:

[0582]

[0583] Or a pharmaceutically acceptable salt, isotope analog, prodrug, or isolated isomer thereof.

[0584] 4. The compound of embodiment 1, having the following formula:

[0585]

[0586] Or a pharmaceutically acceptable salt, isotope analog, prodrug, or isolated isomer thereof.

[0587] 5. The compound of embodiment 1, selected from:

[0588]

[0589]

[0590]

[0591]

[0592] in

[0593] R 21 Selected from C1-C6 alkyl and -O-C1-C6 alkyl;

[0594] Each R 25 Independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, heteroaryl, cyano, and nitro; R other than hydrogen, halogen, cyano, and nitro. 1 and R 2 Each of the groups may be optionally selected by one, two, three, or four independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0595] R 14 R 15 and R 16 Independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -C1-C6 alkyl-aryl. -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, heteroaryl, cyano, and nitro groups, except for hydrogen, halogen, cyano, and nitro groups, are all R groups. 14 R 15 and R 16 Each of the groups may be optionally selected by one, two, three, or four independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0596] 6. In some embodiments, the compounds disclosed herein are selected from:

[0597]

[0598]

[0599]

[0600]

[0601] Or a pharmaceutically acceptable salt, isotope analog, prodrug, or isolated isomer thereof;

[0602] in:

[0603] Each n is independently 1, 2, or 3;

[0604] Each m is independently 0, 1, 2, or 3;

[0605] o is 0, 1, or 2;

[0606] Is it a single bond or a double bond?

[0607] Z is CH2, C(CH2) or C(O);

[0608] X 1 Selected from S, O and N(R) 30 );

[0609] X 2 Selected from bond, N(R) 30 ) and -ON(R 30 )-;

[0610] X 3 Selected from N and C(R) 17 );

[0611] X 4 Selected from N and C(R) 18 );

[0612] Where X 3 and X 4 Only one of them can be N;

[0613] X 5 It is C or Si;

[0614] X 6 Selected from

[0615] X7 Selected from O, S, N(R) 30 ) and CR 5 R 6 ;

[0616] Each X 8 and X 9 Independently selected from O, S, NR 30 CR 9 R 10 CR 5 R 6 and CH2; where X 8 and X 9 They cannot all be the same group

[0617] X 11 Selected from N and CR 1 ;

[0618] X 12 Selected from N and CR 2 ;

[0619] R 1 and R 2 Independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, heteroaryl, cyano, and nitro; R other than hydrogen, halogen, cyano, and nitro. 1 and R 2 Each of the groups may be optionally selected by one, two, three, or four independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0620] R 3 and R 4 Independently selected from hydrogen, C(O)R 31 -SR 30 and -OR 30 ;

[0621] Or rather R 3and R 4 The combination forms an alkyl group, optionally composed of one, two, or three independently selected C1-C6 alkyl, C1-C6 haloalkyl, or -OR group. 30 Oxadiazoles substituted with oxo groups;

[0622] Each R 5 and R 6 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR 30 and -N(R) 30 )2, where when R 5 and R 6 When carbon atoms are adjacent to each other, they can be arbitrarily replaced by carbon-carbon double bonds;

[0623] R 7 R 8 R 9 R 10 R 11 and R 12 Independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, and heteroaryl groups, except for hydrogen and halogens, of the R groups. 7 R 8 R 9 R 10 R 11 and R 12 Each of the groups may be optionally selected by one, two, three, or four independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0624] Or R 7 and R 8 They can combine with the carbon atoms to which they are attached to form 3 to 6-membered carbon spirocycles or 4 to 6-membered heterocyclic spirocycles containing one or two independent heteroatoms selected from N, O and S;

[0625] Or R 7 and R8 They can combine with the carbon atoms they are attached to form Or carbonyl;

[0626] Or R 9 and R 10 They can combine with the atoms they are attached to to form 3 to 6-membered carbon spirocycles or 4 to 6-membered heterocyclic spirocycles containing one or two independent heteroatoms selected from N, O and S;

[0627] Or R 9 and R 10 They can combine with the atoms they are connected to form Or carbonyl;

[0628] Or R 11 and R 12 They can combine with the carbon atoms to which they are attached to form 3 to 6-membered carbon spirocycles or 4 to 6-membered heterocyclic spirocycles containing one or two independent heteroatoms selected from N, O and S;

[0629] Or R 11 and R 12 They can combine with the carbon atoms they are attached to form Or carbonyl;

[0630] Or R 7 and R 9 Together with the atoms they are attached to, they form 4 to 8-membered carbon rings or 4 to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O and S;

[0631] Or R 9 and R 11 Together with the atoms they are attached to, they form 4 to 8-membered carbon rings or 4 to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O and S;

[0632] Or R 7 and R 11 Together with the atoms they are connected to, they form one or two carbon bridges;

[0633] Each R 13 Independently selected from hydrogen or C1-C6 alkyl;

[0634] R 14 R 15 and R 16 Independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -C1-C6 alkyl-aryl. -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R31 -S(O)2R 31 Heterocyclic, aryl, heteroaryl, cyano, and nitro groups, except for hydrogen, halogen, cyano, and nitro groups, are all R groups. 14 R 15 and R 16 Each of the groups may be optionally selected by one, two, three, or four independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0635] R 17 and R 18 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR 30 and -N(R) 30 )2;

[0636] Or R 17 and R 18 They combine with the carbon atoms they are attached to to form double bonds;

[0637] R 19 and R 20 Independently selected from hydrogen, C1-C6 alkyl, C5-C 10 Bicyclic carbocyclic rings, C4-C6 heterocycles, halogens, C1-C6 haloalkyl groups, -OR 30 -N(R) 30 2、-(CH2) n -R 33 and

[0638] R 21 Selected from C1-C6 alkyl and -O-C1-C6 alkyl;

[0639] R 22 Selected from -C1-C6 alkyl-R 23 -C2-C6 alkenyl-R 23 -C2-C6 ynyl-R 23 and bicyclic cycloalkyl-R 23 The R 22 Each of the following may be selected independently by one, two, three, or four from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30-N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0640] R 23 Selected from hydrogen, sugar, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 and -S(O)2R 31 ;and

[0641] Each R 25 Independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, heteroaryl, cyano, and nitro; R other than hydrogen, halogen, cyano, and nitro. 1 and R 2 Each of the groups may be optionally selected by one, two, three, or four independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution of heterocyclic, aryl, heteroaryl, cyano, and nitro groups;

[0642] R 26 Selected from

[0643] R 27 Selected from

[0644] Each R 30 Independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, heterocyclic and C(O)R 31 ;

[0645] Each R31 Independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR 32 -SR 32 -N(R) 32 2. Heterocyclic, aryl, and heteroaryl compounds;

[0646] Each R 32 Independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;

[0647] Each R 33 Independently selected from hydrogen, guanidine, heteroaryl, aryl, -C6H5-OR 30 ;-OR 30 -SR 30 -SeR 30 -N(R) 30 )2、-C(O)R 31 ,

[0648] For compounds of formulas I and II, at least one of the following conditions must be met:

[0649] aX 3 It is C(R) 17 ), and X 4 It is C(R) 18 );

[0650] bR 17 Selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and -OR 30 and -N(R) 30 )2;

[0651] cX 5 It is Si;

[0652] dZ is C(CH2);

[0653] eZ is CH2;

[0654] fR 7 and R 8 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0655] gR 9 and R 10 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0656] hR 11 and R12 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0657] iR 7 and R 9 Together with the atoms they are attached to, they form 4- to 8-membered carbon rings or 4- to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 10 or R 12 It is not hydrogen;

[0658] jR 9 and R 11 Together with the atoms they are attached to, they form 4- to 8-membered carbon rings or 4- to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 8 or R 10 It is not hydrogen;

[0659] kR 7 and R 11 Together with the atoms they are connected to, they form one or two carbon bridges;

[0660] lX 6 Selected from

[0661] mR 3 and R 4 At least one of them is -SR 30 or C(O)R 31 ;or

[0662] nR 3 and R 4 The combination forms an alkyl group, optionally composed of one, two, or three independently selected C1-C6 alkyl, C1-C6 haloalkyl, or -OR group. 30 Oxadiazoles substituted with oxo groups;

[0663] For compounds of formulas X and XI, at least one of the following conditions must be met:

[0664] aX 3 It is C(R) 17 ), and X 4 It is C(R) 18 );

[0665] bR 17 Selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and -OR 30 and -N(R) 30 )2;

[0666] cX5 It is Si;

[0667] dZ is C(CH2);

[0668] eZ is CH2;

[0669] fR 7 and R 8 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0670] gR 9 and R 10 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0671] hR 9 and R 11 Together with the atoms they are attached to, they form 4- to 8-membered carbon rings or 4- to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 10 It is not hydrogen;

[0672] iR 11 and R 12 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon spirocycles; 4 to 6-membered heterocyclic spirocycles containing one or two heteroatoms independently selected from N, O and S; Or carbonyl;

[0673] jR 7 and R 9 Together with the atoms they are attached to, they form 4- to 8-membered carbon rings or 4- to 8-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 10 It is not hydrogen;

[0674] kR 7 and R 11 Together with the atoms they are connected to, they form one or two carbon bridges;

[0675] lR 22 At least three ORs 30 Group substitution;

[0676] mR 23 It's sugar;

[0677] nR 3 and R 4 At least one of them is -SR 30 or C(O)R 31;or

[0678] oR 3 and R 4 The combination forms an alkyl group, optionally composed of one, two, or three independently selected C1-C6 alkyl, C1-C6 haloalkyl, or -OR group. 30 Oxadiazoles substituted with oxo groups;

[0679] For compounds of formula XIV, at least one of the following conditions must be met:

[0680] aX 1 Is it O or N(R)? 30 );

[0681] bR 14 It is not hydrogen;

[0682] cR 1 It is not hydrogen;

[0683] dR 2 It is not hydrogen;

[0684] eR 3 It is not hydrogen; or

[0685] fR 4 It's not hydrogen.

[0686] 7. A compound according to any one of schemes 1-6, where n is 1.

[0687] 8. A compound of any one of embodiments 1-7, wherein each m is independently 0 or 1.

[0688] 9. A compound of any one of embodiments 1-8, wherein Z is C(O).

[0689] 10. A compound of any one of embodiments 1-9, wherein X 1 It is S.

[0690] 11. A compound of any one of embodiments 1-10, wherein X 2 It is a key.

[0691] 12. A compound according to any one of embodiments 1-11, wherein X 3 It is C(R) 17 ).

[0692] 13. A compound of any one of embodiments 1-12, wherein X 4 It is N.

[0693] 14. A compound of any one of embodiments 1-13, wherein X 5 It's C.

[0694] 15. A compound according to any one of embodiments 1-14, wherein X 6 yes

[0695] 16. A compound according to any one of embodiments 1-15, wherein X 7 It is O.

[0696] 17. A compound of any one of embodiments 1-15, wherein X 7 It is CR 5 R 6 .

[0697] 18. A compound of any one of embodiments 1-15, wherein X 7 It is S.

[0698] 19. A compound of any one of embodiments 1-15, wherein X 7 It is N(R) 30 ).

[0699] 20. A compound of any one of embodiments 1-19, wherein X 8 It is CH, and X 9 It is N.

[0700] 21. A compound of any one of embodiments 1-19, wherein X 8 It is CH, and X 9 It is N.

[0701] 22. A compound of any one of embodiments 1-21, wherein X 11 and X 12 All are CH.

[0702] 23. A compound of any one of embodiments 1-21, wherein X 11 and X 12 One of them is CH, and the other is N.

[0703] 24. A compound of any one of embodiments 1-23, wherein R 1 and R 2 Independently selected from hydrogen, halogen, -OR 30 -SR 30 -N(R) 30 )2 and C1-C6 alkyl groups.

[0704] 25. A compound of any one of embodiments 1-23, wherein R 1 and R 2 It is independently selected from hydrogen, halogens and C1-C6 alkyl groups.

[0705] 26. A compound of any one of embodiments 1-23, wherein R 1and R 2 Both are hydrogen.

[0706] 27. A compound of any one of embodiments 1-26, wherein R 3 and R 4 Both are hydrogen.

[0707] 28. A compound of any one of embodiments 1-26, wherein R 3 It is hydrogen, and R 4 It is a hydroxyl group.

[0708] 29. A compound of any one of embodiments 1-26, wherein R 3 and R 4 The combination forms an alkyl group, optionally composed of one, two, or three independently selected C1-C6 alkyl, C1-C6 haloalkyl, or -OR group. 30 Oxadiazoles substituted with oxo groups.

[0709] 30. A compound of any one of embodiments 1-29, wherein R 5 and R 6 All are hydrogen.

[0710] 31. A compound of any one of embodiments 1-30, wherein R 7 It is hydrogen.

[0711] 32. A compound of any one of embodiments 1-31, wherein R 9 It is hydrogen.

[0712] 33. A compound of any one of embodiments 1-30, wherein R 7 and R 11 They combine to form a carbon bridge.

[0713] 34. A compound of any one of embodiments 1-30, wherein R 7 and R 11 They combine to form two carbon bridges.

[0714] 35. A compound of any one of embodiments 1-31, wherein R 11 It is hydrogen.

[0715] 36. A compound according to any one of embodiments 1-31, wherein R 9 and R 11 They combine to form 4-8 member carbon rings.

[0716] 37. A compound of any one of embodiments 1-31, wherein R 9 and R 11 They combine to form a cyclopropyl ring.

[0717] 38. A compound of any one of embodiments 1-35, wherein R10 It is hydrogen.

[0718] 39. A compound of any one of embodiments 1-37, wherein R 10 Selected from halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 and -S(O)2R 31 .

[0719] 40. A compound of any one of embodiments 1-37, wherein R 10 Selected from aryl and heteroaryl groups, each of which is optionally selected by 1, 2, 3 or 4 independently from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substitution with heterocyclic, aryl, heteroaryl, cyano and nitro groups.

[0720] 41. A compound according to any one of embodiments 1-31, wherein R 9 and R 10 They combine to form a spiral ring.

[0721] 42. A compound of any one of embodiments 1-31, wherein R 9 and R 10 They combine to form a 5-membered heterocyclic spiroring.

[0722] 43. A compound of any one of embodiments 1-31, wherein R 9 and R 10 They combine to form a 5-membered carbon ring spiro ring.

[0723] 44. A compound of any one of embodiments 1-40, wherein R 10 It is a methyl group.

[0724] 45. A compound of any one of embodiments 1-44, wherein R 12 It is hydrogen.

[0725] 46. ​​A compound of any one of embodiments 1-45, wherein R 8 It is hydrogen.

[0726] 47. A compound of any one of embodiments 1-46, wherein R 13 It is hydrogen.

[0727] 48. A compound of any one of embodiments 1-46, wherein R 13 It is a C1-C6 alkyl group.

[0728] 49. A compound of any one of embodiments 1-48, wherein R 14 It is a C1-C6 alkyl group.

[0729] 50. A compound of any one of embodiments 1-48, wherein R 14 It is hydrogen.

[0730] 51. A compound of any one of embodiments 1-48, wherein R 14 It is halogen.

[0731] 52. A compound of any one of embodiments 1-48, wherein R 14 It is a haloalkyl group.

[0732] 53. A compound of any one of embodiments 1-48, wherein R 14 OR 30 .

[0733] 54. A compound of any one of embodiments 1-48, wherein R 14 It is -O-phenyl.

[0734] 55. A compound of any one of embodiments 1-54, wherein R 15 It is a C1-C6 alkyl group.

[0735] 56. A compound of any one of embodiments 1-54, wherein R 15 It is hydrogen.

[0736] 57. A compound of any one of embodiments 1-54, wherein R 15 It is halogen.

[0737] 58. A compound of any one of embodiments 1-54, wherein R 15 It is a haloalkyl group.

[0738] 59. A compound of any one of embodiments 1-54, wherein R 15 OR 30 .

[0739] 60. A compound of any one of embodiments 1-54, wherein R 15 It is -O-phenyl.

[0740] 61. A compound of any one of embodiments 1-60, wherein R16 It is a C1-C6 alkyl group.

[0741] 62. A compound of any one of embodiments 1-60, wherein R 16 It is hydrogen.

[0742] 63. A compound of any one of embodiments 1-60, wherein R 16 It is halogen.

[0743] 64. A compound of any one of embodiments 1-60, wherein R 16 It is a haloalkyl group.

[0744] 65. A compound of any one of embodiments 1-60, wherein R 16 Is it OR 30 .

[0745] 66. A compound of any one of embodiments 1-60, wherein R 16 It is -O-phenyl.

[0746] 67. A compound of any one of embodiments 1-66, wherein R 17 It is hydrogen.

[0747] 68. A compound of any one of embodiments 1-67, wherein R 18 It is hydrogen.

[0748] 69. A compound of any one of embodiments 1-68, wherein R 19 It is hydrogen.

[0749] 70. A compound of any one of embodiments 1-68, wherein R 19 Selected from C1-C6 alkyl, C5-C 10 Bicyclic carbocyclic rings, C4-C6 heterocycles, halogens, C1-C6 haloalkyl groups, -OR 30 -N(R) 30 2、-(CH2) n -R 33 and

[0750] 71. A compound of any one of embodiments 1-70, wherein R 20 It is hydrogen.

[0751] 72. A compound of any one of embodiments 1-70, wherein R 20 Selected from C1-C6 alkyl, C5-C 10 Bicyclic carbocyclic rings, C4-C6 heterocycles, halogens, C1-C6 haloalkyl groups, -OR 30 -N(R) 30 2、-(CH2) n -R33 and

[0752] 73. A compound of any one of embodiments 1-70, wherein R 20 It is -(CH2) n -R 33 .

[0753] 74. A compound of any one of embodiments 1-73, wherein R 21 It is a C1-C6 haloalkyl group.

[0754] 75. A compound of any one of embodiments 1-73, wherein R 21 It is an -O-C1-C6 haloalkyl group.

[0755] 76. A compound of any one of embodiments 1-73, wherein R 21 It is optionally composed of 1, 2, 3 or 4 independently selected from SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Phenyl groups substituted with heterocyclic, aryl, heteroaryl, cyano, and nitro groups.

[0756] 77. A compound of any one of embodiments 1-73, wherein R 21 It is optionally composed of 1, 2, 3 or 4 independently selected from SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Heterocyclic, aryl, heteroaryl, cyano and nitro substituents of heteroaryl groups.

[0757] 78. A compound of any one of embodiments 76-77, wherein R 21 It is not replaced.

[0758] 79. A compound of any one of embodiments 76-77, wherein R 21 It is replaced by at least one halogen group.

[0759] 80. A compound of any one of embodiments 76-77, wherein R 21It is substituted with at least one C1-C6 alkyl group.

[0760] 81. A compound of any one of embodiments 76-77, wherein R 21 It is replaced by one fluorinated group.

[0761] 82. A compound of any one of embodiments 76-77, wherein R 21 It is replaced by one methyl group.

[0762] 83. A compound of any one of embodiments 1-82, wherein R 22 It is optionally composed of 1, 2, 3 or 4 independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Substituents of heterocyclic, aryl, heteroaryl, cyano, and nitro groups in -C1-C6 alkyl-R groups 23 .

[0763] 84. A compound of any one of embodiments 1-82, wherein R 22 It is optionally composed of 1, 2, 3 or 4 independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 –C3-C6 alkyl-R substituents of heterocyclic, aryl, heteroaryl, cyano, and nitro groups 23 .

[0764] 85. A compound of any one of embodiments 1-82, wherein R 22 It is optionally composed of 1, 2, 3 or 4 independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -OR 30 -SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 -S(O)2R 31 Bicyclic cycloalkyl groups substituted with heterocyclic, aryl, heteroaryl, cyano, and nitro groups -R 23 .

[0765] 86. A compound of any one of embodiments 1-85, wherein R 23 It is hydrogen.

[0766] 87. A compound of any one of embodiments 1-85, wherein R 23 It's sugar.

[0767] 88. A compound of any one of embodiments 1-85, wherein R 23 Yes - OR 30 .

[0768] 89. A compound of any one of embodiments 1-85, wherein R 23 It is SR 30 -N(R) 30 )2、-C(O)R 31 -S(O)R 31 or -S(O)2R 31 .

[0769] 90. A compound of any one of embodiments 1-89, wherein R 25 It is a C1-C6 alkyl group.

[0770] 91. A compound of any one of embodiments 1-89, wherein R 25 It is hydrogen.

[0771] 92. A compound of any one of embodiments 1-89, wherein R 25 It is halogen.

[0772] 93. A compound of any one of embodiments 1-89, wherein R 25 It is a haloalkyl group.

[0773] 94. A compound of any one of embodiments 1-89, wherein R 25 OR 30 .

[0774] 95. A compound of any one of embodiments 1-89, wherein R 25 It is -O-phenyl.

[0775] 96. A compound of any one of embodiments 1-89, wherein R 25 It's SF5.

[0776] 97. A compound of any one of embodiments 1-96, wherein R 26 yes

[0777] 98. A compound of any one of embodiments 1-96, wherein R 26 Selected from;

[0778]

[0779] 99. A compound of any one of embodiments 1-96, wherein R 26 yes

[0780] 100. A compound of any one of embodiments 1-96, wherein R 26 yes

[0781] 101. A compound of any one of embodiments 1-96, wherein R 26 yes

[0782] 102. A compound of any one of embodiments 1-96, wherein R 26 Selected from;

[0783]

[0784]

[0785] 103. A compound of any one of embodiments 1-102, wherein R 27 yes

[0786] 104. A compound of any one of embodiments 1-102, wherein R 27 yes

[0787] 105. A compound of any one of embodiments 1-102, wherein R 27 yes

[0788] 106. A compound of any one of embodiments 1-105, wherein R 30 It is hydrogen.

[0789] 107. A compound of any one of embodiments 1-105, wherein R 30 It is a C1-C6 alkyl group.

[0790] 108. A compound of any one of embodiments 1-105, wherein R 30 It is a methyl group.

[0791] 109. A compound of any one of embodiments 1-105, wherein R 30 It is a C1-C6 haloalkyl group.

[0792] 110. A compound of any one of embodiments 1-105, wherein R 30 It's CF3.

[0793] 111. A compound of any one of embodiments 1-105, wherein R 30 It is C(O)R 31 .

[0794] 112. A compound of any one of embodiments 1-111, wherein R 31 It is hydrogen.

[0795] 113. A compound according to any one of embodiments 1-111, wherein R 31 It is a C1-C6 alkyl group.

[0796] 114. A compound according to any one of embodiments 1-111, wherein R 31 It is a methyl group.

[0797] 115. A compound according to any one of embodiments 1-111, wherein R 31 It is a C1-C6 haloalkyl group.

[0798] 116. A compound according to any one of embodiments 1-111, wherein R 31 It's CF3.

[0799] 117. A compound of any one of embodiments 1-111, wherein R 31 Yes - OR 32 .

[0800] 118. A compound according to any one of embodiments 1-111, wherein R 31 It is -N(R) 32 )2.

[0801] 119. A compound of any one of embodiments 1-118, wherein R 32 It is hydrogen.

[0802] 120. A compound of any one of embodiments 1-118, wherein R 32 It is a C1-C6 alkyl group.

[0803] 121. A compound of any one of embodiments 1-120, wherein R 33 It is hydrogen.

[0804] 122. A compound of any one of embodiments 1-120, wherein R 33 Independently selected from hydrogen, guanidine, heteroaryl, aryl, -C6H5-OR 30 ;-OR 30 -SR 30 -SeR 30 -N(R) 30 )2 and -C(O)R 31 .

[0805] 123. A compound of any one of embodiments 1-120, wherein R 33 It is guanidine.

[0806] 124. A compound of any one of embodiments 1-120, wherein R 33 Independently selected from hydrogen, guanidine, heteroaryl, aryl, -C6H5-OR 30 ;-OR 30 -SR 30 -SeR 30 -N(R) 30 )2 and -C(O)R 31 .

[0807] 125. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0808]

[0809] Or its pharmaceutically acceptable salt.

[0810] 126. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0811]

[0812] Or its pharmaceutically acceptable salt.

[0813] 127. A compound according to any one of embodiments 1-124, wherein said compound has the following formula;

[0814]

[0815] Or its pharmaceutically acceptable salt.

[0816] 128. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0817]

[0818] Or its pharmaceutically acceptable salt.

[0819] 129. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0820]

[0821] Or its pharmaceutically acceptable salt.

[0822] 130. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0823]

[0824] Or its pharmaceutically acceptable salt.

[0825] 131. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0826]

[0827] Or its pharmaceutically acceptable salt.

[0828] 132. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0829]

[0830] Or its pharmaceutically acceptable salt.

[0831] 133. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0832]

[0833] Or its pharmaceutically acceptable salt.

[0834] 134. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0835]

[0836] Or its pharmaceutically acceptable salt.

[0837] 135. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0838]

[0839] Or its pharmaceutically acceptable salt.

[0840] 136. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0841]

[0842] Or its pharmaceutically acceptable salt.

[0843] 137. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0844]

[0845] Or its pharmaceutically acceptable salt.

[0846] 138. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0847]

[0848] Or its pharmaceutically acceptable salt.

[0849] 139. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0850]

[0851] Or its pharmaceutically acceptable salt.

[0852] 140. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0853]

[0854] Or its pharmaceutically acceptable salt.

[0855] 141. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0856]

[0857] Or its pharmaceutically acceptable salt.

[0858] 142. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0859]

[0860] Or its pharmaceutically acceptable salt.

[0861] 143. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0862]

[0863] Or its pharmaceutically acceptable salt.

[0864] 144. A compound according to any one of embodiments 1-124, wherein said compound has the following formula:

[0865]

[0866] Or its pharmaceutically acceptable salt.

[0867] 145. In some embodiments, the compounds disclosed herein are selected from:

[0868]

[0869]

[0870]

[0871] Or its pharmaceutically acceptable salt.

[0872] 146. In some embodiments, the compounds disclosed herein are selected from:

[0873]

[0874]

[0875]

[0876]

[0877]

[0878]

[0879] Or its pharmaceutically acceptable salt.

[0880] 147. In some embodiments, the compounds disclosed herein are selected from:

[0881]

[0882]

[0883] Or its pharmaceutically acceptable salt.

[0884] 148. In some embodiments, a pharmaceutical composition comprising a compound of any one of embodiments 1-147 and a pharmaceutically acceptable carrier is provided.

[0885] 149. In some embodiments, a method of treating complement-mediated conditions is provided, the method comprising administering to a subject in need a therapeutically effective amount of a compound or pharmaceutical composition thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1-148.

[0886] 150. The method of implementation scheme 149, wherein the subject is a human being.

[0887] 151. The method of implementation scheme 149 or 150, wherein the condition is mediated by C1s.

[0888] 152. The method of any one of implementation schemes 149-151, wherein the condition is C3 glomerular lesion.

[0889] 153. The method of any one of implementation schemes 149-151, wherein the condition is an ophthalmic condition.

[0890] 154. The method of any one of embodiments 149-151, wherein the condition is age-related macular degeneration (AMD).

[0891] 155. The method of any one of implementation schemes 149-151, wherein the condition is paroxysmal nocturnal hemoglobinuria (PNH).

[0892] 156. The method of any one of implementation schemes 149-151, wherein the condition is C3 glomerulonephritis.

[0893] 157. The method of any one of embodiments 149-151, wherein the disease is dense sediment disease.

[0894] 158. The method of any one of implementation schemes 149-151, wherein the condition is angioedema.

[0895] 159. The method of any one of implementation schemes 149-151, wherein the condition is hereditary angioedema.

[0896] 160. The method of any one of implementation schemes 149-151, wherein the condition is autoimmune hemolytic anemia.

[0897] 161. The method of any one of implementation schemes 149-151, wherein the condition is cold agglutinin disease.

[0898] 162. The method of any one of implementation schemes 149-151, wherein the condition is graft rejection.

[0899] 163. The method of any one of Implementation Schemes 149-151, wherein the condition is selected from type 1 hereditary angioedema, type 2 hereditary angioedema, 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, angioedema, acute ACE-induced angioedema, kidney transplantation, and acute kidney injury.

[0900] 164. In some embodiments, a compound of any one of embodiments 1-147 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148, is provided for treating complement-mediated conditions.

[0901] 165. A compound or composition for use in embodiment 164, wherein the subject is a human.

[0902] 166. A compound or composition used in embodiment 164 or 165, wherein the condition is mediated by C1s.

[0903] 167. A compound or composition used in any of embodiments 164-166, wherein the condition is C3 glomerulonephropathy.

[0904] 168. A compound or composition used in any of embodiments 164-166, wherein the condition is an ophthalmic condition.

[0905] 169. A compound or composition for use in any one of embodiments 164-166, wherein the condition is age-related macular degeneration (AMD).

[0906] 170. A compound or composition used in any of embodiments 164-166, wherein the condition is paroxysmal nocturnal hemoglobinuria (PNH).

[0907] 171. A compound or composition used in any of embodiments 164-166, wherein the condition is C3 glomerulonephritis.

[0908] 172. A compound or composition used in any of embodiments 164-166, wherein the condition is dense deposit disease.

[0909] 173. A compound or composition used in any of embodiments 164-166, wherein the condition is angioedema.

[0910] 174. A compound or composition used in any of embodiments 164-166, wherein the condition is hereditary angioedema.

[0911] 175. A compound or composition used in any of embodiments 164-166, wherein the condition is autoimmune hemolytic anemia.

[0912] 176. A compound or composition used in any of embodiments 164-166, wherein the condition is cold agglutinin disease.

[0913] 177. A compound or composition used in any of embodiments 164-166, wherein the condition is graft rejection.

[0914] 178. A compound or composition for use in any one of embodiments 164-166, wherein the condition is selected from type 1 hereditary angioedema, type 2 hereditary angioedema, 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, angioedema, acute ACE-induced angioedema, kidney transplantation, and acute kidney injury.

[0915] 179. In some embodiments, the use of any compound of embodiments 1-147 or a pharmaceutically acceptable salt thereof is provided in the preparation of a medicament for treating complement-mediated conditions.

[0916] 180. Use of embodiment 179, wherein the subject is a human.

[0917] 181. The use of implementation scheme 179 or 180, wherein the condition is mediated by C1s.

[0918] 182. Use of any one of embodiments 179-181, wherein the condition is C3 glomerular lesion.

[0919] 183. The use of any one of embodiments 179-181, wherein the condition is an ophthalmic condition.

[0920] 184. Use of any one of embodiments 179-181, wherein the condition is age-related macular degeneration (AMD).

[0921] 185. Use of any one of embodiments 179-181, wherein the condition is paroxysmal nocturnal hemoglobinuria (PNH).

[0922] 186. Use of any one of embodiments 179-181, wherein the condition is C3 glomerulonephritis.

[0923] 187. Use of any one of embodiments 179-181, wherein the disease is dense sediment disease.

[0924] 188. Use of any one of embodiments 179-181, wherein the condition is angioedema.

[0925] 189. Use of any one of embodiments 179-181, wherein the condition is hereditary angioedema.

[0926] 190. The use of any one of the implementation schemes 179-181, wherein the condition is autoimmune hemolytic anemia.

[0927] 191. Use of any of the embodiments 179-181, wherein the disease is cold agglutinin disease.

[0928] 192. Use of any one of embodiments 179-181, wherein the condition is graft rejection.

[0929] 193. The use of any one of the implementation schemes 179-181, wherein the disease is selected from type 1 hereditary angioedema, type 2 hereditary angioedema, 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, angioedema, acute ACE-induced angioedema, kidney transplantation, and acute kidney injury.

[0930] pharmaceutical preparations

[0931] The active compounds described herein can be administered as pure chemicals to a host in need, but more commonly as pharmaceutical compositions comprising an effective amount of the active compound described herein, or a pharmaceutically acceptable salt, prodrug, isotope analog, N-oxide, or isolated isomer thereof, for a host (typically a human) requiring such treatment. Therefore, in one embodiment, this disclosure provides a pharmaceutical composition for any of the uses described herein, comprising an effective amount of the compound or a pharmaceutically acceptable salt, prodrug, isotope analog, N-oxide, or isolated isomer thereof, and at least one pharmaceutically acceptable carrier. The pharmaceutical composition may contain the compound or its salt as the sole active agent, or, in alternative embodiments, the compound and at least one additional active agent.

[0932] An effective amount of the active compound described herein, or in combination with or alternating with another active agent, or prior to, accompanying, or following the use of another active agent, is sufficient to (a) inhibit the progression of a condition mediated by the complement pathway, including inflammatory, immune (including autoimmune) conditions, or complement-related conditions; (b) resolve inflammatory, immune (including autoimmune) conditions, or complement-related conditions; (c) cure inflammatory, immune (including autoimmune) conditions, or complement-related conditions; or inhibit or prevent the development of inflammatory, immune (including autoimmune) conditions, or complement-related conditions. Therefore, when administered to a patient, an effective amount of the active compound described herein, or a salt or combination thereof, will provide a sufficient amount of active agent to provide clinical benefit.

[0933] The exact amount of the active compound or pharmaceutical composition described herein to be delivered to a host (typically a human) in need will be determined by a healthcare professional to obtain the desired clinical benefit.

[0934] In some embodiments, the pharmaceutical composition is in the form of a unit dosage form containing about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an active compound and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an additional active agent. Examples include 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 an active compound or its salt, N-oxide, isotope analog, or prodrug. In one embodiment, the dosage form comprises 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 an active compound, N-oxide, isotope analog, prodrug, or a salt thereof. The amount of active compound in the dosage form is calculated without reference to the salt. The dosage form may be administered as needed, for example, once daily (qd), twice daily (bid), three times daily (tid), four times daily (qid), every other day (Q2d), every three days (Q3d), or any dosage regimen providing treatment for the condition described herein.

[0935] 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, orally, rectally, as ocular solutions, by injection (including ocular injection), intravenously, intra-aortally, intracranially, subdermally, intraperitoneally, subcutaneously, via the nose, sublingually, intrathecally, or rectally, or by other means, in dosage forms containing conventionally pharmaceutically acceptable carriers. For ocular delivery, the compound may be administered as needed, for example in solution, suspension or other formulation via intravitreal, intrastromal, anterior chamber, subfascial, subretinal, retroocular, periocular, suprachoroidal, subchoroidal, choroidal, conjunctiva, subconjunctival, extrascleral, periocular, transscleral, retroocular, posterior periscleral, pericorneal or lacrimal duct injection or via mucus, mucin or mucosal barrier in an immediate or controlled release manner or via ocular device, injection or topical application formulation (e.g., solution or suspension provided as eye drops).

[0936] Pharmaceutical compositions can be formulated in any pharmaceutically useful form, such as aerosols, creams, gels, gel caps, pills, microparticles, nanoparticles, injectable or infusion solutions, capsules, tablets, syrups, transdermal patches, subcutaneous patches, dry powders, inhaled formulations, in medical devices, suppositories, oral or sublingual formulations, parenteral formulations, or ophthalmic solutions or suspensions. Some dosage forms, such as tablets and capsules, are subdivided into appropriately sized unit doses containing an appropriate amount of the active ingredient, such as an amount effective to achieve the desired purpose.

[0937] 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, 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; 7,404 U.S. Patent Nos. 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.

[0938] The pharmaceutical compositions contemplated herein may optionally include a carrier. The carrier must have sufficiently high purity and sufficiently low toxicity to be suitable for administration to a patient receiving treatment. The carrier may be inert or may have its own pharmaceutical benefits. The amount of carrier used in conjunction with the compound is sufficient to provide the actual amount of substance administered per unit dose of the compound. Categories of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, fillers, flavorings, flow aids, 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 sugars, starches, cellulose, powdered tragacanth gum, malt, gelatin; talc, and vegetable oils.

[0939] 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.

[0940] Examples of drug chelating agents or solubilizers include polyethylene glycol, caffeine, xanthan, gentian acid, and cyclodextrin.

[0941] Examples of disintegrants include sodium carboxyacetic acid starch, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, colloidal silica, and cross-linked sodium carboxymethyl cellulose.

[0942] Examples of binders include methylcellulose, microcrystalline cellulose, starch, and gums such as guar gum and tragacanth gum.

[0943] Examples of lubricants include magnesium stearate and calcium stearate.

[0944] Examples of pH adjusters include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, etc.; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, etc.; and buffers that typically comprise a mixture of an acid and a salt of said acid. Optional other active agents may be included in the pharmaceutical composition, which substantially do not interfere with the activity of the compounds disclosed herein.

[0945] In some 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 contains one or more of the following: glyceryl phosphate; phosphatidylcholine; dipalmitoylphosphatidylcholine (DPPC); dioleoylphosphatidylethanolamine (DOPE); dioleoyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine; cholesterol; cholesterol ester; diacylglycerol; diacylglycerol succinate; diphosphatidylglycerol (DPPG); hexadecyl alcohol; fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; surfactant fatty acids such as palmitic acid or oleic acid; fatty acids; fatty acid monoglycerides; fatty acid diglycerides; fatty acid amides; sorbitol trioleate. Glycocholate; Sorbitol Monolaurate Polysorbate 20 Polysorbate 60 Polysorbate 65 Polysorbate 80 Polysorbate 85 Polyoxyethylene monostearate; Surfactants; Poloxamer; Sorbitol fatty acid esters, such as sorbitol trioleate; Lecithin; Lysophosphatidylserine; Phosphatidylinositol; Sphingomyelin; Phosphatidylethanolamine (cephalin); Cardiolipin; Phosphatidic acid; Cerebrosides; Diceryl phosphate; Dipalmitoylphosphatidylglycerol; Stearamine; Dodecylamine; Hexadecylamine; Acetylpalmitate; Glyceryl castor oil; Hexadecyl stearate; Isopropyl myristate; Tyloxapine; Poly(ethylene glycol) 5000-phosphatidylethanolamine; Poly (Ethylene glycol) 400-monostearate; phospholipids; synthetic and / or natural detergents with high surfactant properties; deoxycholates; cyclodextrins; 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, cyclodextrin, glycogen, hydroxyethyl starch, carrageenan, carrageenan, glycosyl, starch sugar, chitosan, N,O-carboxymethyl chitosan, alginate and alginic acid, starch, chitin, inulin, konjac, glucomannan, lecithin, heparin, hyaluronic acid, gel polysaccharides and xanthan gum, mannitol, sorbitol, xylitol, erythritol, maltitol and lactitol, Pronic polymers, polyethylene, polycarbonate (e.g., poly(1,3-dioxane-2-one)), polyanhydride (e.g., poly(sebacic anhydride)), polyfuric acid Esters, polyamides (e.g., polycaprolactam), polyacetals, polyethers, polyesters (e.g., polylactide, polyglycolic acid, polylactide-co-glycolic acid, polycaprolactone), polyhydroxy acids (e.g., poly((β-hydroxyalkanoate))), poly(orthoester), polycyanoacrylates, polyvinyl alcohol, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polyureas, polystyrene and polyamines, polylysine, polylysine-PEG copolymers and poly(ethyleneimine), poly(ethyleneimine)-PEG copolymers, glycerol monodecanoyl decanoate, propylene glycol, vitamin E TPGS (also known as d-α-tocopherol 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 carboxymethyl cellulose (NaCMC), and hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0946] In some embodiments, the pharmaceutical formulation may include polymers for controlled delivery of the compound, including but not limited to Pluronic polymers, polyesters (e.g., polylactic acid, poly(lactic-co-glycolic acid), polycaprolactone, polyvalerol, poly(1,3-dioxane-2-one)); polyanhydrides (e.g., poly(sebacic anhydride)); polyethers (e.g., polyethylene glycol); polyurethanes; polymethacrylates; polyacrylates; and polycyanoacrylates.

[0947] In some embodiments, the polymer may be modified with polyethylene glycol (PEG), with carbohydrates, and / or with acyclic polyacetals derived from polysaccharides. See, for example, Papisov, 2001, ACS Symposium Series, 786:301, which is incorporated herein by reference.

[0948] The compounds of this disclosure can be formulated as particles. In one embodiment, the particles are or comprise microparticles. In an alternative embodiment, the particles are or comprise nanoparticles.

[0949] In alternative embodiments, common techniques for preparing particles include, but are not limited to, solvent evaporation, solvent removal, spray drying, phase inversion, agglomeration, and cryogenic casting. This document briefly describes suitable methods for particle formulation. Pharmaceutically acceptable excipients may optionally be incorporated into the particles during particle formation, including pH adjusters, disintegrants, preservatives, and antioxidants.

[0950] In one embodiment, particles are obtained by solvent evaporation. In this method, the compounds described herein (or a polymer matrix and one or more of the compounds described herein) are dissolved in a volatile organic solvent such as dichloromethane. The organic solution containing the compounds 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 heating). Nanoparticles of different sizes and morphologies can be obtained by this method.

[0951] Pharmaceutical compositions containing unstable polymers, such as certain polyanhydrides, may degrade during preparation due to the presence of water. For these polymers, granules can be prepared using methods carried out in completely or substantially anhydrous organic solvents.

[0952] Solvent removal can also be used to prepare particles from hydrolyzed unstable compounds. In this method, the compound (or a polymer matrix and one or more compounds) is dispersed or dissolved in a volatile organic solvent such as dichloromethane. This mixture is then suspended in an organic oil (such as silicone oil) by stirring to form an emulsion. Solid particles form from the emulsion, which can then be separated from the supernatant. The external morphology of the spheres produced using this technique is highly dependent on the properties of the drug.

[0953] In one embodiment, the active compound as described herein is administered to a patient in need in the form of particles formed by solvent removal. In another embodiment, this disclosure provides particles formed by solvent removal comprising the compound of this disclosure and one or more pharmaceutically acceptable excipients as defined herein. In another embodiment, particles formed by solvent removal comprise the compound of this disclosure and additional therapeutic agents. In a further embodiment, particles formed by solvent removal comprise the compound of this disclosure, additional therapeutic agents, and one or more pharmaceutically acceptable excipients. In another embodiment, any of the particles formed by solvent removal may be formulated into tablets and then coated to form coated tablets. In an alternative embodiment, particles formed by solvent removal are formulated into tablets, but the tablets are not coated.

[0954] In one embodiment, particles are obtained by spray drying. In this method, a compound (or a polymer matrix and one or more compounds) is dissolved in an organic solvent such as dichloromethane. The solution is pumped through a micronizing nozzle driven by a compressed gas stream, and the resulting aerosol is suspended in a heated air cyclone, causing the solvent to evaporate from the microdroplets, forming particles. This method can be used to obtain microparticles and nanoparticles.

[0955] In one embodiment, the active compound as described herein is administered to a patient in need in the form of a spray-dried dispersion (SDD). In another embodiment, this disclosure provides a spray-dried dispersion (SDD) comprising a compound of this disclosure and one or more pharmaceutically acceptable excipients as defined herein. In another embodiment, the SDD comprises a compound of this disclosure and additional therapeutic agents. In a further embodiment, the SDD comprises a compound of this disclosure, additional therapeutic agents, and one or more pharmaceutically acceptable excipients. In another embodiment, any of the spray-dried dispersions may 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.

[0956] Phase inversion methods can be used to form particles from active compounds as described herein. In this method, a compound (or a polymer matrix and one or more active compounds) is dissolved in a suitable solvent, and the solution is poured into a strong non-solvent to allow the compound to spontaneously generate microparticles or nanoparticles under favorable conditions. This method can be used to produce nanoparticles with a wide size range, including, for example, from nanoparticles to microparticles, typically having a narrow particle size distribution.

[0957] In one embodiment, the active compound as described herein is administered to a patient in need in the form of particles formed via phase inversion. In another embodiment, this disclosure provides particles formed via phase inversion comprising the compound of this disclosure and one or more pharmaceutically acceptable excipients as defined herein. In another embodiment, the particles formed via phase inversion comprise the compound of this disclosure and additional therapeutic agents. In a further embodiment, the particles formed via phase inversion comprise the compound of this disclosure, additional therapeutic agents, and one or more pharmaceutically acceptable excipients. In another embodiment, any of the particles formed via phase inversion may be formulated into tablets and then coated to form coated tablets. In an alternative embodiment, the particles formed via phase inversion are formulated into tablets, but the tablets are not coated.

[0958] Agglomeration-based particle formation techniques are known in the art, for example, as described in GB-B-929406; GB-B-929401; and U.S. Patents 3,266,987; 4,794,000; and 4,460,563. Agglomeration involves separating a solution of a compound (or a polymer matrix and one or more compounds) into two immiscible liquid phases. One phase is a dense, aggregated layer containing a high concentration of said compound, while the second phase contains a low concentration of said compound. Within the dense, aggregated layer, the compound forms nano- or micron-sized droplets that harden into particles. Agglomeration can be induced by temperature changes, the addition of a non-solvent or the addition of a microsalt (simple agglomeration), or by the addition of another polymer to form an interpolymer complex (composite agglomeration).

[0959] In one embodiment, the active compound as described herein is administered to a patient in need in the form of aggregated particles. In another embodiment, this disclosure provides aggregated particles comprising the compound of this disclosure and one or more pharmaceutically acceptable excipients as defined herein. In another embodiment, aggregated particles comprise the compound of this disclosure and additional therapeutic agents. In a further embodiment, aggregated particles comprise the compound of this disclosure, additional therapeutic agents, and one or more pharmaceutically acceptable excipients. In another embodiment, any of the aggregated particles may be formulated into tablets and then coated to form coated tablets. In an alternative embodiment, the aggregated particles are formulated into tablets, but the tablets are not coated.

[0960] A method for casting controlled-release microspheres at very low temperatures is described in U.S. Patent No. 5,019,400 to Gombotz et al. In this method, a compound is dissolved in a solvent. The mixture is then atomized into a container containing a liquid non-solvent at a temperature below the freezing point of the drug solution that would freeze the compound droplets. As the droplets and the non-solvent of the compound are heated, the solvent in the droplets melts and is extracted into the non-solvent, causing the microspheres to harden.

[0961] In one embodiment, the compound of this disclosure is administered to a patient in need in the form of particles formed by cryogenic casting. In another embodiment, this disclosure provides particles formed by cryogenic casting that comprise the compound of this disclosure and one or more pharmaceutically acceptable excipients as defined herein. In another embodiment, the particles formed by cryogenic casting comprise the compound of this disclosure and additional therapeutic agents. In a further embodiment, the particles formed by cryogenic casting comprise the compound of this disclosure, additional therapeutic agents, and one or more pharmaceutically acceptable excipients. In another embodiment, any of the particles formed by cryogenic casting may be formulated into tablets and then coated to form coated tablets. In an alternative embodiment, the particles formed by cryogenic casting are formulated into tablets, but the tablets are not coated.

[0962] In one aspect of this disclosure, an effective amount of the active compound as described herein is incorporated into nanoparticles, for example, to facilitate delivery and / or prolong release delivery. The use of nanoscale materials provides the ability to alter fundamental physical properties, such as solubility, diffusivity, blood circulation half-life, drug release characteristics, and / or immunogenicity. Numerous nanoparticle-based therapeutic and diagnostic agents have been developed for the treatment of cancer, diabetes, pain, asthma, allergies, and infections. These nanoscale agents offer more efficient and / or more convenient routes of administration, lower therapeutic toxicity, extended product lifecycles, and ultimately reduced healthcare costs. As a therapeutic agent delivery system, nanoparticles allow for targeted delivery and controlled release.

[0963] Furthermore, nanoparticle-based compound delivery can be used to release compounds at sustained rates, thereby reducing the frequency of administration; to deliver drugs in a targeted manner to minimize systemic side effects; or to simultaneously deliver two or more drugs for combination therapy to produce synergistic effects and suppress drug resistance. Many nanotechnology-based therapeutic products have been approved for clinical use. Liposomes and polymer-based conjugates constitute a large proportion of these products. See Zhang, L. et al., *Nanoparticles in Medicine: Therapeutic Applications and Developments*, Clin. Pharm. and Ther., 83(5):761-769, 2008.

[0964] Methods for preparing nanoparticles are known in the art. See, for example, Muller, RH et al., Solidlipid 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 granted to Consien et al.; WO 2012 / 145801 under Kanwar; US 8,580,311 granted to Armes, S. et al.; Petros, RA and DeSimone, JM, Strategies in the design of nanoparticles for therapeutic applications, Nature Reviews / Drug Discovery, Vol. 9: 615-627, 2010; US 8,465,775; US 8,444,899; US 8,420,124; US 8,263,129; US 8,158,728; 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 the above references are incorporated herein by reference. Other methods have been described in the literature (see, for example, 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. Patents 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)), US Patent No. 5,543,158 granted to Gref et al. or WO published by Von Andrian et al. WO2009 / 051837; 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) and poly(amide) dendritic polymers (Kukowska-Latallo et al., 1996, Proc. Natl. Acad. Sci., USA, 93:4897; Tang et al., 1996, Bioconjugate Chem., 7:703; Haensler et al., 1993, Bioconjugate Chem., 4:372; Putnam et al., 1999, Macromolecules, 32:3658; Barrera et 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 poly(4-hydroxy-L-proline ester) (Putnam et al., 1999, Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem. Soc.).U.S. Patent Nos. 121:5633; 6,123,727; 5,804,178; 5,770,417; 5,736,372; 5,716,404; 6,095,148; 5,837,752; 5,902,599; 5,696,175; 5,514,378; 5,512,600; 5,399,665; 5,019,379; 5,010,167; 4,806,62 U.S. Patent No. 1; U.S. Patent Nos. 4,638,045 and 4,946,929; Wang et al., 2001, J. Am. Chem. Soc., 123:9480; Lim et al., 2001, J. Am. Chem. Soc., 123:2460; Langer, 2000, Acc. Chem. Res., 33:94; Langer, 1999, J. Control. Release, 62:7; and Uhrich et al., 1999, Chem. Rev., 99:3181; Concise Encyclopedia of Polymer Science and Polymeric Amines and Ammonium Salts, ed. Goethals, Pergamon Press, 1980; Principles of Polymerization, ed. Odian, John Wiley & Sons, 4th ed., 2004; Contemporary Polymer Chemistry, ed. Allcock et al., Prentice-Hall, 1981; Deming et al., 1997, Nature, 390:386; and U.S. Patents 6,506,577, 6,632,922, 6,686,446 and 6,818,732; C. Astete et al., “Synthesis and characterization of PLGA nanoparticles” J. Biomother. 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. Patent No. 6,632,671 to Unger, granted on October 14, 2003, are all incorporated herein by reference.

[0965] In one embodiment, the polymer particles are between about 0.1 nm and about 10,000 nm, about 1 nm and about 1,000 nm, about 10 nm and 1,000 nm, about 1 nm and 100 nm, about 1 nm and 10 nm, about 1 nm and 50 nm, about 100 nm and 800 nm, about 400 nm and 600 nm, or about 500 nm. In one embodiment, the microparticles have a size not exceeding 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 may be covalently coupled to polymers used in the nanoparticles, such as polystyrene particles, PLGA particles, PLA particles, or other nanoparticles.

[0966] The pharmaceutical compositions according to this disclosure can be formulated for oral administration. These compositions may contain any amount of the active compound to achieve the desired results, such as between 0.1 and 99 wt.%, and typically at least about 5 wt.%. Some embodiments contain at least about 10%, 15%, 20%, 25 wt.% to about 50 wt.%, or about 5 wt.% to about 75 wt.%.

[0967] Pharmaceutical compositions suitable for rectal administration are typically in the form of unit-dose suppositories. These are prepared by blending the active compound with one or more conventional solid carriers (e.g., cocoa butter) and then molding the resulting mixture.

[0968] Pharmaceutical compositions suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils. Carriers that may be used include petrolatum, lanolin, polyethylene glycol, alcohols, transdermal penetration enhancers, and combinations of two or more of these.

[0969] Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches adapted to maintain close contact with the recipient's epidermis for an extended period of time. Pharmaceutical compositions suitable for transdermal administration can also be delivered via iontophoresis (see, for example, Pharmaceutical Research 3(6):318(1986)) and are typically in the form of optionally buffered aqueous solutions of the active compound. In one embodiment, a microneedle patch or device is provided for delivering a drug through or into biological tissue, particularly the skin. The microneedle patch or device allows for drug delivery across or into the skin or other tissue barriers at clinically relevant rates with minimal or no damage, pain, or irritation to the tissue.

[0970] Suitable pharmaceutical compositions for pulmonary administration can be delivered via a wide range of passively driven and actively powered single / multi-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 mesh nebulizers. The selection of a suitable pulmonary delivery device depends on a variety of parameters, such as the nature of the drug and its formulation, the site of action, and the pathophysiology of the lungs.

[0971] Further non-limiting examples of inhaled drug delivery devices and methods include, for example, US 7,383,837 entitled "Inhalation Device" (SmithKline Beecham Corporation); WO / 2006 / 033584 entitled "Powder Inhaler" (Glaxo SmithKline Pharmaceuticals SA); WO / 2005 / 044186 entitled "Inhalable Pharmaceutical Formulations Employing Desiccating Agents and Methods of Administering the Same" (Glaxo Group Ltd and SmithKline Beecham Corporation); US 9,095,670 entitled "Inhalation Device and Method of Dispensing Medicament"; US 8,205,611 entitled "Dry Powder Inhaler" (Astrazeneca AB); and WO / 2013 / 038170 entitled "Inhaler" (Astrazeneca AB). AB and AstraZeneca UK Ltd.); US / 2014 / 0352690 entitled "Inhalation Device with Feedback System", US 8,910,625 entitled "Inhalation Device for Use in Aerosol Therapy" and US / 2015 / 0165137 (Vectura GmbH);US 6,948,496, titled "Inhalers"; US / 2005 / 0152849, titled "Powders Comprising Anti-adherent Materials for Use in Dry Powder Inhalers"; US 6,582,678, US 8,137,657, US / 2003 / 0202944, and US / 2010 / 0330188, titled "Carrier Particles for Use in Dry Powder Inhalers"; US 6,221,338, titled "Method of Producing Particles for Use in Dry Powder Inhalers"; US 6,989,155, titled "Powders"; and US 6,989,155, titled "Pharmaceutical Compositions for Treating Premature Ejaculation by..." US / 2007 / 0043030, titled "Pulmonary Inhalation"; US 7,845,349, titled "Inhaler"; US / 2012 / 0114709 and US 8,101,160, titled "Formulations for Use in Inhaler Devices"; US / 2013 / 0287854, titled "Compositions and Uses"; US / 2014 / 0037737 and US 8,580,306, titled "Particles for Use in a Pharmaceutical Composition"; US / 2015 / 0174343, titled "Mixing Channel for an Inhalation Device"; US 7,744,855 and US / 2010 / 0285142, titled "Method of Making Particles for Use in a Pharmaceutical Composition"; and US / 2010 / 0285142, titled "Pharmaceutical Formulations for..." Dry Powder Inhalers” US 7,541,022, US / 2009 / 0269412 and US / 2015 / 0050350 (Vectura Limited).;

[0972] Many methods and devices for delivering drugs to the eye are known in the art. The following patents and patent applications (incorporated in their entirety) describe non-limiting examples: US 8,192,408 (Psivida Us, Inc.) entitled “Ocular trocarassembly”; US 7,585,517 (Macusight, Inc.) entitled “Transcleral delivery”; US 5,710,182 and US 5,795,913 (Santen OY) entitled “Ophthalmic composition”; US 8,663,639 entitled “Formulations for treating ocular diseases and conditions”; US 8,486,960 entitled “Formulations and methods for vascularpermeability-related diseases or conditions”; US 8,367,097 and US 8,927,005 entitled “Liquidformulations for treatment of diseases or conditions”; and US 8,367,097 and US 8,927,005 entitled “Delivering substance and drug delivery system using the US 7,455,855 (Santen Pharmaceutical Co., Ltd.) titled "same"; WO / 2011 / 050365 titled "Conformable TherapeuticShield For Vision and Pain" and WO / 2009 / 145842 titled "Therapeutic Device for Pain Management and Vision" (Forsight Labs, LLC); US 9,066,779 and US 8,623,395 titled "Implantable therapeutic device"; WO / 2014 / 160884 titled "Ophthalmic Implant for Delivering Therapeutic Substances"; and US 8,399,006, US 8,277,830, US 8,795,712, and US 8,808 titled "Posterior segment drug delivery".727, US 8,298,578 and WO / 2010 / 088548, WO / 2014 / 152959 and US20140276482 entitled "Systems for Sustained Intraocular Delivery of Low Solubility Compounds from a Port Delivery System Implant", US 8,905,963 and US 9,033,911 entitled "Injector apparatus and method for drug delivery", WO / 2015 / 057554 entitled "Formulations and Methods for Increasing or Reducing Mucus", and US 8,715,712 and US 8,939 entitled "Ocular insert apparatus and methods".948. 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 Treatment of Ocular Pain"; and WO / 2011 / 050327, titled "Small Molecule Delivery with Implantable Therapeutic Device". The following are listed as relevant publications: WO / 2013 / 022801 ("Device"), WO / 2012 / 019047 ("Subconjunctival Implant for Posterior Segment Drug Delivery"), WO / 2012 / 068549 ("Therapeutic Agent Formulations for Implanted Devices"), WO / 2012 / 019139 ("Combined Delivery Methods and Apparatus"), WO / 2013 / 040426 ("Ocular Insert Apparatus and Methods"), WO / 2012 / 019136 ("Injector Apparatus and Method for Drug Delivery"), and WO / 2013 / 040247 ("Fluid Exchange Apparatus and Methods") (ForSight Vision4, Inc.).

[0973] The following are additional non-limiting examples of how to deliver active compounds: WO / 2015 / 085251 (Envisia Therapeutics, Inc.) entitled “Intracameral Implant for Treatment of an Ocular Condition”; WO / 2011 / 008737 (Envisia Therapeutics, Inc.) entitled “Engineered Aerosol Particles, and Associated Methods”; WO / 2013 / 082111 (Geometrically Engineered Particles and Methods for Modulating Macrophage or Immune Responses) entitled “Degradable compounds and methods of use thereof, particularly with particle replication in non-wetting templates”; WO / 2009 / 132265 (Interventional drug delivery system and associated methods) entitled “Polymer particle composite having high fidelity order, size, and WO / 2008 / 100304 titled "Nanoparticle fabrication methods, systems, and materials" (Liquidia Technologies, Inc. and the University of North Carolina at Chapel Hill); WO / 2010 / 009087 (Liquidia) titled "Iontophoretic Delivery of a Controlled-Release Formulation in the Eye" Technologies, Inc. and Eyegate Pharmaceuticals, Inc.The following are relevant legal documents: 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 device, 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.).

[0974] Other non-limiting examples of drug delivery to the eye include, for example, WO2011 / 106702 and US 8,889,193 entitled “Sustained delivery of therapeutic agents to an eye compartment”, WO2013 / 138343 and US 8,962,577 entitled “Controlled release formulations for the delivery of HIF-1 inhibitors”, WO / 2013 / 138346 and US2013 / 0272994 entitled “Non-Linear Multiblock Copolymer-Drug Conjugates for the Delivery of Active Agents”, and WO2005 / 072710 and US 8,957 entitled “Drug and Gene Carrier Particles that Rapidly Move Through Mucus Barriers”.034. Titles: “Compositions and Methods for Enhancing Transport Through Mucous” (WO2008 / 030557, US2010 / 0215580, US2013 / 0164343); “Compositions and Methods Relating to Reduced Mucoadhesion” (WO2012 / 061703, US2012 / 0121718, US2013 / 0236556); “Rapid Diffusion of Large Polymeric Nanoparticles in the Mammalian Brain” (WO2012 / 039979, US2013 / 0183244); “Mucus Penetrating Gene Carriers” (WO2012 / 109363, US2013 / 0323313); “Nanoparticles with enhanced mucosal penetration or decreased” WO 2013 / 090804 and US2014 / 0329913, titled "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"; and US2013 / 0323179, titled "Nanocrystals, Compositions, and Methods that Aid Particle Transport in Mucus" (The Johns Hopkins University and Kala Pharmaceuticals).Kala Pharmaceuticals, Inc.; WO / 2015 / 066444 entitled "Compositions and methods for ophthalmic and / or other applications"; WO / 2014 / 020210 and WO / 2013 / 166408 entitled "Pharmaceutical nanoparticles showing improved mucosal transport"; US 9,022,970 entitled "Ophthalmic injection device including dosage control device"; WO / 2011 / 153349 entitled "Ophthalmic compositions comprising pbo-peo-pbo block copolymers"; WO / 2011 / 140203 entitled "Stabilized ophthalmic galactomannan formulations"; WO / 2011 / 068955 entitled "Ophthalmic emulsion"; and WO / 2011 / 068955 entitled "Injectable aqueous ophthalmic composition and method of use". The following patents are relevant to drug delivery: WO / 2011 / 037908 ("therefor"), US2007 / 0149593 ("Pharmaceutical Formulation for Delivery of Receptor Tyrosine Kinase Inhibiting (RTKi) Compounds to the Eye"), and US 8,632,809 (Alcon, Inc.) ("Water insoluble polymer matrix for drug delivery").

[0975] Other non-limiting examples of drug delivery devices and methods include, for example, US 2009 / 0203709 (Abbott Laboratories) entitled “Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor”; US 2005 / 0009910 entitled “Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of aprodrug”; US 20130071349 entitled “Biodegradable polymers for lowering intraocular pressure”; US 8,481,069 entitled “Tyrosine kinase microspheres”; US 8,465,778 entitled “Method of making tyrosine kinase microspheres”; and US 8,465,778 entitled “Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods”. US 8,409,607, US 8,512,738 and US 2014 / 0031408, titled "Biodegradable intravitreal tyrosine kinase implants"; US 2014 / 0294986, titled "Microsphere Drug Delivery System for Sustained Intraocular Release"; US 8,911,768 (Allergan, Inc.), titled "Methods For Treating Retinopathy With Extended Therapeutic Effect"; and US 6,495,164 (Alkermes Controlled Therapeutics, Inc.), titled "Preparation of injectable suspensions having improved injectability".);WO 2014 / 047439 (Akina, Inc.) with the title "Biodegradable Microcapsules Containing Filling Material"; WO 2010 / 132664 (Baxter International Inc., Baxter Healthcare SA) with the title "Compositions And Methods For Drug Delivery"; US 2012 / 0052041 (The Brigham and Women’s Hospital, Inc.) with the title "Polymeric nanoparticles with enhanced drug loading and methods of use thereof"; US 2014 / 0178475, US 2014 / 0248358 and US 20140249158 (BIND Therapeutics, Inc.) with the title "Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same"; "Polymer microparticles for drug delivery" (Danbiosyst UK Ltd.US 5,869,103, titled "Pegylated Nanoparticles"; US 8628801 (Universidad de Navarra), titled "Ocular drug delivery system"; US 2014 / 0107025 (Jade Therapeutics, LLC), titled "Agent delivering system comprised of microparticles and biodegradable gel with an improved releasing profile and methods of use thereof"; US 6,287,588, titled "Agent delivering system comprised of microparticles within a biodegradable to improve release profiles"; US 6,589,549 (Macromed, Inc.), titled "Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles"; and US 6,007,845 and US 5,578,325 (Massachusetts Institute of Technology), titled "Nanoparticles and microparticles of non-linear hydrophilichydrophobic multiblock copolymers". Technology), US 2004 / 0234611, US 2008 / 0305172, US 2012 / 0269894 and US20130122064 (Novartis Ag) entitled "Ophthalmic depot formulations for periocular or subconjunctival administration"; US 6,413,539 (Poly-Med, Inc.) entitled "Block polymer".The following are relevant patents: US 2007 / 0071756 (Peyman) titled "Delivery of an agent to ameliorate inflammation"; US 20080166411 (Pfizer, Inc.) titled "Injectable Depot Formulations And Methods For Providing Sustained Release Of Poorly Soluble Drugs Comprising Nanoparticles"; US 6,706,289 (PR Pharmaceuticals, Inc.) titled "Methods and compositions for enhanced delivery of bioactive molecules"; and US 8,663,674 (Surmodics) titled "Microparticle containing matrices for drug delivery".

[0976] Use of active compounds to treat selected conditions

[0977] On one hand, effective amounts of the active compound or its salt or composition as described herein are used to treat medical conditions, which are inflammatory or immune symptoms, conditions mediated by complement cascades (including dysfunctional cascades) (including complement-related conditions or conditions related to alternative complement pathways), cellular conditions that adversely affect the ability of cells to participate in or respond to normal complement activity, or abnormal or undesirable complement-mediated responses to medical treatments (such as surgery or other medical procedures or administration of drugs or biological agents, blood transfusions or other allogeneic tissue or fluid administration).

[0978] Complement-mediated diseases or conditions are those in which the amount or activity of complement causes an individual's disease or condition.

[0979] In some implementations, complement-mediated diseases or conditions are selected from the group consisting of autoimmune diseases, cancer, hematological diseases, infectious diseases, inflammatory diseases, ischemia-reperfusion injury, neurodegenerative diseases, neurodegenerative conditions, eye diseases, kidney diseases, graft rejection, vascular diseases, and vasculitis.

[0980] In some implementations, complement-mediated diseases or conditions are autoimmune diseases. In some implementations, complement-mediated diseases or conditions are cancer.

[0981] In some implementation schemes, complement-mediated diseases or conditions are infectious diseases.

[0982] In some implementations, complement-mediated diseases or conditions are inflammatory diseases.

[0983] In some implementations, complement-mediated diseases or conditions are hematological disorders.

[0984] In some implementations, complement-mediated disease or condition is local ischemia-reperfusion injury.

[0985] In some implementations, the complement-mediated disease or condition is an eye disease. In some implementations, the complement-mediated disease or condition is a kidney disease.

[0986] In some implementations, complement-mediated disease or condition is graft rejection.

[0987] In some implementations, complement-mediated disease or condition is antibody-mediated graft rejection.

[0988] In some implementations, complement-mediated diseases or conditions are vascular diseases.

[0989] In some implementations, complement-mediated diseases or conditions are vasculitis.

[0990] In some implementations, complement-mediated diseases or conditions are neurodegenerative diseases or conditions.

[0991] In some implementations, complement-mediated diseases are neurodegenerative diseases.

[0992] In some implementations, the complement-mediated condition is a neurodegenerative disease. In some implementations, the complement-mediated disease or condition is tau proteinosis.

[0993] In some respects, an effective amount of the active compound described herein or a pharmaceutically acceptable salt thereof is used to treat medical conditions of the central nervous system (CNS) or peripheral nervous system conditions involving complement activation. In several embodiments, the CNS condition is acquired brain or spinal cord injury, including but not limited to ischemia-reperfusion injury or stroke, traumatic brain injury (TBI), and spinal cord injury (SCI).

[0994] In several implementations, the condition is a neurodegenerative condition. In several implementations, the condition is a neuroinflammatory condition.

[0995] In some respects, the active compounds described herein, or pharmaceutically acceptable salts thereof, are used to treat Alzheimer's disease (AD). AD is characterized by two hallmark pathologies: amyloid-β (Aβ) plaques and neurofibrillary tangles containing hyperphosphorylated tau. Recent research has involved complement in the pathogenesis of AD, including genome-wide association studies that have identified single nucleotide polymorphisms (SNPs) in genes encoding complement protein clustering protein (CLU) and CR1 (CR1) that are associated with the risk of late-onset AD. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., March 4, 2019. Biomarker studies have also identified complement proteins and activating products in plasma and / or CSF that distinguish AD from controls and predict the risk of progression to AD. (Id.)

[0996] In some respects, effective amounts of the active compounds described herein or pharmaceutically acceptable salts thereof are used to treat certain forms of frontotemporal dementia, including but not limited to Pick's disease, sporadic frontotemporal dementia and frontotemporal dementia with Parkinson's disease associated with chromosome 17, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and subacute sclerosing panencephalitis.

[0997] In some respects, effective amounts of the active compounds described herein or pharmaceutically acceptable salts thereof are used to treat multiple sclerosis (MS). Multiple sclerosis (MS) is the most common cause of neurological dysfunction in young people in the Nordic-Caucasian population, with a lifetime risk of approximately 1 in 400. C3 deposition has been shown in the brains of MS patients. T cell clones (TCCs) have been shown to be associated with capillary endothelial cells, primarily within plaques and adjacent to white matter. C activation has also been shown to localize to areas of active myelin destruction, with TCCs depositing only in such areas. C3d has been shown to be associated with short segments of destroyed myelin in plaques with low-grade active demyelination, and provides evidence that C contributes 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.

[0998] In some respects, effective amounts of the active compound described herein or pharmaceutically acceptable salts thereof are used to treat neuromyelitis optica (NMO). Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that primarily affects the optic nerve and spinal cord. It has traditionally been considered a variant of MS, but has recently been redefined according to new criteria using a combination of phenotypic subtyping and the newly developed disease biomarker NMO-immunoglobulin G (IgG) (sensitivity for NMO reporting is 58–76%, and specificity is 85–99%). NMO patients have higher levels of C3a and anti-C1q antibodies than healthy controls. C3a levels are associated with disease activity, neurological dysfunction, and aquaporin-4 IgG. Nytrova et al., Complement activation inpatients with neuromyelitis optica. J Neuroimmunol. 2014 Sep 15; 274(1-2):185-91.

[0999] In some respects, effective amounts of the active compounds described herein or their pharmaceutically acceptable salts are used to treat amyotrophic lateral sclerosis (ALS). ALS is caused by the progressive loss of upper and lower (α) motor neurons, leading to denervation 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 post-ALS tissue; C3 activation fragments and TCC in pathological regions; C4d and TCC staining in degenerated neurons and glial cells in the motor cortex and spinal cord of ALS, and upregulation of C5aR1 in pathological regions. C3d and C4d have been found on oligodendrocytes and degenerated neurites in the spinal cord and motor cortex, surrounded by CR4-positive microglia, and C1q, C3, and TCC have been shown to be present even in the motor endplates of the intercostal muscles in ALS donors, even in the early stages of the disease process. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., March 4, 2019.

[1000] In some respects, effective amounts of the active compounds described herein or pharmaceutically acceptable salts thereof are 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, a protein that forms the Lewy body, a pathological marker of the disease. Patients present with resting tremor, bradykinesia, and rigidity. Complement activation is associated with α-synuclein and the Lewy body in Parkinson's disease; in vitro studies have shown that the disease-associated splice variant α-synuclein 112, rather than the full-length protein, causes complement activation. In vivo, the localization of C3d, C4d, C7, and C9 in the Lewy body has been reported. Recently, the deposition of iC3b and C9 in the Lewy body and substantia nigra neurons has been reported, and iC3b immunoreactivity has been shown to increase with normal aging and to be further elevated in PD compared to age-matched controls. Furthermore, the ratio of C3 / Aβ42 or FH / Aβ42 in the CSF has been shown to be correlated with 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., March 4, 2019. In some implementations, the subjects to be treated have Parkinson's disease with dementia (PDD).

[1001] In some respects, effective amounts of the active compound described herein or pharmaceutically acceptable salts thereof are used to treat Huntington's disease (HD). HD is an autosomal dominant inherited neurodegenerative disease characterized by progressive motor symptoms, psychiatric disorders, and dementia. It is caused by the amplification of the triple-base-pair (CAG) repeat sequence (39–121 repeats compared to the normal range of 8–39 repeats) in exon 1 of the HTT gene, which is translated into polyglutamine bundles at the N-terminus of the protein. This leads to polyglutamine length-dependent misfolding and accumulation of huntingtin in the striatum and cortex (layers 3, 5, and 6), followed by neuronal loss in these regions, which then spreads to the hippocampus. Studies have shown that neurons, astrocytes, and myelin sheaths in the caudate nucleus and striatum of HD are immunoreactive to C1q, C4, C3, and neoepitopes in iC3b and TCC. Expression of mRNAs encoding early complement components C1q (c-chain), C1r, C3 and C4, complement regulator C1INH, cluster protein, MCP, DAF and CD59, and complement receptors C3a and C5a has been shown to be upregulated in the HD striatum. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., March 4, 2019.

[1002] In some respects, effective amounts of the active compound described herein or pharmaceutically acceptable salts thereof are used to treat aerophilic granule dementia, British amyloid angiopathy, cerebral amyloid angiopathy, Creutzfeldt-Jakob disease, boxer's dementia, diffuse neurofibrillary tangles with calcification, Down syndrome, frontotemporal degeneration, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, inclusion body myositis, multiple system atrophy (MSA), myotonic dystrophy, Niemann-Pick type C disease, and non-Guamanian motor neuron disease with neurofibrillary tangles. Tangles, post-encephalitis Parkinson's disease, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, simple tangles dementia, multi-infarct dementia, ischemic stroke, chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), and stroke.

[1003] In some respects, effective amounts of the active compound described herein or a pharmaceutically acceptable salt thereof are used to treat hereditary motor and sensory neuropathy (HMSN).

[1004] In some implementations, the hereditary and sensory neuropathy is Chuck-Mali-Dus (CMT) disease.

[1005] In some implementations, HSMN is type 1A or type 1B Charcot–Marie–Tooth disease.

[1006] In some implementations, HSMN is Chuck-Mally-Dus disease type 2.

[1007] In some implementations, HSMN stands for Dejerine–Sottas disease (type 3 Chuck-Mali-Dus disease).

[1008] In some implementations, HSMN stands for Refsum disease.

[1009] In some embodiments, HSMN is Chuck-Mali-Dus disease with cone features. In some embodiments, HSMN is Chuck-Mali-Dus disease type 6. In some embodiments, HSMN is HMSN+ retinitis pigmentosa.

[1010] In some implementations, an effective amount of the active compound described herein or a pharmaceutically acceptable salt thereof is used to treat Churg-Strauss syndrome.

[1011] In some implementations, an effective amount of the active compound described herein or a pharmaceutically acceptable salt thereof is used to treat peripheral artery disease (PAD).

[1012] In some respects, effective amounts of the active compound described herein or its pharmaceutically acceptable salts are used to treat myasthenia gravis affecting the CNS.

[1013] In some respects, effective amounts of the active compound described herein or its pharmaceutically acceptable salts are used to treat Lewy body dementia.

[1014] In some respects, effective amounts of the active compound described herein or its pharmaceutically acceptable salts may be used to treat individuals suffering from prion diseases.

[1015] In some respects, effective amounts of the active compound described herein or its pharmaceutically acceptable salts are used to treat Behcet's disease.

[1016] In some respects, effective amounts of the active compound described herein or its pharmaceutically acceptable salts are used to treat congenital myasthenia gravis.

[1017] In some respects, effective amounts of the active compound described herein or its pharmaceutically acceptable salts are used to treat subacute sclerosing panencephalitis (SSPE).

[1018] In some respects, effective amounts of the active compound described herein or its pharmaceutically acceptable salts are used to treat Guillain-Barré syndrome.

[1019] In some respects, the CNS conditions to be treated are demyelinating diseases, including but not limited to demyelinating myelin cell diseases and leukostrophic diseases.

[1020] In some respects, the CNS conditions to be treated are demyelinating myeloid cleavage diseases, including but not limited to multiple sclerosis, neuromyelitis optica, neuromyelitis optica spectrum disorders (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); McDonalds-positive multiple sclerosis, acute hemorrhagic leukoencephalitis, Rasmussen's encephalitis, Marburg multiple sclerosis, pseudoswelling and edematous multiple sclerosis, and Balo concentric sclerosis. Multiple sclerosis (concentric sclerosis), diffuse myelin rupture sclerosis, solitary sclerosis, multiple sclerosis with cavitation, myelocortical multiple sclerosis (MCMS), atypical opto-spinal multiple sclerosis, simple spinal multiple sclerosis, HLA DRB3*02:02 Multiple sclerosis, autoimmune GFAP astrocytopathy, chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barré syndrome, progressive inflammatory neuropathy, Lewis-Sumner syndrome, combined central and peripheral demyelination (CCPD), Bickerstaff brainstem encephalitis, Fisher syndrome, trigeminal neuralgia, NMDAR anti-NMDA receptor encephalitis, primary progressive MS (PPMS), OPA1 variant multiple sclerosis, KIR4.1 multiple sclerosis, aquaporin-associated multiple sclerosis, chronic cerebrospinal venous insufficiency (CCSVI or CCVI), diffuse sclerosis, and Schilder's disease.

[1021] In some respects, the conditions to be treated are demyelinating leukodystrophy, including but not limited to myelitis, central pontine myelinolysis (CPM), extrapontine myelinolysis, tabes dorsalis, progressive multifocal leukoencephalopathy, leukoencephalopathy with white matter loss, axonoglobulin leukoencephalopathy, reversible postleukoencephalopathy syndrome, megalencephalopathy with subcortical cysts, megalencephalopathy with subcortical cysts, hypertensive leukoencephalopathy, metachromatic leukodystrophy, Krabbe disease, Canavan disease, X-linked adrenoleukodystrophy, Alexander disease, cerebral tendinous xanthomas, Pelizaeus–Merzbacher disease, and Rifsum disease.

[1022] In some implementations, an effective amount of the active compound described herein or a pharmaceutically acceptable salt thereof is used to treat Buerger's disease, also known as thromboangiitis obliterans.

[1023] In some implementations, an effective amount of the active compound described herein or a pharmaceutically acceptable salt thereof is used to treat giant cell arteritis.

[1024] In some embodiments, an effective amount of the active compound described herein or a pharmaceutically acceptable salt thereof is used to treat Raynaud's disease.

[1025] In some respects, the CNS conditions to be treated are demyelinating diseases of the peripheral nervous system, including but not limited to Guillain-Barré syndrome and its chronic counterparts, chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy, Chuck-Maly-Dus disease and its counterparts, hereditary neuropathy with a tendency to compressive paralysis, copper deficiency-related conditions (peripheral neuropathy, spinal cord lesions, and rare optic neuropathy), and progressive inflammatory neuropathy.

[1026] In some respects, the CNS conditions to be treated are neuroinflammatory conditions. In some implementations, the conditions to be treated include, but are not limited to, cranial arteritis; giant cell arteritis; Holmes-Adie syndrome; inclusion body myositis (IBM); meningitis; neuroparaneoplastic syndromes, including but not limited to Lambert-Eton myasthenia gravis, stiff-person syndrome, encephalomyelitis (inflammation of the brain and spinal cord), myasthenia gravis, cerebellar degeneration, limbic and / or brainstem encephalitis, neurogenic myotonia and oculoclonus (involving eye movements) and sensory neuropathy; polymyositis; transverse myelitis; vasculitis, including temporal arteritis; arachnoiditis; Kingsburn syndrome or oculoclonus-myoclonus syndrome (OMS); or Saint Vitus Dance or Sydenham chorea (SD).

[1027] In some implementations, an effective amount of the active compound described herein or a pharmaceutically acceptable salt thereof is used to treat transverse myelitis.

[1028] In some embodiments, the CNS condition to be treated is peripheral neuropathy. In some implementations, peripheral neuropathy is mononeuropathy. In some implementations, neuropathy is polyneuropathy. In some implementations, polyneuropathy is distal axonal lesion, diabetic neuropathy, demyelinating polyneuropathy, small fiber peripheral neuropathy, polyneuritis, polyneuropathy, autonomic neuropathy, or neuritis.

[1029] In some embodiments, an effective amount of the active compound described herein or a pharmaceutically acceptable salt thereof is used to treat autoimmune vascular diseases. 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, granulomatous disease with polyangiitis, eosinophilic granulomatous disease with polyangiitis, Behcet's disease, Kawasaki disease, Burger's disease, and "localized" granulomatous disease with polyangiitis.

[1030] In some embodiments, the active compound or its salt or composition as described herein is used to treat arteritis. In some embodiments, arteritis includes, but is not limited to, giant cell arteritis, Takayasuarteritis, temporal arteritis, and polyarteritis nodosa.

[1031] In some embodiments, methods for treating glomerulonephritis are provided. In some embodiments, the glomerulonephritis is membranoproliferative glomerulonephritis (MPGN). In some embodiments, MPGN is type I MPGN. In some embodiments, MPGN is type II MPGN. In some embodiments, MPGN is type III MPGN. In some embodiments, MPGN is C3 glomerulonephritis (C3G). In some embodiments, MPGN is dense deposit disease (DDD). In some embodiments, MPGN is C4 deposit disease.

[1032] In some embodiments, glomerulonephritis is IC-MPGN. In some embodiments, glomerulonephritis is membranous glomerulonephritis. In some embodiments, glomerulonephritis is IgA nephropathy. In some embodiments, glomerulonephritis is post-infectious glomerulonephritis. In some embodiments, glomerulonephritis is rapidly progressive glomerulonephritis, such as type I (Goodpassuia syndrome), type II, or type III rapidly progressive glomerulonephritis.

[1033] In some embodiments, a method for treating paroxysmal nocturnal hemoglobinuria (PNH) is provided, comprising administering to the 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 pharmaceutically acceptable salt, prodrug, isotope analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition.

[1034] In some embodiments, a method for treating hereditary angioedema (HAE) is provided, comprising administering to a host an effective amount, optionally in a pharmaceutically acceptable composition, 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 pharmaceutically acceptable salt, prodrug, isotope analog, N-oxide, or isolated isomer thereof. Mutations in the SERPING1 gene cause type I and type II hereditary angioedema. Hereditary angioedema is a condition characterized by recurrent episodes of severe swelling (angioedema). The most common areas of swelling in the body are the extremities, face, intestines, and airways. The SERPING1 gene provides instructions for the production of C1 inhibitor proteins, which are important for controlling inflammation. C1 inhibitors block the activity of certain pro-inflammatory proteins. Mutations causing type I hereditary angioedema result in decreased levels of C1 inhibitors in the blood, while mutations causing type II result in the production of dysfunctional C1 inhibitors. In the absence of adequate levels of functional C1 inhibitors, an excess of protein fragments (peptides) called bradykinin is produced. Bradykinin promotes inflammation by increasing the leakage of fluid through the blood vessel walls into body tissues. This excessive accumulation of fluid in body tissues leads to flare-ups of swelling seen in individuals with type I and type II hereditary angioedema.

[1035] In some embodiments, a method for treating cold agglutinin disease (CAD) is provided, comprising administering to the 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 pharmaceutically acceptable salt, prodrug, isotope analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition. CAD is a rare autoimmune hemolytic disease with potentially severe acute and chronic consequences driven by C1 activation of the classical complement pathway.

[1036] In some implementations, methods for treating atypical hemolytic uremic syndrome (aHUS) are provided, comprising administering to the 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 pharmaceutically acceptable salt, prodrug, isotope analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition. Atypical hemolytic uremic syndrome is a disease that primarily affects renal function. It can occur at any age and results in the formation of abnormal blood clots (thrombi) in the small blood vessels of the kidneys. If these clots restrict or obstruct blood flow, they can lead to serious medical problems. Atypical hemolytic uremic syndrome is characterized by three main features associated with abnormal coagulation: hemolytic anemia, thrombocytopenia, and renal failure.

[1037] In another embodiment, a method of treating a host for wet or dry age-related macular degeneration (AMD) is provided, comprising administering an effective amount, optionally in a pharmaceutically acceptable composition, 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 pharmaceutically acceptable salt, prodrug, isotope analog, N-oxide, or isolated isomer thereof. In another embodiment, a method of treating a host for rheumatoid arthritis is provided, comprising administering an effective amount, optionally in a pharmaceutically acceptable composition, 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 pharmaceutically acceptable salt, prodrug, isotope analog, N-oxide, or isolated isomer thereof.

[1038] In another embodiment, a method of treating multiple sclerosis in a host is provided, 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 pharmaceutically acceptable salt, prodrug, isotope analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition.

[1039] The active compound, or its pharmaceutically acceptable salt, prodrug, isotope analog, N-oxide, or isolated isomer, which may be optionally included in a pharmaceutically acceptable composition as disclosed herein, may also be used in combination with or alternately with a second agent (in the same or different dosage form) to reduce or mitigate the side effects of the second agent.

[1040] For example, in some implementations, the active compound may be used in combination with adoptive cell transfer therapy to reduce inflammatory responses associated with such therapy, such as cytokine-mediated responses, like cytokine response syndrome.

[1041] In some implementations, adoptive cell transfer therapy is chimeric antigen receptor T cells (CAR T) or dendritic cells used to treat hematologic or solid tumors, such as B-cell-related hematologic cancers.

[1042] In some implementations, the hematologic or solid tumor is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), pancreatic cancer, glioblastoma, or a cancer that expresses CD19.

[1043] In some implementations, adoptive cell transfer therapy is a non-engineered T-cell therapy, wherein the T cells have been activated and / or expanded to one or more viruses or tumor antigens. In some implementations, the associated inflammatory response is a cytokine-mediated response.

[1044] In some embodiments, the second agent is a cell that has been transformed to express a protein, wherein the protein in the host is mutated or has been otherwise impaired. In some embodiments, the transformed cell includes a CRISPR gene.

[1045] Another embodiment is provided, which includes administering to a host, optionally in a pharmaceutically acceptable composition, an effective amount of the active compound or a pharmaceutically acceptable salt, prodrug, isotope analog, N-oxide, or isolated isomer thereof, to treat eye, lung, gastrointestinal, or other conditions.

[1046] Any compound described herein (e.g., formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX) may be administered to the eye in any desired form of administration, including via intravitreal, intrastromal, intraanterior chamber, subfascial, subretinal, retroocular, periocular, suprachoroidal, choroidal, subchoroidal, conjunctival, subconjunctival, extrascleral, parascleral, scleral, pericortical, and lacrimal duct injection or via mucus, mucin, or mucosal barrier, in an immediate or controlled release manner. In some embodiments, the active compound includes a lipophilic group, such as a lipophilic acyl group, which is delivered to the eye in a polymeric drug delivery system such as polylactic acid, polylactide-co-glycolic acid, polyglycolic acid, or other erosive polymers or combinations thereof, or in other types of lipophilic substances for ocular delivery. In some implementations, the lipophilic active molecule is more soluble in polymers or other forms of delivery systems than in ocular fluids.

[1047] In other embodiments of this disclosure, the active compounds provided herein can be used to treat or prevent complement-mediated conditions in the host. As examples, this disclosure includes methods for treating or preventing complement-related conditions induced by antibody-antigen interactions, immune or autoimmune conditions, or ischemic injury. This disclosure also provides methods for reducing inflammatory or immune responses (including autoimmune responses) mediated or influenced by the classical complement pathway.

[1048] In some embodiments, the condition is selected from fatty liver and conditions derived from fatty liver, such as non-alcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, and liver failure. In some embodiments of this disclosure, a method is provided to treat a host's fatty liver disease by administering an effective amount of an active compound as described herein, or a salt or composition thereof.

[1049] In another embodiment, the active compound or its salt or composition as described herein is used to modulate an immune response before or during surgery or other medical procedures. A non-limiting example is the use in connection with acute or chronic graft-versus-host disease, a common complication of organ transplantation, allogeneic tissue transplantation, and potentially also of blood transfusions.

[1050] In some embodiments, this disclosure provides a method for treating or preventing dermatomyositis by administering an effective amount of an active compound, as described herein, or a salt or composition thereof, to a subject in need.

[1051] In some embodiments, this disclosure provides a method for treating or preventing amyotrophic lateral sclerosis (ALS) by administering an effective amount of an active compound, as described herein, or a salt or composition thereof, to a subject in need.

[1052] In some embodiments, this disclosure provides a method for treating or preventing abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, or performing hemodialysis by administering an effective amount of the active compound or its salt or composition as described herein to a subject in need.

[1053] In another embodiment, a method is provided for treating or preventing a host cytokine or inflammatory response in response to the administration of a drug or biological therapeutic agent (e.g., CAR T-cell therapy or monoclonal antibody therapy) by administering an effective amount of an active compound as described herein, or a salt or composition thereof. Various types of cytokine or inflammatory responses can occur in response to a variety of factors, such as the administration of biological therapeutic agents.

[1054] In some implementations, the cytokine or inflammatory response is cytokine release syndrome. In other implementations, the cytokine or inflammatory response is tumor lysis syndrome (which also leads to cytokine release). Symptoms of cytokine release syndrome range from fever, headache, and rash to bronchospasm, hypotension, and even cardiac arrest. Severe cytokine release syndrome is described as a cytokine storm and can be fatal.

[1055] Fatal cytokine storms have been observed in response to infusions of several monoclonal antibody therapies. 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., “Invivo 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.

[1056] This article also covers adverse immune responses mediated by the use of active compounds, salts, or combinations thereof as described herein in patients receiving bispecific T-cell conjugates (BiTEs). Bispecific T-cell conjugates direct T cells to target and bind to specific antigens on the surface of cancer cells. For example, blinatumomab (Amgen) is a BiTE that has recently been approved as a second-line therapy for Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia. Blinatumomab is administered via continuous intravenous infusion over a 4-week cycle. The use of BiTE agents is associated with adverse immune responses, including cytokine release syndrome. The most significantly elevated cytokines in ACT-related CRS include IL-10, IL-6, and IFN-γ (Klinger et al., Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19 / CD3-bispecific BiTE antibody blinatumomab. Blood (2012) 119:6226–6233).

[1057] In another embodiment, the condition is superficial scleritis, idiopathic superficial scleritis, anterior superficial scleritis, or posterior superficial scleritis. In some embodiments, the condition is idiopathic anterior uveitis, HLA-B27-associated uveitis, herpetic kerouveitis, Posner-Schlossman syndrome, Fuchs' heterochromia iridocyclitis, or cytomegalovirus anterior uveitis.

[1058] In some embodiments, this disclosure provides a method for treating or preventing IC-MPGN by administering an effective amount of an active compound, as described herein, or a salt or composition thereof, to a subject in need.

[1059] In some embodiments, this disclosure provides a method for treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering an effective amount of an active compound, as described herein, or a salt or composition thereof, to a subject in need.

[1060] In some embodiments, this disclosure provides a method for treating or preventing hereditary angioedema (HAE) by administering an effective amount of an active compound, as described herein, or a salt or composition thereof, to a subject in need.

[1061] In some embodiments, this disclosure provides a method for treating or preventing cold agglutinin disease (CAD) by administering an effective amount of an active compound, as described herein, or a salt or composition thereof, to a subject in need.

[1062] In some embodiments, this disclosure provides a method for treating or preventing atypical hemolytic syndrome (aHUS) by administering an effective amount of an active compound, as described herein, or a salt or composition thereof, to a subject in need.

[1063] In some embodiments, this disclosure provides a method for treating or preventing age-related macular degeneration (AMD) by administering an effective amount of an active compound, as described herein, or a salt or composition thereof, to a subject in need.

[1064] In some embodiments, this disclosure provides a method for treating or preventing rheumatoid arthritis by administering an effective amount of an active compound, as described herein, or a salt or composition thereof, to a subject in need.

[1065] In some embodiments, this disclosure provides a method for treating or preventing multiple sclerosis by administering an effective amount of an active compound, as described herein, or a salt or composition thereof, to a subject in need.

[1066] In some embodiments, this disclosure provides a method for treating or preventing myasthenia gravis by administering an effective amount of an active compound, as described herein, or a salt or composition thereof, to a subject in need.

[1067] In some embodiments, this disclosure provides a method for treating or preventing atypical hemolytic uremic syndrome (aHUS) by administering an effective amount of an active compound, as described herein, or a salt or composition thereof, to a subject in need.

[1068] In another embodiment, this disclosure provides a method for treating or preventing conditions described herein by administering an effective amount of an active compound or its salt or composition as described herein to a subject in need, the conditions including: vitreous inflammation, 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 diseases (e.g., hemorrhagic dengue fever); masquerade syndrome, contact dermatitis, trauma-induced inflammation, UVB-induced inflammation, eczema, granuloma annulare, or acne.

[1069] In another embodiment, the condition is selected from: 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, anaphylactic reaction, allogeneic transplantation, fluid and vascular graft rejection, graft dysfunction, graft-versus-host disease, Graves' disease, adverse drug reactions, or chronic graft vascular disease; allergic bronchopulmonary aspergillosis, allergic neuritis, drug allergy, radiation-induced lung injury, eosinophilic pneumonia, radiographic contrast agent allergy, obliterative bronchiolitis, or interstitial lung disease. Pneumonia; Parkinson's disease-dementia complex, sporadic frontotemporal dementia, frontotemporal dementia with Parkinson's disease associated with chromosome 17, frontotemporal degeneration, simple tangles dementia, cerebral amyloid angiopathy, cerebrovascular disease, certain forms of frontotemporal dementia, chronic traumatic encephalopathy (CTE), Parkinson's disease with dementia (PDD), aerophilic granule dementia, boxer's dementia, Lewy body dementia (DLB) or multi-infarct dementia; Creutzfeldt-Jakob disease, Huntington's disease, multifocal motor neuron disease (MMN), prion amyloid angiopathy, polymyositis, post-encephalitis Parkinson's disease, subacute sclerosing panencephalitis, non-Guam motor neuron disease with neurofibrillary tangles, neuroregeneration, and diffuse neurofibrillary tangles with calcification.

[1070] In some implementations, the condition is selected from: atopic dermatitis, dermatitis, dermatomyositis, bullous pemphigoid, scleroderma, sclerosing dermatomyositis, psoriatic arthritis, pemphigus vulgaris, discoid lupus erythematosus, cutaneous lupus, chilblain-like lupus erythematosus, or lupus-lichen planus overlap syndrome; cryoglobulinemia-related vasculitis, mesenteric / intestinal vascular disease, peripheral vascular disease, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), IL-2-induced vascular leakage syndrome, or immune complex vasculitis; angioedema, helliple syndrome, sickle cell disease, platelet transfusion ineffectiveness. Refractoriness), red blood cell casts or typical or infectious hemolytic uremic syndrome (tHUS); hematuria, hemorrhagic shock, drug-induced thrombocytopenia, autoimmune hemolytic anemia (AIHA), azotemia, vascular and / or lymphatic inflammation, rotational atherectomy or delayed hemolytic transfusion reaction; British amyloid angiopathy, Burger's disease, bullous pemphigoid, C1q nephropathy, cancer and devastating antiphospholipid syndrome.

[1071] In another embodiment, the condition is selected from: wet (exudative) AMD, dry (non-exudative) AMD, choroidal retinal degeneration, choroidal neovascularization (CNV), choroiditis, RPE function loss, vision loss (including visual acuity or visual field loss), vision loss originating from 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; pseudophaccal bullous keratopathy, symptomatic macular degeneration-related conditions, optic nerve degeneration, photoreceptor degeneration, cone degeneration, photoreceptor cell loss, pars plana cyclitis, scleritis, proliferative vitreoretinopathy, or drusen formation; chronic urticaria, Chag-Strauss syndrome, cold agglutinin disease (CAD), corticobasal degeneration (CBD), cryoglobulinemia, cyclitis, Bruch's membrane injury, Degos' disease, diabetic angiopathy, elevated liver enzymes. Hyperendocrine disorders, endotoxemia, bullous epidermolysis or acquired bullous epidermolysis; primary mixed cryoglobulinemia, excessive blood urea nitrogen (BUN), focal segmental glomerulosclerosis, Gerstmann-Straussler-Schenk disease, giant cell arteritis, gout, Hallewarden-Schpattz disease, Hashimoto's thyroiditis, Henoch-Schonlein purpuric nephritis or abnormal urinary sediment; hepatitis, hepatitis A, hepatitis B, hepatitis C or human immunodeficiency virus (HIV) More common viral infections include those from families such as Flaviviridae, Retroviridae, Coronaviridae, Poxviridae, Adenoviridae, Herpesviridae, Caliciviridae, Reoviridae, Picornaviridae, Clostridiumviridae, Orthomyxoviridae, Rhabdoviridae, or Hepatodeoxyribonucleoviridae; Neisseria meningitidis, Shiga toxin-associated hemolytic uremic syndrome (STEC-HUS), hemolytic uremic syndrome (HUS); Streptococcus and post-streptococcal glomerulonephritis.

[1072] In a further implementation, the condition is selected from: hyperlipidemia, hypertension, hypoalbuminemia, hypovolemic shock, hypocomplementemia-associated urticarial vasculitis syndrome, hypophosphatemia, hypovolemic shock, idiopathic pneumonia syndrome or idiopathic pulmonary fibrosis; inclusion body myositis, intestinal ischemia, iridocyclitis, iritis, juvenile chronic arthritis, Kawasaki disease (arteritis) or lipuremia; membranoproliferative glomerulonephritis (MPGN) I, microscopic polyangiitis, mixed cryoglobulinemia. Niemann-Pick disease, type A molybdenum cofactor deficiency (MoCD), pancreatitis, panniculitis, Pick's disease, polyarteritis nodosa (PAN), progressive subcortical gliosis, proteinuria, decreased glomerular filtration rate (GFR) or renal vascular disease; multiple organ failure, multiple system atrophy (MSA), myotonic dystrophy, Niemann-Pick disease type C, chronic demyelinating diseases or progressive supranuclear palsy; spinal cord injury, spinal muscular atrophy, vertebral arthropathy, Reiter's syndrome. Syndrome), spontaneous pregnancy loss, recurrent pregnancy loss, preeclampsia, synucleinosis, Goran's arteritis, postpartum thyroiditis, thyroiditis, type I cryoglobulinemia, type II mixed cryoglobulinemia, type III mixed cryoglobulinemia, ulcerative colitis, uremia, urticaria, venous air thrombosis (VGE) or Wegener's granulomatosis; von Hippel-Lindau disease, ocular histoplasmosis, hard drusen, soft drusen, pigmented nodules and loss of photoreceptors and / or retinal pigment epithelial cells (RPE).

[1073] In some embodiments, the active compound or its salt or composition as described herein may be used to treat or prevent conditions selected from: 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 (Canale-Smith syndrome), autoimmune neutropenia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful obesity (Dalkken disease), adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, eosinophilic fasciitis (Shullman syndrome), Felty syndrome, IgG4-related disease, mixed connective tissue disease (MCTD), relapsing rheumatism (Hench-Rosenberg syndrome), Parry-Roman syndrome, and other related conditions. Meyenburg syndrome, Parsonage-Turner syndrome, relapsing polychondritis (Meyenburg-Altherr-Uehlinger syndrome), retroperitoneal fibrosis, rheumatic fever, Schnitzler syndrome, fibromyalgia, neurogenic myotonia (Isaac's disease), paraneoplastic degeneration, autoimmune inner ear disease, Meniere's disease, interstitial cystitis, autoimmune pancreatitis, Zika virus-related diseases, Chikungunya virus-related diseases, subacute bacterial endocarditis (SBE), IgA nephropathy, IgA vasculitis, polymyalgia rheumatica, rheumatoid vasculitis, alopecia areata, autoimmune progesterone dermatitis, herpetic dermatitis, erythema nodosum, pemphigoid of pregnancy, hidradenitis suppurativa, lichen sclerosus, linear IgA disease (LAD), morphine sclerosus, myositis, acute pityriasis lichenoides. (The following are listed as examples of diseases and related conditions:) lichenoides et varioliformis acuta), post-myocardial infarction vitiligo syndrome (Dusler syndrome), post-pericardiotomy syndrome, autoimmune retinopathy, Cogan syndrome, Graves' ophthalmopathy, woody conjunctivitis, Moren's ulcer, oculoclonus myoclonus syndrome, optic neuritis, retinocochlear cerebrovascular disease (Susac syndrome), sympathetic ophthalmitis, Tolosa-Hunt syndrome, interstitial lung disease, antisynthetic enzyme syndrome, Addison's disease, type I autoimmune polyendocrine syndrome (APS), type II autoimmune polyendocrine syndrome (APS), type III autoimmune polyendocrine syndrome (APS), disseminated sclerosis (multiple sclerosis).Type II), rapidly progressive glomerulonephritis (RPGN), juvenile rheumatoid arthritis, arthritis related to initiation and termination of arthritis, reactive arthritis (Reiter's syndrome), autoimmune hepatitis or lupus-like hepatitis, primary biliary cirrhosis (PBS), primary sclerosing cholangitis, microscopic colitis, latent lupus (undifferentiated connective tissue disease (UCTD)), acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-n-methyl-D-aspartate receptor encephalitis, Barlow concentric sclerosis (Sch Ilders' disease, Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenia gravis syndrome, Oshtoran syndrome, pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS), progressive inflammatory neuropathy, restless legs syndrome, stiff-person syndrome, Sydenhem syndrome, transverse myelitis, lupus vasculitis, leukocytoclastic vasculitis, microscopic polyangiitis, polymyositis, and ocular ischemia-reperfusion injury.

[1074] Examples of eye conditions that can be treated according to the compositions and methods disclosed herein include amoebic keratitis, fungal keratitis, bacterial keratitis, viral keratitis, and discoid keratitis. Keratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis, corneal dystrophy, Fuchs corneal endothelial dystrophy, Sjögren's syndrome, Stevens-Johnson syndrome, autoimmune dry eye disease, environmental dry eye disease, corneal neovascularization disease, prevention and treatment of corneal transplant rejection, 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.

[1075] In a further embodiment, the condition is selected from glaucoma, diabetic retinopathy, bullous skin diseases (including bullous pemphigoid, pemphigus, and epidermolysis bullosa), ocular cicatricial pemphigoid, uveitis, adult macular degeneration, diabetic retinitis pigmentosa, macular edema, diabetic macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, moderate uveitis, shotgun retinochoroiditis, sympathetic ophthalmitis, ocular cicatricial pemphigoid, ocular pemphigus, non-arterial ischemic optic neuropathy, postoperative inflammation and retinal vein occlusion, and central retinal vein occlusion (CVRO).

[1076] In some embodiments, complement-mediated diseases include ophthalmic 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 disclosed herein are suitable for treating diseases and conditions related to fatty acid metabolism, including obesity and other metabolic disorders.

[1077] Conditions that can be treated or prevented by the active compounds or their salts or combinations described herein include, but are not limited to: hereditary angioedema, capillary leak syndrome, hemolytic uremic syndrome (HUS), neurological disorders, Guillain-Barré syndrome, central nervous system diseases and other neurodegenerative conditions, glomerulonephritis (including membranoproliferative glomerulonephritis), SLE nephritis, proliferative nephritis, liver fibrosis, tissue regeneration and nerve regeneration or Barraquer-Simons syndrome; the inflammatory effects of sepsis, and systemic inflammatory response syndrome (SIRS). Inappropriate or unwanted complement activation syndromes; interleukin-2 induced toxicity during IL-2 therapy; inflammatory conditions; inflammation in autoimmune diseases; systemic lupus erythematosus (SLE); lupus nephritis; arthritis; immune complex disorders and autoimmune diseases; systemic lupus erythematosus or lupus erythematosus; ischemia / reperfusion injury (I / R injury); myocardial infarction; myocarditis; ischemia-reperfusion symptoms; balloon angioplasty; atherosclerosis; post-pump syndrome in cardiopulmonary bypass or renal bypass; renal ischemia; mesenteric artery reperfusion after aortic reconstruction; antiphospholipid syndrome. Autoimmune heart disease, ischemia-reperfusion injury, obesity or diabetes; Alzheimer's disease, stroke, schizophrenia, traumatic brain injury, trauma, Parkinson's disease, epilepsy, graft rejection, prevention of pregnancy loss, biomaterial reactions (e.g., in hemodialysis, transplantation), hyperacute allogeneic graft rejection, xenograft rejection, transplantation, psoriasis, burns, including thermal or crush injuries such as burns or frostbite; asthma, allergies, acute respiratory distress syndrome (ARDS), cystic fibrosis, adult respiratory distress syndrome, dyspnea, hemoptysis, chronic obstructive pulmonary disease (COPD). COPD, emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, inert dust and minerals (e.g., silicon, coal dust, beryllium and asbestos), pulmonary fibrosis, organic dust disease, chemical injury (due to irritating gases and chemicals such as chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia and hydrochloric acid), smoke injury, thermal injury (e.g., burns, frostbite), bronchoconstriction, allergic pneumonia, parasitic diseases, Goodpassuia syndrome (antiglomerular basement membrane nephritis), pulmonary vasculitis, Pauci immune vasculitis, and immune complex-related inflammation.

[1078] In some embodiments, a method for treating sickle cells of a host is provided, comprising administering an effective amount of an active compound as described herein, or a salt or combination thereof.

[1079] In some embodiments, methods for treating a host’s immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), or idiopathic thrombocytopenic purpura (ITP) are provided, comprising administering an effective amount of an active compound as described herein, or a salt or combination thereof.

[1080] In some embodiments, a method for treating ANCA-vasculitis in a host is provided, comprising administering an effective amount of an active compound as described herein, or a salt or combination thereof.

[1081] In some embodiments, a method for treating host IgA nephropathy is provided, comprising administering an effective amount of an active compound as described herein, or a salt or combination thereof.

[1082] In some embodiments, a method of treating rapidly progressive glomerulonephritis (RPGN) in a host is provided, comprising administering an effective amount of an active compound as described herein or a salt or combination thereof.

[1083] In some embodiments, a method of treating lupus nephritis in a host is provided, comprising administering an effective amount of an active compound as described herein, or a salt or combination thereof.

[1084] In some embodiments, a method for treating hemorrhagic dengue fever in a host is provided, comprising administering an effective amount of an active compound as described herein, or a salt or combination thereof.

[1085] In alternative embodiments, the active compound or its salts or compositions as described herein are used to treat autoimmune diseases. The complement pathway enhances the ability of antibodies and phagocytes to clear microorganisms and damaged cells from the body. It is part of the innate immune system and is an essential process in healthy individuals. Inhibition of the complement pathway will reduce the body's immune system response. Therefore, the object of this disclosure is to treat autoimmune diseases by administering an effective dose of the active compound or its salts or compositions as described herein to a subject in need.

[1086] In some embodiments, autoimmune diseases are caused by the activity of the complement system. In some embodiments, autoimmune diseases are caused by the activity of the alternative complement pathway. In some embodiments, autoimmune diseases are caused by the activity of the classical complement pathway. In another embodiment, autoimmune diseases are caused by mechanisms of action not directly related to the complement system, such as excessive proliferation of T lymphocytes or excessive production of cytokines.

[1087] Non-limiting examples of autoimmune diseases include: lupus, allogeneic graft rejection, autoimmune thyroid diseases (such as Graves' disease and Hashimoto's thyroiditis), autoimmune uveitis, giant cell arteritis, inflammatory bowel diseases (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.

[1088] In some embodiments, the active compound or its salt or composition as described herein is used to treat lupus. Non-limiting examples of lupus include systemic lupus erythematosus, cutaneous lupus, discoid lupus erythematosus, frostbite-like lupus erythematosus, and lupus-lichen planus overlap syndrome.

[1089] Systemic lupus erythematosus (SLE) is a general category of diseases that includes both systemic and cutaneous manifestations. The systemic form of the disease can present with both cutaneous and systemic manifestations. However, there are also forms that affect only the skin without affecting the whole body. For example, SLE is an inflammatory disease of unknown etiology that primarily occurs in women and is characterized by joint symptoms, a butterfly rash, recurrent pleurisy, pericarditis, generalized gonadal lesions, splenomegaly, and involvement of the CNS and progressive renal failure. Most patients (over 98%) have antinuclear antibodies in their serum, including anti-DNA antibodies. High titers of anti-DNA antibodies are essentially specific to SLE. The standard treatment for this disease has been the administration of corticosteroids or immunosuppressants.

[1090] 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 condition that primarily affects the skin, characterized by well-defined spots and plaques showing erythema, clogged hair follicles, scaling, telangiectasia, and atrophy. Symptoms are often triggered by sun exposure, and early lesions are erythematous, round, scaly papules 5 to 10 mm in diameter, showing clogged hair follicles. DLE lesions most commonly appear on the cheeks, nose, scalp, and ears, but they can also generalize on the upper trunk, the extensor surfaces of the limbs, and the oral mucosa. If left untreated, the central lesions will atrophy and leave scars. Unlike SLE, antibodies against double-stranded DNA (e.g., DNA binding tests) are almost always absent in DLE.

[1091] Diabetes may refer to type 1 or type 2 diabetes. In some embodiments, the active compound or its salt or composition as described herein is provided in a dose effective for treating a patient with type 1 diabetes. In some embodiments, the active compound or its salt or composition as described herein is provided in a dose effective for treating a patient with type 2 diabetes.

[1092] Type 1 diabetes is an autoimmune disease. Autoimmune diseases occur when the body's infection-fighting system (the immune system) attacks a part of the body. In type 1 diabetes, the pancreas produces little or no insulin.

[1093] In some implementations, complement-mediated diseases or conditions include graft rejection. In some implementations, complement-mediated diseases or conditions are antibody-mediated graft rejection.

[1094] In some respects, the active compounds or their salts or compositions described herein are used to treat proliferative diseases, including but not limited to cancer. Suitable targets for the administration of the active compounds or their salts described herein include, but are not limited to, estrogen receptor-positive cancers, HER2-negative advanced breast cancer, advanced 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, as well as lung and bronchial cancer, colon adenocarcinoma, rectal adenocarcinoma, central nervous system germ cell tumors, teratomas, estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, familial testicular germ cell tumors, HER2-negative breast cancer, HER2-positive breast cancer, male breast cancer, immature ovarian teratomas, mature ovarian teratomas, monoblastic and highly specialized ovarian teratomas, and pregnancy-related cancers. Ketone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, recurrent colon cancer, recurrent extragonadal germ cell tumors, recurrent extragonadal non-seminomatous 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 non-seminomatous 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 non-seminomatous germ cell tumors, stage IV extragonadal seminoma, stage IV melanoma, stage IV ovarian germ cell tumors, stage IV rectal cancer, immature testicular teratoma, mature testicular teratoma. In a specific implementation scheme,Targeted cancers include estrogen receptor-positive, HER2-negative advanced breast cancer, advanced 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, as well as lung cancer and bronchial cancer, metastatic colorectal cancer, metastatic melanoma with CDK4 mutations or amplification, or cisplatin-resistant unresectable germ cell tumors. Lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal 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 cancers, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CN) cancer. S) Tumors, primary CNS lymphomas, spinal cord axis tumors, brainstem gliomas, pituitary adenomas, fibrosarcomas, myxosarcomas, chondrosarcomas, osteosarcomas, chordomas, malignant fibrous histiocytomas, hemangiosarcomas, angiosarcomas, lymphangiosarcomas, mesotheliomas, leiomyosarcomas, rhabdomyosarcomas, squamous cell carcinomas; epidermoid carcinomas, malignant skin and appendage tumors, adenocarcinomas, hepatocellular carcinomas, hepatocellular carcinomas, renal cell carcinomas, adrenal adenoid tumors, bile duct carcinomas. Transitional cell carcinoma, choriocarcinoma, seminoma, embryonal cell carcinoma, anaplastic glioma; glioblastoma multiforme, neuroblastoma, medulloblastoma, malignant meningioma, malignant schwannoma, neurofibrosarcoma, parathyroid carcinoma, medullary thyroid carcinoma, bronchial carcinoid, pheochromocytoma, islet cell carcinoma, malignant carcinoid, malignant paraganglioma, melanoma, Merkel cell carcinoma, phyllodes cystic sarcoma, salivary gland carcinoma, thymic carcinoma, bladder cancer, and Wilms' tumor. Hematologic disorders or hematologic malignancies, including but not limited to bone marrow disorders, lymphomas, leukemia, lymphoma, myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD), mast cell disorders, and myeloma (e.g., multiple myeloma); T-cell or NK-cell lymphomas, such as but not limited to: peripheral T-cell lymphoma; anaplastic large cell lymphoma, such as anaplastic lymphoma kinase (ALK) positive, ALK negative anaplastic large cell lymphoma, or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphoma;Examples include mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous aggressive epidermophilic CD8+ cytotoxic T-cell lymphoma; primary cutaneous γ-δ T-cell lymphoma; primary cutaneous small / medium CD4+ T-cell lymphoma and lymphomatoid papulosis; adult T-cell leukemia / lymphoma (ATLL); germinal NK-cell lymphoma; enteropathy-associated T-cell lymphoma; hematologic splenic γ-δ T-cell lymphoma; and lymphoblastic lymphoma. Nasal NK / T-cell lymphoma; treatment-related T-cell lymphoma; lymphoma following 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 in children (associated with chronic active EBV infection); varicella-like lymphoma; adult T-cell leukemia / lymphoma; bowel-related T-cell lymphoma; hepatocellular and splenic T-cell lymphoma; or subcutaneous panniculitis-like T-cell lymphoma.

[1095] In some implementations, the methods described herein can be used to treat a host, such as a human, suffering from lymphoma or a lymphocytic or myeloid cell proliferation disorder or abnormality. For example, the methods described herein can be administered to a host suffering from Hodgkin lymphoma or non-Hodgkin lymphoma. For example, the host may have non-Hodgkin's lymphoma, such as, but not limited to: AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; germinal NK cell lymphoma; Burkitt's lymphoma; Burkitt-like lymphoma (small non-lytic cell lymphoma); chronic lymphocytic leukemia / small lymphocytic lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathy-associated T-cell lymphoma; follicular lymphoma; hepatosplenic γ-δ T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; pediatric lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; treatment-associated T-cell lymphoma; or Waldenstrom's macroglobulinemia. Macroglobulinemia (HGL) is a type of Hodgkin lymphoma, including but not limited to: tuberous sclerosis classical Hodgkin lymphoma (CHL); mixed cellularity CHL; lymphocyte-depleted CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin lymphoma; or nodular lymphocyte-predominant HL, specific B-cell lymphoma, 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 lymphoma; mediastinal large B-cell lymphoma; nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary exudative lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; hairy cell leukemia; unclassifiable splenic lymphoma / leukemia; diffuse splenic red pulp small B-cell lymphoma; hairy cell leukemia - variant. Lymphoplasmacytic lymphoma; Heavy chain diseases, such as alpha heavy chain disease, gamma heavy chain disease, and μ heavy chain disease; Plasma cell myeloma; Solitary plasmacytoma of bone; Extraosseous plasmacytoma; Primary cutaneous follicular center lymphoma; T-cell-rich / histiocytic large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; Primary mediastinal (thymic) large B-cell lymphoma; Leg-type primary cutaneous DLBCL; A LK+ large B-cell lymphoma; plasmablastic lymphoma; HHV8-associated multicentric large B-cell lymphoma; Kaselman disease; unclassifiable B-cell lymphoma with features between diffuse large B-cell lymphoma; or unclassifiable B-cell lymphoma with features between diffuse large B-cell lymphoma and classical Hodgkin lymphoma; leukemia, such as acute or chronic leukemia of lymphoid or bone marrow origin, such as, 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 implementations, the patient has acute myeloid leukemia, such as undifferentiated AML (M0); myeloblastic leukemia (M1; with / without minimum cell maturation); myeloblastic leukemia (M2; mature cells); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or eosinophilic M4 variant [M4E]); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7), small cell lung cancer, retinoblastoma, HPV-positive malignancies such as Cervical cancer and certain head and neck cancers; MYC-amplified tumors such as Burkitt's lymphoma and triple-negative breast cancer; certain types of sarcomas; certain types of non-small cell lung cancer; certain types of melanoma; certain types of pancreatic cancer; certain types of leukemia; certain types of lymphoma; certain types of brain cancer; certain types of colon cancer; certain types of prostate cancer; certain types of ovarian cancer; certain types of uterine cancer; certain types of thyroid and other endocrine tissue cancers; certain types of salivary gland cancer; certain types of thymic carcinoma; certain types of kidney cancer; certain types of bladder cancer; and certain types of testicular cancer.

[1096] In some respects, the active compounds or salts thereof described herein can be used to preserve organs or blood products or to 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 products, 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, erythrocytes, or reticulocytes.

[1097] In some embodiments, the active compound or its salt or composition as described herein prevents or delays the onset of at least one symptom of a complement-mediated disease or condition in an individual. In some embodiments, the active compound or its salt or composition as described herein alleviates or eliminates at least one symptom of a complement-mediated disease or condition in an individual. Examples of symptoms include, but are not limited to, symptoms associated with autoimmune diseases, cancer, hematological disorders, infectious diseases, inflammatory diseases, ischemia-reperfusion injury, neurodegenerative diseases, neurodegenerative conditions, kidney diseases, graft rejection, eye diseases, vascular diseases, or vasculitis. Symptoms can be neurological symptoms, such as cognitive impairment, memory impairment, loss of motor function, etc. Symptoms can also be related to the activity of the C1s protein in an individual's cells, tissues, or fluids. Symptoms can also be related to the degree of complement activation in an individual's cells, tissues, or fluids.

[1098] In some embodiments, administration of an active compound as described herein, or a salt or composition thereof, to an individual modulates complement activation in the individual's cells, tissues, or fluids. In some embodiments, administration of an active compound as described herein, or a salt or composition thereof, to an individual inhibits complement activation in the individual's cells, tissues, or fluids. For example, in some embodiments, when an active compound as described herein, or a salt or composition thereof, is administered as a monotherapy or in combination therapy at one or more doses to an individual suffering from a complement-mediated disease or condition, complement activation in the individual is inhibited 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 complement activation in the individual prior to treatment with the compound described herein.

[1099] In some embodiments, the active compound or its salt or composition as described herein reduces C3 deposition on erythrocytes; for example, in some embodiments, the active compound or its salt or composition as described herein reduces deposition of C3b, iC3b, etc., on RBCs. In some embodiments, the active compound or its salt or composition as described herein inhibits complement-mediated erythrocyte lysis.

[1100] In some embodiments, the active compound or its salt or composition as described herein reduces C3 deposition on platelets; for example, in some embodiments, the active compound or its salt or composition as described herein reduces deposition of C3b, iC3b, etc., on platelets.

[1101] In some embodiments, administration of the active compound or its salt or composition as described herein results in outcomes selected from the group consisting of: (a) reduced complement activation; (b) improved cognitive function; (c) reduced neuronal loss; (d) decreased phosphate-Tau levels in neurons; (e) reduced glial cell activation; (f) reduced lymphocyte infiltration; (g) reduced macrophage infiltration; (h) reduced antibody deposition; (i) reduced glial cell loss; (j) reduced oligodendrocyte loss; (k) reduced dendritic cell infiltration; (l) reduced neutrophil infiltration; (m) reduced erythrocyte lysis; (n) reduced erythrocyte phagocytosis; (o) reduced platelet phagocytosis; (p) reduced platelet lysis; (q) transplantation. Improved graft survival; (r) reduced macrophage-mediated phagocytosis; (s) improved visual acuity; (t) improved motor control; (u) improved thrombosis; (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 erythrocytes (e.g., reduced deposition of C3b, iC3b, etc. on RBCs); and (ad) reduced C3 deposition on platelets (e.g., reduced deposition of C3b, iC3b, etc. on platelets); and (ae) reduced anaphylatoxin production; (af) autoantibodies. Reduced antibody-mediated blister formation; (ag) reduced autoantibody-induced pruritus; (ah) reduced autoantibody-induced erythema; (ai) reduced autoantibody-mediated skin erosion; (aj) reduced transfusion-induced erythrocyte destruction; (ak) alloantibody-induced erythrocyte lysis; (al) transfusion-induced hemolysis; (am) alloantibody-mediated thrombolysis; (an) transfusion-induced thrombolysis; (ao) reduced mast cell activation; (ap) reduced mast cell histamine release; (aq) decreased vascular permeability; (ar) reduced edema; (as) reduced complement deposition on the endothelium of the transplanted graft; (at) within the transplanted graft. Reduced production of anaphylatoxins in the skin; (au) reduced separation at the dermal-epidermal junction; (av) reduced production of anaphylatoxins at the dermal-epidermal junction; (aw) reduced alloantibody-mediated complement activation in the endothelium of transplanted grafts; (ax) reduced antibody-mediated loss of neuromuscular junctions; (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-related mortality; and (bg) reduced autoantibody-related morbidity.

[1102] In some embodiments, when the active compound or its salt or composition as described herein is administered as a monotherapy or in combination therapy at one or more doses to an individual suffering from a complement-mediated disease or condition, it effectively achieves a reduction of one or more of the following outcomes 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 or extent of the individual's outcome before treatment with the active compound: (a) complement activation; (b) cognitive decline; (c) (d) Neuronal loss; (e) Phospho-Tau levels in neurons; (f) Glial cell activation; (g) Lymphocyte infiltration; (h) Macrophage infiltration; (i) Antibody deposition; (j) Glial cell loss; (k) Oligodendrocyte loss; (l) Dendritic cell infiltration; (m) Neutrophil infiltration; (n) Erythrocyte phagocytosis; (o) Platelet phagocytosis; (p) Platelet lysis; (q) Transplant rejection; (r) Macrophage-mediated phagocytosis; (s) Visual loss; (t) Antibody-mediated complement activation; (u) Autoantibody-mediated complement activation; (v) Demyelination; (w) Eosinophilia.

[1103] In some embodiments, when the active compound or its salt or composition as described herein is administered as a monotherapy or in combination therapy at one or more doses to an individual suffering from a complement-mediated disease or condition, it effectively achieves an improvement of one or more of the following outcomes 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 or extent of the individual's outcome before treatment with the active compound: a) cognitive function; b) transplant survival; c) visual acuity; d) motor control; e) thrombosis; f) coagulation; g) renal function; and h) hematocrit (red blood cell count).

[1104] In some embodiments, administration of an active compound or its salt or composition as described herein to an individual reduces complement activation in that individual. For example, in some embodiments, when an active compound or its salt or composition as described herein is administered as a monotherapy or in combination therapy at one or more doses to an individual suffering from a complement-mediated disease or condition, it 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 complement activation prior to treatment with the active compound or its salt.

[1105] In some embodiments, administration of the active compound as described herein, or its salts or compositions, improves an individual's cognitive function. For example, in some embodiments, when the active compound described herein is administered as a monotherapy or in combination therapy at one or more doses to an individual suffering from a complement-mediated disease or condition, it improves the individual's cognitive function 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 individual's cognitive function before treatment with the active compound.

[1106] In some embodiments, administration of the active compound or its salts or compositions as described herein reduces the rate of cognitive decline in an individual. For example, in some embodiments, when the active compound or its salts are administered as a monotherapy or in combination therapy at one or more doses to an individual suffering from a complement-mediated disease or condition, 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 before treatment with the active compound or its salts.

[1107] In some embodiments, administration of an active compound or its salt or composition as described herein to an individual reduces the individual's neuronal loss. For example, in some embodiments, when the active compound or its salt is administered as a monotherapy or in combination therapy at one or more doses to an individual suffering from a complement-mediated disease or condition, it reduces the individual's neuronal loss 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 individual's neuronal loss before treatment with the active compound.

[1108] In some embodiments, administration of an active compound or its salt or composition as described herein to an individual reduces the level of phosphate-Tau in that individual. For example, in some embodiments, when the active compound or its salt is administered as a monotherapy or in combination therapy at one or more doses to an individual suffering from a complement-mediated disease or condition, it reduces the level of phosphate-Tau 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 phosphate-Tau in the individual before treatment with the active compound or its salt.

[1109] In some embodiments, administration of an active compound or its salt or composition as described herein to an individual reduces glial cell activation in that individual. For example, in some embodiments, when the active compound or its salt is administered as a monotherapy or in combination therapy at one or more doses to an individual suffering from a complement-mediated disease or condition, it reduces glial cell 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 glial cell activation prior to treatment with the active compound or its salt. In some embodiments, the glial cells are astrocytes or microglia.

[1110] In some embodiments, administration of the active compound or its salts or compositions as described herein to an individual reduces lymphocyte infiltration in that individual. For example, in some embodiments, when the active compound or its salts are administered as a monotherapy or in combination therapy at one or more doses to an individual suffering from a complement-mediated disease or condition, the lymphocyte infiltration 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 before treatment with the active compound or its salts.

[1111] In some embodiments, administration of an active compound or its salt or composition as described herein to an individual reduces macrophage infiltration in that individual. For example, in some embodiments, when the active compound or its salt is administered as a monotherapy or in combination therapy at one or more doses to an individual suffering from a complement-mediated disease or condition, it 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 before treatment with the active compound or its salt.

[1112] In some embodiments, administration of an active compound or its salt or composition as described herein to an individual reduces antibody deposition in that individual. For example, in some embodiments, when the active compound or its salt is administered as a monotherapy or in combination therapy at one or more doses to an individual suffering from a complement-mediated disease or condition, it 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 prior to treatment with the active compound or its salt.

[1113] In some embodiments, administration of an active compound or its salt or composition as described herein to an individual reduces the production of anaphylatoxins (e.g., C3a, C4a, C5a) in the individual. For example, in some embodiments, when the active compound or its salt is administered as a monotherapy or in combination therapy at one or more doses to an individual suffering from a complement-mediated disease or condition, it reduces the production of anaphylatoxins 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 prior to treatment with the active compound or its salt.

[1114] This disclosure provides the use of the active compound of the present disclosure or a salt thereof, or a pharmaceutical composition comprising the active compound of the present disclosure or a salt thereof and a pharmaceutically acceptable excipient, for treating an individual suffering from a complement-mediated disease or condition. In some embodiments, this disclosure provides the use of the active compound of the present disclosure or a salt thereof for treating an individual suffering from a complement-mediated disease or condition. In some embodiments, this disclosure provides the use of a pharmaceutical composition comprising the active compound of the present disclosure or a salt thereof and a pharmaceutically acceptable excipient for treating an individual suffering from a complement-mediated disease or condition.

[1115] Combination therapy

[1116] In one aspect of this disclosure, the active compound or its salt or composition as described herein may be provided in combination with or alternately with an effective amount of at least one other therapeutic agent, or in a manner preceding, accompanying, or following at least one other therapeutic agent, for example, for treating the conditions listed herein. Non-limiting examples of a second active agent for such combination therapy are provided below.

[1117] In some embodiments, the active compound or its salt or composition as described herein may be provided in combination with or alternately with at least one additional complement system inhibitor or a second active compound with a different biological mechanism of action. In the following and general description herein, whenever any term referring to an active compound or its salt or composition as described herein is used, it should be understood that, unless otherwise stated or inconsistent with this document, it is considered to include pharmaceutically acceptable salts, prodrugs, or compositions.

[1118] In a non-limiting embodiment, the active compound or its salt or composition as described herein may be provided together with a protease inhibitor, a soluble complement modulator, a therapeutic antibody (monoclonal or polyclonal), a complement component inhibitor, a receptor agonist, a chemotherapeutic agent, or siRNA.

[1119] In other embodiments, the active compound described herein is administered in combination with or alternately with an antibody targeting tumor necrosis factor (TNF), said antibody including but not limited to infliximab. Adalimumab Sertolizumab Golimumab Or receptor fusion proteins, such as etanercept In some implementations, the agent used for combination therapy is a biosimilar of any of the agents specified above, including but not limited to... (Infliximab biosimilar) (Infliximab biosimilar) (adalimumab biosimilar) (adalimumab biosimilar) (adalimumab biosimilar) (Etanercept biosimilar) and (Etanercept biosimilar).

[1120] In another embodiment, the active compound described herein may be administered in combination with or alternately with an anti-CD20 antibody, including but not limited to rituximab. Ophamumab Tosimomumab Orbital Beads Temozolomide Octolizumab Or vetuzumab. In some implementations, the agent used for combination therapy is a biosimilar of any of the agents specified above, including but not limited to... (Rituximab biosimilar).

[1121] In alternative embodiments, the active compound described herein may be administered in combination with or alternately with an anti-IL6 antibody, including but not limited to tocilizumab. Situximab salimib Cilukumab, clazazumab, vobalizumab, olozazumab, and WBP216 (MEDI5117). In some implementations, the agent used for combination therapy is a biosimilar of any of the agents specified above, including but not limited to BAT1806 (a tocilizumab biosimilar).

[1122] In alternative embodiments, the active compound described herein may be administered in combination with or alternately with an IL17 inhibitor, including but not limited to secukinumab (Cosentyx) and ixekizumab. Padarumab Bimecrolimus, ALX-0761, CJM112, CNTO6785, LY3074828, SCH-900117, and MSB0010841. In some embodiments, the agent used for combination therapy is a biosimilar of any of the agents specified above.

[1123] In alternative embodiments, the active compound as described herein may be administered in combination with or alternately with a p40 (IL12 / IL23) inhibitor, including but not limited to uterotumab. And brenumab (ABT874). In some implementations, the agent used for combination therapy is a biosimilar of any of the agents specified above, including but not limited to FYB202 (a biosimilar of uteroclosporine) and (Utetraclosab biosimilar).

[1124] In alternative embodiments, the active compound described herein may be administered in combination with or alternately with an IL23 inhibitor, including but not limited to rexazumab. Tiramizumab Gusekumab Mijicillinumab and brecurumab. In some implementations, the agents used in combination therapy are biosimilars of any of the agents specified above.

[1125] In alternative embodiments, the active compound as described herein may be administered in combination with or alternately with an interferon-alpha antibody, such as, but not limited to, cifamomumab, anilumamumab, and rolizumab. In some embodiments, the agent used for combination therapy is a biosimilar of any of the agents specified above.

[1126] In alternative embodiments, the active compound as described herein may be administered in combination with or alternately with a kinase inhibitor, such as, but not limited to, JAK1 / JAK3 inhibitors, such as, but not limited to, tofacitinib. In alternative embodiments, the active compound described herein may be administered in combination with or alternately with a JAK1 / JAK2 inhibitor, such as, but not limited to, baricitinib. and ruxolitinib

[1127] In alternative embodiments, the active compound as described herein may be administered in combination with or alternately with an anti-VEGF agent, such as, but not limited to, aflibercept (…). Regeneron Pharmaceuticals); Ranibizumab ( Genentech and Novartis); Pilgartanib OSI Pharmaceuticals and Pfizer); bevacizumab ( Genentech / Roche) and Ziv-Abercep

[1128] In alternative embodiments, the active compound described herein may be administered in combination with or alternately with a tyrosine kinase inhibitor, such as, but not limited to, lapatinib. Sunitinib Axitinib Pazopanib; Sorafenib Ponatinib Regrafini Cabozantinib Van der Thani Ramucirumab Lenvatinib Sidnibal Acetate, squalamine lactate, and corticosteroids.

[1129] In another embodiment, the active compound as described herein may be administered in combination with or alternately with an immune checkpoint inhibitor. Non-limiting examples of checkpoint inhibitors include anti-PD-1 or anti-PDL1 antibodies, such as nivolumab. Pembrolizumab Pildizumab, 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 durvalumab And KN035 or anti-CTLA4 antibodies, such as ipilimumab Trimelimumab, AGEN1884, and AGEN2041 (Agenus).

[1130] Non-limiting examples of surfactants that can be used in combination with the active compounds described herein include, but are not limited to:

[1131] Protease inhibitors: Plasma-derived Cl-INH concentrates, such as... (Sanquin) (CSL Behring, Lev Pharma) (CSL Bering) Recombinant human Cl inhibitors, such as Litonavir ( Abbvie, Inc.

[1132] Soluble complement modulators: Soluble complement receptor 1 (TP10) (Avant Immunotherapeutics); sCR1-sLex / TP-20 (Avant Immunotherapeutics); MLN-2222 / CAB-2 (Millenium Pharmaceuticals); Mirococept (Inflazyme Pharmaceuticals);

[1133] Therapeutic antibody: eculizumab / (Alexion Pharmaceuticals); Peroxyzil (Alexion Pharmaceuticals); Raoulizumab / (Alexion Pharmaceuticals); BCD-148 (Biocad); ABP-959 (Amgen); SB-12 (Samsung Bioepsis); Genmab A / S; TNX-234 (Tanox); TNX-558 (Tanox); TA106 (Taligen Therapeutics); Neutrazumab (G2 Therapies); Novelmed Therapeutics; HuMax-CD38 (Genmab A / S); Compounds in Novelmed Therapeutics listed in WO 2018 / 140956 (Alexion Pharmaceuticals);

[1134] Complement component inhibitors: Campstatin / POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix); 4(1MEW)APL-1, APL-2 (Apellis); CP40 / AMY-101, PEG-Cp40 (Amyndas); Eculizumab / (Alexion Pharmaceuticals); Peroxyzil (Alexion Pharmaceuticals); Raoulizumab / (Alexion Pharmaceuticals);

[1135] Multiple kinase inhibitors: Sorafenib Tosylate Imatinib Mesylate Sunitinib malate Ponatinib Axitinib Nidanip Pazopanib HCl Dovirtinib (TKI-258, Oncology Ventures); Gefitinib Linivanil (ABT-869); Clenoni (CP-868596); Masetinib (AB1010); Tevozani Motrazinib diphosphate (AMG-706); Amovatinib (MP-470); TSU-68 (SU6668, olatinib); CP-673451; Ki8751; Tilatinib (BAY 57-9352); PP121; KRN 633; ​​MK-2461; Tyrosine phosphorylation inhibitor (Tyrphostin, AG 1296); Sennoside B; AZD2932; and Trapidil;

[1136] 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);

[1137] Complement C3 or CAP C3 convertase targeting molecules: TT30 (CR2 / CFH) (Alexion); TT32 (CR2 / CR1) (Alexion Pharmaceuticals); Naphamostat (FUT-175, Futhan) (Torri Pharmaceuticals); Casciosab, NM9308 (Novelmed); CVF, HC-1496 (InCode); ALXN1102 / ALXN1103 (TT30) (Alexion Pharmaceuticals); rFH (Optherion); H17 C3 (C3b / iC3b) (EluSysTherapeutics); Mini-CFH (Amyndas); Mirococept (APT070); sCR1 (CDX-1135) (Celldex); CRIg / CFH; Anti-CR3, anti-MASP2, anti-MASP3, anti-C1s, and anti-C1n molecules: (Takeda); TNT003 (Bioverativ / Sanofi); BIVV009 (fka TNT009; Bioverativ / Sanofi); BIVV020 (Bioverativ / Sanofi); OMS721 (Omeros); and OMS906 (Omeros);

[1138] Factor B and Factor Bb inhibitors: IONIS-FB-LRx (Ionis Pharmaceuticals); for example, as described in U.S. Patent Publication 20190071492 under Allergan, International Publication WO2017176651 under True North Therapeutics (now Sanofi), U.S. Patent 9,243,070 (Novelmed); NM8074 (Novelmed); and further described below;

[1139] Plasma kallikrein inhibitors: and

[1140] Bradykinin receptor antagonists:

[1141] Factor D inhibitors, as further described below.

[1142] Receptor agonists: PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717 (Jerini);

[1143] Other: Recombinant human MBL (rhMBL; Enzon Pharmaceuticals); imides and glutarimide derivatives, such as thalidomide, lenalidomide, pomalidomide; and other non-limiting examples that may be used in combination with or alternate with the active compounds described herein or their salts or compositions include the following.

[1144]

[1145]

[1146]

[1147]

[1148] In some implementations, the agent used for combination therapy is a biosimilar of any of the agents specified above.

[1149] In some embodiments, the active compound or its salt or composition as described herein may be provided together with a compound that inhibits the metabolism of an enzyme by which a protease inhibitor is applied. In some embodiments, the compound or salt may be provided together with ritonavir.

[1150] In some embodiments, the active compound or its salt or composition as described herein may be provided in combination with a terminal complement inhibitor (e.g., a complement C5 inhibitor or a C5 convertase inhibitor). In another embodiment, the active compound or its salt or composition as described herein may be provided in combination with eculizumab, a monoclonal antibody against complement factor C5, and marketed by Alexion Pharmaceuticals under the trade name [trade name missing]. Manufacturing and marketing. Eculizumab has been approved by the U.S. FDA for the treatment of PNH and aHUS. In another embodiment, the active compound as described herein, or a salt or composition thereof, may be provided in combination with uracilumab, a monoclonal antibody against complement factor C5, manufactured by Alexion Pharmaceuticals under the trade name [trade name missing]. Production and sales. Raoulizumab has been approved by the US FDA for the treatment of PNH. Other C5 and C5 converting enzyme inhibitors include, but are not limited to, semdicillan (Alnylam); prozelimab (Regeneron); BCD-148 (Biocad); ABP-959 (Amgen); SB-12 (Samsung Bioepis Co., Ltd.); LFG316 (Novartis); coversin (nomacopan; Akari); zilupulan (Ra Pharma); kovarimab (SKY59; Roche / Chugai); and mubodina (Adienne Pharma).

[1151] In some embodiments, the active compound or its salt or composition as described herein is administered in combination with an anti-inflammatory agent, an antimicrobial agent, an anti-angiogenic agent, an immunosuppressant, an antibody, a steroid, an anti-hypertensive agent, or a combination thereof. Examples of such drugs include amikacin, acetaminophen, anthraquinone, anthracycline, azole, amphotericin B, bevacizumab, camptothecin, cefuroxime, chloramphenicol, chlorhexidine, chlorhexidine digluconate, clotrimazole, clotrimazole cephalosporins, corticosteroids, dexamethasone, desamethazone, econazole, ceftazidime, epipodophyllotoxin, fluconazole, flucytosine, fluoropyrimidines, fluoroquinolones, gatifloxacin, glycopeptides, imidazoles, itraconazole, ivermectin, ketoconazole, levofloxacin, macrolides, miconazole, miconazole nitrate, moxifloxacin, natamycin, neomycin, nystatin, ofloxacin, polyhexamethylene biguanide, prednisolone, prednisolone acetate, piperacanib, platinum analogs, polymyxin B, hydroxychloroquine. Propoxybenzonatine ethanesulfonate, pyrimidine nucleoside, ranibizumab, squalane lactate, sulfonamides, triamcinolone, triamcinolone acetonide, triazoles, vancomycin, anti-vascular endothelial growth factor (VEGF) agents, VEGF antibodies, VEGF antibody fragments, vinca alkaloids, timolol, betalol, travoprost, latanoprost, bimatoprost, brimonidine, dzodamine, acetazolamide, pilucarpine, ciprofloxacin, azithromycin, gentamicin, tobramycin, cefazolin, voriconazole, ganciclovir, cidofovir, phosphonoformic acid, diclofenac, napafenamide, ketorolac, ibuprofen, indomethacin, fluocinolone, rimexone, anecrol, cyclosporine, methotrexate, tacrolimus, anti-PDGFR molecules and combinations thereof.

[1152] In some embodiments of this disclosure, the active compound or its salt or composition as described herein may be administered in combination with or alternately with at least one immunosuppressant. As a non-limiting example, the immunosuppressant may be a calcineurin inhibitor, such as cyclosporine or ascomycin, such as cyclosporine A. FK506 (tacrolimus), pimecrolimus, mTOR inhibitors such as rapamycin or its derivatives such as sirolimus Everolimus Tesirolimus, zotalimus, biolimus-7, biolimus-9, rapalog, such as fosfolimus, imidazolidinedione, and rapalog 1H, SIP receptor modulators, such as fingolimod or its analogues, anti-IL-8 antibodies, mycophenolic acid or its salts, such as sodium salts, or their prodrugs, such as mycophenolate mofetil. OKT3 (ORTHOCLONE) Prednisone Buquina sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyguanidin, tropelimus, leflunomide CTLAI-Ig, anti-CD25, anti-IL2R, balithiba Dalizumab Imidazolidin, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus) ), CTLA4lg (abatacept), berazepam, LFA3lg, etanercept (produced by Immunex) (For Sale) Adalimumab Infliximab Anti-LFA-1 antibody, nastatin Enmumab plus vemumab, anti-thymocyte immunoglobulin, cililumab, afasiproxetine plus filizumab, poliostazine, mesalazine, asacol, codeine phosphate, benorilate, fenbufen, naproxen, diclofenac, etodoxacin and indomethacin, tocilizumab (Actemra), sylvant, cosentyx, stelara, lisazumab, cifamumab, aspirin and ibuprofen.

[1153] Examples of anti-inflammatory agents include methotrexate, dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate, flumethonol acetate, flumethonol, clotiprednisolone etopolate, methylhydroxysone, prednisolone acetate, prednisolone sodium phosphate, difluprednisolone, rimexolone, hydrocortisone, hydrocortisone acetate, lodoxamine tromethamine, aspirin, ibuprofen, sulprofen, piroxicam, meloxicam, flurbiprofen, naproxen, ketoprofen, tenoxicam, diclofenac sodium, ketotifen fumarate, diclofenac sodium, napafenamide, bromofenac, flurbiprofen sodium, sulprofen, celecoxib, naproxen, rofecoxib, glucocorticoids, diclofenac, and any combination thereof. In some embodiments, the active compound or its salt or composition as described herein is combined with one or more nonsteroidal anti-inflammatory drugs (NSAIDs) selected from the following: naproxen sodium (Anaprox), celecoxib (Celebrex), sulindac (Clinoril), oxaprazin (Daypro), disalcidil, dolobid, piroxicam (Feldene), indomethacin (Indocin), lodine, meloxicam (Mobic), naproxen (Naprosyn), naproxen (Relafen), ketorolac tromethamine (Toradol), naproxen / esomeprazole (Vimovo), and diclofenac (Voltaren), and combinations thereof.

[1154] In some embodiments, the active compound, or its salt or composition, as described herein, is administered in combination with or alternately with an omega-3 fatty acid or a peroxisome proliferator-activated receptor (PPAR) agonist. Omega-3 fatty acids are known to reduce serum triglycerides by inhibiting DGAT and by stimulating peroxisome and mitochondrial β-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 (e.g., fish oil) are good sources of EPA and DHA, which have been found to regulate lipid metabolism. Omega-3 fatty acids have been found to have beneficial effects on cardiovascular disease, particularly risk factors for mild hypertension and hypertriglyceridemia, and on the activity of coagulation factor VII phospholipid complexes. Omega-3 fatty acids lower serum triglycerides, increase serum HDL-cholesterol, reduce systolic and diastolic blood pressure and pulse rate, and decrease the activity of coagulation factor VII phospholipid complexes. Furthermore, omega-3 fatty acids appear to be well-tolerated and do not cause any serious side effects. One form of omega-3 fatty acid is a concentrate of long-chain polyunsaturated omega-3 fatty acids derived from fish oil, containing DHA and EPA, and marketed under a trademark. Sales. This form of omega-3 fatty acid is described, for example, in U.S. Patents 5,502,077, 5,656,667, and 5,698,594, the disclosures of which are incorporated herein by reference.

[1155] Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors associated with retinol, steroid, and thyroid hormone receptors. Three distinct PPAR subtypes exist, products of different genes, commonly designated PPAR-α, PPAR-β / δ (or δ only), and PPAR-γ. The general class of pharmacological agents that stimulate peroxisome activity is called PPAR agonists, such as PPAR-α agonists, PPAR-γ agonists, and PPAR-δ agonists. Some pharmacological agents are combinations of PPAR agonists, such as α / γ agonists, and some others have dual agonist / antagonist activity. Fibrates such as fenofibrate, bezafibrate, clofibrate, and gemfibrozil are PPAR-α agonists and are used to lower triglyceride-rich lipoproteins, increase HDL, and reduce atherogenic dense LDL in patients. Fibrates are typically administered orally to these patients. Fenofibrate, or 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropionic acid, 1-methylethyl ester, has been considered a medicinal active ingredient for many years due to its efficacy in lowering blood triglyceride and cholesterol levels.

[1156] In some embodiments, this disclosure provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need an effective amount of an active compound as described herein, or a salt or composition thereof, in combination with an anti-VEGF agent. Non-limiting examples of anti-VEGF agents include, but are not limited to, aflibercept (…). Regeneron Pharmaceuticals); Ranibizumab ( Genentech and Novartis); Pilgartanib OSI Pharmaceuticals and Pfizer); bevacizumab (Avastin; Genentech / Roche); lapatinib Sunitinib Axitinib Pazopanib; Sorafenib Ponatinib Regrafini Cabozantinib (Abometyx) ); Van der Tany Ramucirumab Lenvatinib ziv-Abercep Sidnibal Acetate, squalene lactate, and corticosteroids, including but not limited to triamcinolone acetonide.

[1157] In some embodiments, this disclosure provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need an effective amount of an active compound or its salt or composition as described herein in combination with a complement C5 inhibitor, said complement C5 inhibitor being, for example, a non-limiting example of a complement C5 inhibitor described herein and referred to in the table above as a potential therapeutic agent for combination therapy, including but not limited to eculizumab (Alexion Pharmaceuticals); uracilizumab (Alexion Pharmaceuticals); LFG316 (Novartis / Morphosys); semdicillin, semdicillin / ALN-CC5 (Alnylam); ARC1005 (Novo Nordisk); Coversin (Akari Therapeutics); Mubodine (Adienne Pharma); RA101348 (Ra Pharma); SOBI002 (Swedish Orphan Biovitrum); SOMAmer (SomaLogic); Erdigna (Adienne Pharma); Pharma); ARC1905 (Ophthotech); MEDI7814 (MedImmune); NOX-D19 (Noxxon); IFX-1, CaCP29 (InflaRx); PMX53, PMX205 (Cephalon, Teva); CCX168 (ChemoCentryx); ADC-1004 (AlligatorBioscience); 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.); zilupulan (Ra Pharma); and kovarimab (SKY59; Roche / Chugal).

[1158] In some embodiments, this disclosure provides a method for treating or preventing age-related macular degeneration (AMD) by administering to a subject in need an effective amount of an active compound or its salt or composition as described herein in combination with an anti-prescription agent, such as the anti-prescription agent described above, including but not limited to NM9401 (Novelmed).

[1159] In some embodiments, this disclosure provides a method for treating or preventing age-related macular degeneration (AMD) by administering to a subject in need an effective amount of an active compound or its salt or composition as described herein in combination with a complement C3 inhibitor, said complement C3 inhibitor being, for example, the complement C3 inhibitors described above, including but not limited to, campstatin or campstatin analogues, such as campstatin / 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); naftomostat (FUT-175, Futhan) (Torri Pharmaceuticals); Casio monoclonal antibody, NM9308 (Novelmed); CVF, HC-1496 (InCode) ALXN1102 / ALXN1103 (TT30) (Alexion Pharmaceuticals); rFH (Optherion); H17 C3 (C3b / iC3b) (EluSys Therapeutics); Mini-CFH (Amyndas) Mirococept (APT070); sCR1 (CDX-1135) (Celldex); and CRIg / CFH.

[1160] In some embodiments, this disclosure provides a method for treating or preventing age-related macular degeneration (AMD) by administering to a subject in need an effective amount of an active compound, or a salt or composition thereof, as described herein, in combination with an anti-factor H or anti-factor B agent selected from anti-FB siRNA (Alnylam); FCFD4514S (Genentech / Roche) SOMAmer for CFB and CFD (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6 and AMY-301 (Amyndas).

[1161] In some embodiments, this disclosure provides a method for treating or preventing age-related macular degeneration (AMD) by administering to a subject in need an effective amount of an active compound, or a salt or composition thereof, as described herein, in combination with an anti-MASP2, anti-C1s, or anti-CR3 molecule, such as, but not limited to: Cynryze (ViroPharma / Baxter); TNT003 (True North); OMS721 (Omeros); OMS906 (Omeros); and Imprime PGG (Biothera).

[1162] In some embodiments, this disclosure provides a method for treating or preventing age-related macular degeneration (AMD) by administering to a subject in need an effective amount of an active compound or its salt or composition as described herein in combination with a variety of kinase inhibitors, such as those described herein, including but not limited to sorafenib tosylate. Imatinib Mesylate Sunitinib malate Ponatinib Axitinib Nidanip Pazopanib HCl Dovirtinib (TKI-258, Oncology Ventures); Gefitinib Linivanil (ABT-869); Clenoni (CP-868596); Masetinib (AB1010); Tevozani Modexenib diphosphate (AMG-706); Amovatinib (MP-470); TSU-68 (SU6668, olatinib); CP-673451; Ki8751; Tiratitinib (BAY 57-9352); PP121; KRN 633; ​​MK-2461; Tyrosine phosphorylation inhibitor (AG1296); Sennoside B; AZD2932; and Trapidil.

[1163] In some embodiments, this disclosure provides a method for treating or preventing cold agglutinin disease (CAD) by administering to a subject in need an effective amount of an active compound or its salt or composition as described herein in combination with a complement C5 inhibitor, said complement C5 inhibitor being, for example, a non-limiting example of a complement C5 inhibitor described herein and referred to in the table above as a potential therapeutic agent for combination therapy, including but not limited to eculizumab (Alexion Pharmaceuticals); ravolizumab (Alexion Pharmaceuticals); LFG316 (Novartis / Morphosys); semdicillin, semdicillin / ALN-CC5 (Alnylam); ARC1005 (Novo Nordisk); Coversin (Akari Therapeutics); Mubodine (Adienne Pharma); RA101348 (Ra Pharma); SOBI002 (Swedish Orphan Biovitrum); SOMAmer (SomaLogic); Erdigna (Adienne Pharma). 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.); zilupulan (Ra Pharma); and kovarimab (SKY59; Roche / Chugal).

[1164] In some embodiments, this disclosure provides a method for treating or preventing cold agglutinin disease (CAD) by administering to a subject in need an effective amount of an active compound or its salt or composition as described herein in combination with an anti-prescription agent, such as anti-prescription agents as described above, including but not limited to NM9401 (Novelmed).

[1165] In some embodiments, this disclosure provides a method for treating or preventing cold agglutinin disease (CAD) by administering to a subject in need an effective amount of an active compound or its salt or composition as described herein in combination with a complement C3 inhibitor, said complement C3 inhibitor being, for example, the complement C3 inhibitors described above, including but not limited to, campstatin or campstatin analogues, such as campstatin / 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); naftomostat (FUT-175, Futhan) (Torri Pharmaceuticals); Casiomab, NM9308 (Novelmed); CVF, HC-1496 (InCode) ALXN1102 / ALXN1103 (TT30) (Alexion Pharmaceuticals); rFH (Optherion); H17 C3 (C3b / iC3b) (EluSys Therapeutics); Mini-CFH (Amyndas) Mirococept (APT070); sCR1 (CDX-1135) (Celldex); and CRIg / CFH.

[1166] In some embodiments, this disclosure provides a method for treating or preventing cold agglutinin disease (CAD) by administering to a subject in need an effective amount of an active compound, or a salt or composition thereof, as 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 for CFB and CFD (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6 and AMY-301 (Amyndas).

[1167] In some embodiments, this disclosure provides a method for treating or preventing cold agglutinin disease (CAD) by administering to a subject in need an effective amount of an active compound as described herein, or a salt or composition thereof, in combination with an anti-MASP2, anti-C1s, or anti-C1n molecule, such as, but not limited to, those anti-MASP2, anti-C1s, or anti-C1n molecules. (Takeda); (Bering CSL) (Pharming) (Bering CSL); TNT003 (Bioverativ / Sanofi); BIVV009 (Bioverativ / Sanofi); BIVV020 (Bioverativ / Sanofi); OMS721 (Omeros); OMS906 (Omeros); and Imprime PGG (Biothera)

[1168] In some embodiments, this disclosure provides a method for treating or preventing cold agglutinin disease (CAD) by administering to a subject in need an effective amount of an active compound or its salt or composition as described herein, in combination with a variety of kinase inhibitors, such as those described herein, including but not limited to sorafenib tosylate. Imatinib Mesylate Sunitinib malate Ponatinib Axitinib Nidanip Pazopanib HCl Dovirtinib (TKI-258, Oncology Ventures); Gefitinib Linivanil (ABT-869); Clenoni (CP-868596); Masetinib (AB1010); Tevozani Modexenib diphosphate (AMG-706); Amovatinib (MP-470); TSU-68 (SU6668, olatinib); CP-673451; Ki8751; Tiratitinib (BAY 57-9352); PP121; KRN 633; ​​MK-2461; Tyrosine phosphorylation inhibitor (AG1296); Sennoside B; AZD2932; and Trapidil.

[1169] In some embodiments, this disclosure provides a method for treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject of need an effective amount of an active compound as described herein, or a salt or composition thereof, in combination with an additional complement system inhibitor or another active compound with a different biological mechanism of action. In another embodiment, this disclosure provides a method for treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject of need an effective amount of an active compound as described herein, or a salt or composition thereof, in combination with or alternately with eculizumab or ravolizumab.

[1170] In another embodiment, this disclosure provides a method for treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering, in combination with or alternately with CP40, an effective amount of the active compound as described herein or a salt or composition thereof to a subject in need.

[1171] In some embodiments, an additional agent is PEGylated CP40. CP40 is a peptide inhibitor that exhibits a strong binding affinity for C3b and inhibits hemolysis of erythrocytes in paroxysmal nocturnal hemoglobinuria (PNH). In some embodiments, additional agents are complement component inhibitors, such as, but not limited to, campstatin / 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 (GW786034HCl); Dovirtinib (TKI-258, CHIR-258); Linivanib (ABT-869); Clennonib (CP-868596); Macitinib (AB1010); Tevozanib (AV-951); Motasenib diphosphate (AMG-706); Amovatinib (MP-470); TSU-68 (SU6668, Olantinib); CP-673451; Ki8751; Tilatinib; PP121; Pazopanib; KRN633; Dovirtinib (TKI-258) disaccharide; MK-2461; Tyrosine phosphorylation inhibitor (AG) 1296); Dovirtinib (TKI258) lactate; Sennoside B; Sunitinib; AZD2932; and Trapidil; Anti-factor H or anti-factor B agents, such as anti-FB siRNA (Alnylam); FCFD4514S (Genentech / Roche) SOMAmer for CFB and CFD (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6 and AMY-301 (Amyndas); Complement C3 or CAP C3 convertase targeting molecules, such as, but not limited to, TT30 (CR2 / CFH) (Alexion); TT32 (CR2 / CR1) (Alexion Pharmaceuticals); Naphamostat (FUT-175, Futhan) (Torri Pharmaceuticals); Casiomab, NM9308 (Novelmed); CVF, HC-1496 (InCode); ALXN1102 / ALXN1103 (TT30) (Alexion Pharmaceuticals); rFH (Optherion); H17 C3 (C3b / iC3b) (EluSys Therapeutics);Mini-CFH (Amyndas), Mirococept (APT070); sCR1 (CDX-1135) (Celldex); CRIg / CFH, anti-CR3, anti-MASP2, anti-C1s or anti-C1n molecules, such as but not limited to Cinryze (Takeda); TNT003 (True North); OMS721 (Omeros); OMS906 (Omeros); and Imprime PGG (Biothera);

[1172] In some embodiments, this disclosure provides a method for treating or preventing rheumatoid arthritis by administering, in combination or alternately with other complement system inhibitors or active agents acting through different mechanisms of action, an effective amount of a composition comprising an active compound as described herein or a salt or composition thereof to a subject in need.

[1173] In another embodiment, this disclosure provides a method for treating or preventing rheumatoid arthritis by administering, in combination with or alternately with methotrexate, an effective amount of the active compound as described herein, or a salt or combination thereof, to a subject in need.

[1174] In some embodiments, the active compound or its salt or composition as described herein is administered in combination with or alternately with at least one other therapeutic agent selected from: salicylates, including aspirin ( BAYER ) and bis(salicylates) Nonsteroidal anti-inflammatory drugs (NSAIDs); non-selective inhibitors of cyclooxygenases (COX-1 and COX-2) enzymes, including diclofenac. Ibuprofen Ketoprofen Naproxen Piroxicam (Feldene), Etoduolic Acid Indomethacin, Oxaptin Naphazoline Meloxicam Selective cyclooxygenase-2 (COX-2) inhibitors, including celecoxib. Disease-modifying antirheumatic drugs (DMARDs), including imidazolidinedione Cyclosporine (Sandimmune) ), gold salt Hydroxychloroquine Leflunomide Methotrexate Penicillamine and sulfasalazine Biologics, including abatacept Inasip Infliximab Adalimumab and Analexin Corticosteroids, including betamethasone Cortisone Dexamethasone Methylprednisolone Prednisolone Prednisone Aristocort; gold salts, including aurenophenone. Glucosamine Aurolate; Myochrysine; or any combination thereof.

[1175] In some embodiments, this disclosure provides a method for treating or preventing multiple sclerosis by administering, in combination or alternately with other complement system inhibitors or active agents acting through different mechanisms of action, an effective amount of an active compound as described herein or a salt or combination thereof to a subject of need.

[1176] In another embodiment, this disclosure provides a method for treating or preventing multiple sclerosis by administering, in combination with or alternately with a corticosteroid, an effective amount of an active compound as described herein or a salt or combination thereof to a subject in need.

[1177] Examples of corticosteroids include, but are not limited to, prednisone, dexamethasone, methylprednisolone, and methylprednisolone. In some embodiments, the active compound as described herein, or a salt or composition thereof, is combined with at least one anti-multiple sclerosis agent, for example selected from the following: (teriflunomide) (interferon β-1a) (interferon β-1b) (Glatiramer acetate) (interferon β-1b) (Fingomod) (alemumab), Novantrone (mitoxantrone) (Pegylated interferon β-1a) (interferon β-1a) (Dimethyl fumarate) (Natazumab) (Methylprednisolone), high-dose oral administration (Prednisolone), HPACTHAR (ACTH) or combinations thereof.

[1178] In some embodiments, the active compound or its salt or composition as described herein may be used in combination with other pharmaceutical agents to mitigate or reduce the side effects of the agents. For example, in some embodiments, the active compound or its salt or composition as described herein may be used in combination with adoptive cell transfer therapy to reduce inflammatory responses associated with such therapy, such as cytokine-mediated responses, such as cytokine release syndrome. In some embodiments, adoptive cell transfer therapy includes the use of chimeric antigen receptor T cells (CAR T). In some embodiments, adoptive cell transfer therapy includes the use of chimeric antigen receptor T cells (CAR T) or dendritic cells to treat hematologic or solid tumors, such as B-cell-related hematologic cancers. In some embodiments, the hematologic or solid tumor is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), pancreatic cancer, glioblastoma, or CD19-expressing cancer.

[1179] In other alternative embodiments, the active compound or its salt or composition as described herein may be provided in combination with eculizumab or ravolizumab for the treatment of PNH, aHUS, STEC-HUS, ANCA-vasculitis, AMD, CAD, C3 glom...

Claims

1. A compound selected from: or a pharmaceutically acceptable salt thereof; in: Each n is 1; Each m is independently 0 or 1; Z is C(O); X 1 It is S; X 2 is the key; X 3 is C(R 17 ); X 4 is N; X 5 is C or Si; X 6 yes X 7 Selected from O and CR 5 R 6 ; R 1 and R 2 All are hydrogen; R 3 and R 4 are hydrogen; or R 3 is hydrogen, R 4 It is hydroxyl; R 5 and R 6 All are hydrogen; R 7 , R 8 , R 11 and R 12 each of is hydrogen; R 9 Selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR 30 and phenyl; and R 10 Selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR 30 and phenyl; or or R 9 and R 10 Together with the atoms to which they are attached, they 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; or carbonyl; or R 9 and R 11 Together with the atoms to which they are attached, they form a 3- to 8-membered carbon ring, and R 10 It is hydrogen; or R 7 and R 11 Together with the atoms to which they are attached, they form 1 or 2 carbon bridges, and R 10 It is hydrogen; Each R 13 It is hydrogen; R 14 , R 15 and R 16 independently selected from hydrogen, halogen, C1-C6 alkyl and -O-phenyl; R 17 It is hydrogen; R 19 and R 20 All are hydrogen; R 21 is selected from C1-C6 haloalkyl, -O-C1-C6 haloalkyl, C1-C6 alkyl, -O-C1-C6 alkyl, phenyl and -O-phenyl, wherein R 21 Each of the groups is optionally substituted with 1, 2, 3 or 4 substituents independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; Each R 25 Independently selected from hydrogen, SF5, halogen and C1-C6 alkyl; R 26 yes R 29 is a C1-C6 alkyl group; Each R 30 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl and phenyl; and Each R 32 It is hydrogen; Wherein for the compounds of Formula I and Formula II, at least one of the following is satisfied: a.X 5 is Si; B R 9 and R 10 Together with the carbon to which they are attached, they 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; or carbonyl; C 9 and R 11 Together with the atoms to which they are attached, they form a 3- to 8-membered carbon ring; or dR 7 and R 11 Together with the atoms to which they are attached, they form 1 or 2 carbon bridges; and Wherein for the compound of formula XIV, R 14 Not hydrogen.

2. The compound according to claim 1, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof, wherein R 21 Selected from C1-C6 alkyl and -O-C1-C6 alkyl.

4. A compound according to any one of claims 1 to 3, wherein X 5 It is C.

5. The compound according to any one of claims 1 to 3, wherein R 3 and R 4 All are hydrogen.

6. A compound according to any one of claims 1 to 3, wherein R 3 is hydrogen, and R 4 It's a hydroxyl group.

7. A compound according to any one of claims 1 to 3, wherein: (i)R 7 is hydrogen, and R 11 is hydrogen; and / or (ii) R 9 is hydrogen; or R 9 and R 10 Combine to form a spiro ring; or R 9 and R 11 Combine to form a cyclopropyl ring or a 4-8 membered carbon ring.

8. The compound according to claim 7, wherein R 9 and R 10 Combine to form a 5-membered heterocyclic spiro ring or a 5-membered carbocyclic spiro ring.

9. The compound according to claim 7, wherein R 9 and R 11 Combine to form a cyclopropyl ring.

10. The compound according to claim 7, wherein R 10 It's methyl.

11. A compound according to any one of claims 1 to 3, wherein R 21 Selected from: (i) C1-C6 haloalkyl; (ii) -O-C1-C6 haloalkyl; and (iii) phenyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl.

12. The compound according to claim 11, wherein (a) R 21 is unsubstituted, (b) R 21 is substituted by at least one halogen group, or (c) R 21 Substituted with at least one C1-C6 alkyl group.

13. The compound according to claim 12, wherein R 21 Substituted with 1 fluorinated group.

14. The compound according to claim 12, wherein R 21 Substituted with 1 methyl group.

15. A compound according to any one of claims 1 to 3, wherein R 30 Selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl.

16. The compound according to claim 15, wherein R 30 It's methyl.

17. The compound according to claim 15, wherein R 30 It's CF3.

18. The compound according to claim 15, wherein R 31 It's methyl.

19. The compound according to claim 15, wherein R 31 It's CF3.

20. The compound according to claim 1, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

21. A compound selected from: or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 21 and a pharmaceutically acceptable carrier.

23. Use of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 22 in the preparation of a medicament for treating a C1s-mediated condition selected from ophthalmic conditions, C3 glomerulopathy, paroxysmal nocturnal hemoglobinuria (PNH), angioedema, autoimmune hemolytic anemia, cold agglutinin disease, transplant rejection, trauma, inflammation, sepsis, multiple organ dysfunction syndrome, endotoxemia, end-stage renal disease, renal failure, neuromyelitis optica, common variable immunodeficiency and asthma.

24. The use according to claim 23, wherein the condition is selected from age-related macular degeneration (AMD), C3 glomerulonephritis, dense deposit disease, hereditary angioedema, angioneurotic edema, acute ACE-induced angioedema, ischemic reperfusion injury, acute kidney injury, delayed graft function, antibody-mediated rejection and allergic asthma.

25. The use according to claim 23, wherein the medicament is administered to a human subject.

Images