RU2801278C2 - Aryl, heteroaryl and heterocyclic pharmaceutical compounds for the treatment of medical disorders - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound selected from

and its pharmaceutically acceptable salt. The invention also relates to a pharmaceutical composition for the treatment of a disorder mediated by complement factor D, based on the said compound.

EFFECT: new compounds and a pharmaceutical composition based on them have been obtained, which can be used in medicine for the treatment of disorders mediated by complement factor D, for example, ophthalmic, respiratory, cardiovascular and other diseases.

25 cl, 19 dwg, 2 tbl

Description

Cross-references to related applications

The present application claims priority under U.S. Patent Application No. 62/465,782, filed March 1, 2017; and U.S. Application No. 62/466,301, filed March 2, 2017; where the contents of each are incorporated into this application by reference for all purposes.

Field of invention

The present invention provides aryl, heteroaryl and heterocyclic drugs for the treatment of medical disorders such as complement-mediated disorders.

State of the art

The complement system is part of the innate immune system that does not adapt to changes during the lifetime of the host, but is recruited and used by the adaptive immune system. For example, it aids or supplements the ability of antibodies and phagocytic cells to eliminate pathogens. This complex regulatory pathway allows for rapid response to pathogenic organisms while protecting host cells from destruction. More than thirty proteins and protein fragments make up the complement system. These proteins act through opsonization (increased phagocytosis of antigens), chemotaxis (attraction of macrophages and neutrophils), cell lysis (damage to the membranes of foreign cells), and agglutination (aggregation and binding together of pathogens).

The complement system is activated in three ways: classical, alternative and lectin. Complement factor D plays an early and central role in the activation of the alternative pathway of the complement cascade. Activation of the alternative complement pathway is initiated by spontaneous hydrolysis of the thioether bond at C3 to form C3(H ₂ O), which binds to Factor B to form the C3(H ₂ O)B complex. Complement Factor D acts by cleaving Factor B in the C3(H ₂ O)B complex to form Ba and Bb. The Bb fragment remains bound to C3(H ₂ O) to form an alternative pathway for C3-convertase C3(H ₂ O)Bb. In addition, C3b generated by any of the C3 convertases also associates with factor B to form C3bB, which factor D cleaves to activate the C3bBb late stage alternative pathway C3 convertase. This latter form of the alternative C3 convertase pathway can provide important downstream amplification in all three of the defined complement pathways, ultimately leading to the recruitment and assembly of additional factors in the complement pathway, including the cleavage of C5 to C5a and C5b. C5b acts in conjunction with factors C6, C7, C8 and C9 in a membrane attack complex that can destroy pathogenic cells by cell lysis.

Dysfunction or excessive complement activation has been associated with certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. For example, activation of the alternative pathway of the complement cascade promotes the production of C3a and C5a, both potent anaphylatoxins that also play a role in a number of inflammatory disorders. Therefore, in some cases it is desirable to reduce the response of the complement pathway, including the alternative complement pathway. Some examples of complement-mediated disorders include age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis, and rheumatoid arthritis.

Age-related macular degeneration (AMD) is the leading cause of vision loss in industrialized countries. Based on a number of genetic studies, there is evidence of an association between the complement cascade and macular degeneration. Individuals with mutations in the gene encoding complement factor H have a fivefold increased risk of macular degeneration, and individuals with mutations in other complement factor genes also have an increased risk of AMD. People with factor H mutations also have elevated levels of C-reactive protein, a marker of inflammation. Without adequate factor H function, the alternative pathway of the complement cascade is overactivated, resulting in cell damage.

Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant hematological disorder characterized by the expansion of hematopoietic stem cells and mature blood progeny cells that are deficient in certain surface proteins. RBCs in PNH are unable to modulate complement activation on their surface, leading to the typical feature of PNH, chronic complement-mediated intravascular anemia. Currently, only one product, the anti-C5 monoclonal antibody eculizumab, has been approved in the US for the treatment of PNH. However, many patients treated with eculizumab remain anemic and many patients still require blood transfusions. In addition, treatment with eculizumab requires lifelong intravenous injections.

Additional complement-mediated disorders include those classified as component C3 glomerulopathy (C3G). C3G is a newly defined entity consisting of dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) that encompasses the chronic kidney disease population where increased activity of the alternative complement pathway and terminal complement components leads to the formation of glomerular deposits composed exclusively of the C3 component. complement and in the absence of immunoglobulin (Ig).

Immune complex membrane proliferative glomerulonephritis (IC-MPGN) is a kidney disease that shares many clinical, pathological, genetic and laboratory features with C3G, and therefore can be considered a C3G related disease. In the majority of patients with IC-MPGN, the underlying disease or disorder is most often infections, autoimmune diseases, or monoclonal gammopathy for which renal disease is secondary. Patients with idiopathic IC-MPGN may have low C3 levels and normal C4 levels similar to those seen with C3G, as well as many of the same genetic or acquired factors that are associated with abnormal alternative pathway activity. Although hypotheses currently exist suggesting that most IC-MPGN is due to overactivity of the classical pathway, patients with low C3 and normal C4 are likely to have significant overactivity of the alternative pathway. IC-MPGN patients with low C3 and normal C4 may benefit from alternative pathway inhibition.

Other disorders that are associated with the complement cascade include atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia or hemodialysis, optic neuromyelitis (NMO), myasthenia gravis (MG), fatty liver, non-alcoholic steatohepatitis (NASH), inflammation of the liver, cirrhosis of the liver, liver failure, dermatomyositis and amyotrophic lateral sclerosis.

Factor D is an attractive target for inhibition or regulation of the complement cascade due to its early and significant role in the alternative complement pathway and its potential role in signal amplification in the classical and lectin complement pathways. Factor D inhibition effectively interrupts the pathway and attenuates the formation of the membrane attack complex.

Although initial attempts have been made to develop factor D inhibitors, there are currently no clinically approved small molecule factor D inhibitors. Examples of factor D inhibitor compounds are described in the following inventions.

U.S. Patent 6,553,340 to Biocryst Pharmaceuticals entitled "Compounds useful in the complement, coagulate and kallikrein pathways and method for their preparation" describes fused bicyclic ring compounds that are potential factor D inhibitors. Development of the factor D inhibitor BCX1470 was terminated due to lack of specificity and short half-life of the compound.

PCT Patent Publication WO 2012/093101 owned by Novartis entitled "Indole compounds or analogues correspondingly useful for the treatment of age-related macular degeneration" describes certain factor D inhibitors. Additional factor D inhibitors are described by Novartis in PCT Patent Publications WO 2013/ WO 2013/192345, WO 2014/002051, WO 2014/002052, WO 2014/002053, WO 2014/002054, WO 2014/002057, WO 2014/002058, WO 2014/0 02059, WO2014/005150, WO2014/ 009833, WO 2014/143638, WO 2015/009616, WO 2015/009977 and WO 2015/066241.

An article published by Novartis titled "Structure-Based Library Design and Fragment Screening for the Identification of Reversible Complement Factor D Protease Inhibitors" (Vulpetti et al., J. Med. Chem. 10.1021/acs.jmedchem.6b01684) describes a virtual active site mapping for regions that contribute a lot to binding energy using factor D crystal structure and NMR-based screening (structure-based drug design (SBDD) and fragment-based screening (FBD)). Another Novartis article titled "Small-molecule factor D inhibitors targeting the alternative complement pathway" (Maibaum et al., Nat. Chem. Bio. 2016; 12;1105) discloses small molecule inhibitors developed using a structural approach combined with screening. fragment based.

PCT patent publication WO 2017/098328 from Lifesci Pharmaceuticals entitled "Therapeutic Inhibitory Compounds" describes various factor D inhibitors with variations in the heterocyclic ring of the central heterocyclic ring. PCT patent publication WO 2018/015818 is also entitled "Therapeutic Inhibitory Compounds" and describes factor D inhibitors without a cyclic central core.

PCT Patent Publication WO 2004/045518 Bristol-Myers Squibb entitled "Open chain prolyl urea-related modulators of androgen receptor function" describes open chain prolyl urea and thiourea compounds for the treatment of androgen receptor related conditions such as age-related diseases, such as sarcopenia.

PCT patent publication WO 1999/048492 owned by Japan Tobacco Inc. entitled "Amide derivatives and nociceptin antagonists" describes compounds with a proline-like core and aromatic substituents linked to the proline core via amide bonds useful in the treatment of pain.

Ferring B.V. and Yamanouchi Pharmaceutical Co. 1TD. PCT patent publication WO 1993/020099 titled "CCK and/or gastrin receptor ligands" describes compounds with a proline-like core and heterocyclic substituents linked to the proline core via amide linkages for the treatment of, for example, gastric disorders or pain.

PCT patent publication WO 1995/029697 by Alexion Pharmaceuticals entitled "Methods and compositions for the treatment of glomerulonephritis and other inflammatory diseases" describes antibodies directed to the C5 complement pathway for the treatment of glomerulonephritis and inflammatory conditions involving pathological activation of the complement system. The anti-C5 antibody eculizumab (Soliris®) from Alexion Pharmaceutical is currently the only specific complement antibody on the market and is the first and only approved treatment for paroxysmal nocturnal hemoglobinuria (PNH).

On February 25, 2015, Achillion Pharmaceuticals filed for PCT Patent No. PCT/US 2015/017523 and US patent application no. 14/631,090 entitled "Alkyne Compounds for Treatment of Complement Mediated Disorders"; PCT patent application no. PCT/US 2015/017538 and US patent application no. 14/631,233 entitled "Amide Compounds for Treatment of Complement Mediated Disorders"; PCT patent application no. PCT/US 2015/017554 and US patent application no. 14/631,312 entitled "Amino Compounds for Treatment of Complement Mediated Disorders"; PCT patent application no. PCT/US 2015/017583 and US patent application no. 14/631,440 entitled "Carbamate, Ester, and Ketone Compounds for Treatment of Complement Mediated Disorders"; PCT patent application no. PCT/US 2015/017593 and US Patent Application No. 14/631,625 entitled "Aryl, Heteroaryl, and Heterocyclic Compounds for Treatment of Complement Mediated Disorders"; PCT patent application no. PCT/US 2015/017597 and US patent application no. 14/631,683 entitled "Ether Compounds for Treatment of Complement Mediated Disorders"; PCT patent application no. PCT/US 2015/017600 and US patent application no. 14/631,785 entitled "Phosphonate Compounds for Treatment of Complement Mediated Disorders"; and patent application PCT No. PCT/US 2015/017609 and US patent application no. 14/631,828 entitled "Compounds for Treatment of Complement Mediated Disorders" and US Patent Application No. 14/630,959 entitled "Factor D Inhibitors Useful for Treating Infectious Disorders." Additional factor D complement inhibitors are described in US Patent Nos. 9,828,396; 9,695,205; 9,598,446; 9,732,103; 9,796,741; 9,732,104; 9,663,543; 9,758,537 and 9,643,986; international publications Nos. WO 2015/130784; WO 2015/130795; WO 2015/130806; WO 2015/130830; WO2015/130838; WO2015/130842; WO 2015/130845 and WO 2015/130854; and US Patent Publications Nos. US 2017-0298084; US 2016-0362398; US 2017-0189410; US 2017-0298085; US 2018-0030075; US 2016-0362399; US 2018-0022766; US 2016-0362433; US 2017-0260219; US 2016-0362432; US 2018-0022767; US 2016-0361329 and US 2017-0226142; all owned by Achillion Pharmaceuticals, Inc.

Given the wide range of medical disorders caused by negative immune or inflammatory responses, new compounds are needed for treatment.

The essence of the invention

The present invention includes a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition, wherein at least one of R ¹² or R ¹³ in group A is an aryl, heteroaryl or heterocyclic substituent which is R ³² . In one embodiment, a compound or salt or composition thereof, as described herein, is used to treat a medical disorder that is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade), a disorder or abnormality of a cell that adversely affects the cell's ability to participate in or respond to normal complement activity, including the alternative complement pathway, or an undesired complement-mediated response to medical treatment, such as surgery or other medical procedure, or administration of a pharmaceutical or biopharmaceutical drug, blood transfusion, or other administration of allogeneic tissue, or liquids.

In certain aspects of the invention, the compound provided herein contains one or more of the following:

a. ring A formula:

b. ring A formula:

c. ring A formula:

d. ring B formula:

e. ring C, selected from:

f. ring C formula:

g. ring C selected from a proline spirocycle (such as that described in the article published by Litter et al. titled "Development of a Manufacturing Process for an HCV Protease Inhibitor Candidate Molecule" (Organic Process Research & Development 2015, 19, 270-283) ;

h. R ³² selected from a cyclic sulfonimidamide (such as that described in the article published by Pemberton et al. titled "Synthesis and Functionalization of Cyclic Sulfonimidamides: A Novel Chiral Heterocyclic Carboxylic Acid Biostere" (ACS Med. Chem Letters 2012, 3, 574 -578);

i. A compound of the invention with at least one R ²⁰¹ substituent selected from aminoalkyl-, alkylaminoalkyl-, heterocycloalkyl-, and hydroxyalkyl; -alkyl-O-alkyl, including -CH ₂ OCH ₃ , -alkyl-S-alkyl, -alkyl-N(alkyl)-alkyl, -alkyl-NH-alkyl, -aliphatic moiety-O-aliphatic moiety, -aliphatic moiety -S-aliphatic moiety, -aliphatic moiety-N(aliphatic moiety)-aliphatic moiety, -aliphatic moiety-NH-aliphatic moiety, -aliphatic moiety-O-heterocycle, -aliphatic moiety-S-heterocycle, -aliphatic moiety-N( aliphatic fragment)-heterocycle, -aliphatic fragment-NH-heterocycle, -alkyl-NHC(O)haloalkyl, -alkyl-NR ⁹ C(O)haloalkyl, -alkyl-C(O)NHhaloalkyl, -alkyl-C(O) NR ⁹ haloalkyl, -alkyl-NHC(O) haloalkyl, -alkyl-NR ⁹ C(O)aliphatic moiety, -alkyl-C(O)NHaliphatic moiety, -alkyl-NR ⁹ C(O)aliphatic moiety, -alkyl- NR ⁹ C(O)aliphatic, -substituted alkyl-N(R ⁹ )-substituted alkyl, alkyl-heteroaryl, heteroaryl, heterocycle, alkyl-heterocycle, -alkyl-O-haloalkyl, -N(aliphatic) ₂ ; and where each R ²⁰¹ may be optionally substituted as defined in the terminology section below, and where each R ²⁰¹ may be optionally substituted with R ³⁰¹ which may be directly linked to R ²⁰¹ or may be linked to R ²⁰¹ via amino, hydroxyl, thio, carboxyl, phosphate, phosphonate or sulfonate bond optionally and appropriately;

j. A compound with at least one R ²⁰¹ substituent on ring A;

k. A compound with at least one R ²⁰¹ substituent on ring B;

l. A compound with at least one R ²⁰¹ substituent on ring C;

m. Certain stable acylated embodiments and acyl prodrugs of the present invention which include an R ³⁰¹ substituent, as further described below.

These compounds can be used to treat medical conditions in a patient in need thereof, usually a human. The active compound may act as an inhibitor of the factor D complement cascade. In one embodiment, a method of treating such a disorder is provided, which comprises administering an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition, as described in more detail below.

In some embodiments, compounds are provided that have minimal effect on a BSEP (bile salt exporting pump) (e.g., with an IC ₅₀ greater than about 20, 30, 40, 50, 60, 75, or 100 μM or greater) or with a therapeutic a BSEP index relative to complement factor D inhibition (eg, IC ₅₀ - BSEP inhibition/IC _{50 -} complement inhibitor D inhibition) of at least 50, 100, 200, 300, 400, 500, 750, or 1000 or more. BSEP inhibition is correlated with cholestatic drug-induced liver injury. Some compounds of the present invention with low BSEP inhibition have at least one R ²⁰¹ .

In some embodiments, the compounds of the present invention exhibit minimal hydrolysis of the amide bond between the C-ring and the B-ring in vivo, for example by incorporating a proline that has a cis-substituent to the proline-carbonyl bond towards the B-ring. In some embodiments, the cis substituent is at the Q3 position or at the Q2 position, or is a group that connects Q3 and Q2.

It has also been found that inserting a B-ring substituent ortho to the amide (e.g. 2-(L1)-3-methyl-6-substituted pyridine or 2-(L1)-3-cyclopropyl-6-substituted pyridine) can reduce the possibility of formation of reactive metabolites.

In one aspect of the invention, an acylated R ³⁰¹ variant of the active compound of the invention is provided which has an extended half-life or other beneficial pharmacokinetic properties that can be achieved by in vivo stabilization of albumin. In some embodiments, the implementation of the acylated analogue may include several fragments linked in a linear, branched or cyclic manner. In some embodiments, one or more amino acids are used as the fatty acid-terminated linker. In one non-limiting example, a non-natural amino acid, such as described below, for example, 8-amino-3,6-dioxaoctanoic acid (one or more in sequence), is covalently linked to a selected complement factor D inhibitor of the present invention through a functional group, such as a carboxylic acid, sulfonyl, hydroxyl or amino group. See, in general, Lau, et al., "Discovery of the Once-Weekly Glucagon-Like Peptide-l (GLP-1) Analogue Semiglutide", J. Med. Chem., 2015, 58, 7370-7380. In this embodiment, 8-amino-3,6-dioxaoctanoic acid or a similar molecule is covalently linked to an aliphatic acid, including but not limited to C ₁₆ , C ₁₈ , C ₂₀ aliphatic acid or dicarboxylic acid, including but not limited to , C ₈ , C ₁₀ , C ₁₂ , C ₁₄ , C ₁₆ , C ₁₈ or C ₂₀ diacid. One or more amino acids may also be used in the selected configuration to add length or functionality. More generally, non-limiting embodiments include the use of a divalent linker moiety, such as a dicarboxylic acid, amino acid, diamine, hydroxycarboxylic acid, hydroxyamine, dihydroxy compound, or other compound that has at least two functional groups that can link the parent molecule to another binding moiety, and which can be stabilized with albumin in vivo. In some embodiments, 2, 3, 4, or 5 linking moieties are covalently linked in a sequential, branched, or cyclic manner to the parent compound. In some embodiments, the R ³⁰¹ acyl group is located at a position of the active compound that does not significantly adversely affect complement factor D inhibition of the molecule, such as (i) a substituent on the R ³² group or (ii) a substituent on a C-ring such as proline, or as a substituent on a C-ring substituent such as R ¹ , R ² or R ³ , including, for example, a bridge moiety such as a fused cyclopropyl on a proline ring. In some embodiments, the acyl group has a C ₁₂ , C ₁₄ , C ₁₆ , C ₁₈ , C ₂₀ , C ₂₂ or C ₂₄ aliphatic or heteroaliphatic carbon range.

In one embodiment, the disorder is associated with an alternative pathway of the complement cascade. In yet another embodiment, the disorder is associated with the classical complement pathway. In a further embodiment, the disorder is associated with the lectin complement pathway. Alternatively, the active compound, or a salt or prodrug thereof, may act by a different mechanism of action than the complement cascade, or in particular as a complement factor D inhibitor, to treat the disorder described herein.

In one embodiment, a method of treating C3 glomerulonephritis (C3G) is provided which comprises administering to a patient an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or its isolated isomer, optionally in a pharmaceutically acceptable composition. In one embodiment, a method of treating paroxysmal nocturnal hemoglobinuria (PNH) is provided which comprises administering to a patient an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or its isolated isomer, optionally in a pharmaceutically acceptable composition. In another embodiment, a method is provided for treating wet or dry age-related macular degeneration (AMD) in a patient, which comprises administering to the patient an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog , N-oxide or its isolated isomer, optionally in a pharmaceutically acceptable composition. In another embodiment, a method of treating rheumatoid arthritis in a patient is provided, which comprises administering to the patient an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof. , optionally in a pharmaceutically acceptable composition. In another embodiment, a method of treating multiple sclerosis in a patient is provided, which comprises administering to the patient an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof. , optionally in a pharmaceutically acceptable composition.

In other embodiments, the active compound, or a salt or prodrug thereof, as described herein, can be used to treat fatty liver and conditions resulting from fatty liver, non-alcoholic steatohepatitis (NASH), inflammation of the liver, cirrhosis and liver failure, dermatomyositis, or amyotrophic lateral sclerosis.

The active compound or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide or isolated isomer thereof, optionally in a pharmaceutically acceptable composition as described herein, is also useful for administration in combination (in the same or different dosage form) or for alternating with a second pharmaceutical agent for use in reducing or reducing the side effect of the second pharmaceutical agent. For example, in one embodiment, the active compound can be used in combination with adoptive cell transfer therapy to reduce the inflammatory response associated with such therapy, for example, a cytokine-mediated response such as cytokine response syndrome. In one embodiment, the adoptive cell transfer therapy is a chimeric antigen receptor (CAR T) or dendritic cell therapy used to treat a hematologic or solid tumor, eg, B cell-associated hematologic cancer. In one embodiment, the hematologic or solid tumor is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), pancreatic cancer, glioblastoma, or cancer that expresses CD19. In one embodiment, the inflammatory response elicited is a cytokine-mediated response.

Another embodiment is provided which comprises administering an effective amount of the active compound, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition, to a patient for the treatment of an ocular, pulmonary, gastrointestinal, or other disorder, in which you can get a therapeutic effect from external or local delivery.

Any of the compounds described herein (e.g., Formula I, Formula II, Formula III, Formula IV, or Formula V) may be administered to the eye in any desired form of administration, including intravitreal, intrastromal, intracameral, subtenon, sub-retinal, retrobulbar, peribulbar, suprachoroidal, choroidal, subchoroidal, conjunctival, subconjunctival, episcleral, posterior parascleral, scleral, pericorneal, and nasolacrimal injections or via mucus, mucin, or mucosal barrier, by immediate or controlled release. In some embodiments, the active compound comprises a lipophilic group, such as a lipophilic acyl group, that is delivered to the eye in a polymeric drug delivery system, such as polylactic acid, polylactide-co-glycolide, polyglycolide, or another degradable polymer, or a combination thereof, or other type of lipophilic material to be delivered to the eye. In some embodiments, the lipophilic active molecule is more soluble in the polymeric or other form of the delivery system than in the ocular fluid. In other embodiments, the active compound provided herein can be used to treat or prevent a disorder in a patient mediated by complement factor D or an excess or disruptive amount of the C3 complement component of the complement enhancement loop. As examples, the invention includes methods for treating or preventing complement-related disorders that are induced by antibody-antigen interactions, a component of an immune or autoimmune disorder, or ischemic injury. The invention also relates to methods for reducing inflammation or an immune response, including an autoimmune response, mediated or dependent on factor D.

In another embodiment, a method of treating a patient, usually a human, with a complement system-mediated disorder is provided, which comprises administering a prophylactic antibiotic or vaccine to reduce the likelihood of bacterial infection during treatment using one of the compounds described herein. In embodiments, the patient, usually a human, is administered a prophylactic vaccine before, during, or after treatment with one of the compounds described herein. In some embodiments, a prophylactic antibiotic is administered to a patient, usually a human, before, during, or after treatment with one of the compounds described herein. In some embodiments, the infection is a meningococcal infection (eg, sepsis and/or meningitis), aspergillosis, or an infection caused by an encapsulated organism, such as Streptococcus pneumoniae or Haemophilus influenza type b (Hib), especially in children. In other embodiments, the vaccine or antibiotic is administered to the patient following infection with an infection due to or concomitant with inhibition of the complement system.

The present disclosure provides a compound of Formula I, Formula II, or Formula III:

or a pharmaceutically acceptable salt, isotopic analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

Where:

A is selected from A1, A2 and A3;

B is selected from B1, B2 and B3;

or B is B4;

B4 is defined separately below;

C is selected from C1, C2, C3 and C4;

or C is C5;

C5 is defined separately below;

and where for the compounds of Formula I there is at least one of the following restrictions: A is A3, B is B3, or C is C4;

C1 represents

Q ¹ is N(R ¹ ), C(R ¹ R ^1' ), C(R ¹ R ^1' )C(R ¹ R ^1' ), C(R ¹ R ^1' )C(R ¹ R ^{1 '} )C(R ¹ R ^1' ), S or O;

Q ² is C(R ² R ^2' ), C(R ² R ^2' )C(R ² R ^2' ), C(R ² R ^2' )C(R ² R ^2' )C(R ² R ^2' ), N(R ² ), S, O or C(R ² R ^2' )O;

Q ³ is N(R ³ ), S, O, C(R ³ R ^3' ), C(R ³ R ^3' )C(R ³ R ^3' ) or C(R ³ R ^3' )C( R ³ R ^3' )C(R ³ R ^3' );

X ¹ and X ² are independently N, CH or CZ;

or X ¹ and X ² together represent C=C;

where X ¹ is directly connected to L3, and X ² is directly connected to L; And

where Q ¹ , Q ² , Q ³ , X ¹ and X ² are selected so that the result is a stable connection;

Z is F, Cl, NH ₂ , CH ₃ , CH ₂ D, CHD ₂ or CD ₃ ;

R ¹ , R ^1' , R ² , R ^2' , R ³ and R ^3' are independently selected in each case, if necessary, and only in the case of the formation of a stable compound, from hydrogen, R ²⁰¹ , R ³⁰¹ , halogen (and, typically fluorine, chlorine, bromine), hydroxyl, nitro, cyano, amino, alkyl, including C ₁ -C ₆ alkyl, alkenyl, including C ₂ -C ₆ alkenyl, alkynyl, including C ₂ -C ₆ alkynyl, alkoxy, including C ₁ -C ₆ alkoxy, alkanoyl, including C ₂ -C ₆ alkanoyl, thioalkyl, including C ₁ -C ₆ alkylthio, hydroxyC ₁ -C ₆ alkyl, aminoC ₁ -C ₆ alkyl, -C ₀ -C ₄ alkylNR ⁹ R ¹⁰ , -C(O)OR ⁹ , -OR', -NR'R'', -OC(O)R ⁹ , -NR ⁹ C(O)R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ , -NR ⁹ C(O)OR ¹⁰ , haloalkyl, including C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ haloalkoxy;

or R ¹ and R ^1' are taken together to form a 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, or S;

or R ³ and R ^3' are taken together to form a 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, or S;

or R ² and R ^2' are taken together to form a 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring;

where each of the above spiro rings may be optionally substituted with 1 or more substituents independently selected from R ²⁰¹ , halogen (and in particular F), hydroxyl, cyano, -COOH, alkyl, including C ₁ -C ₄ alkyl (and, in particular methyl), alkenyl, including C ₂ -C ₄ alkenyl, alkynyl, including C ₂ -C ₄ alkynyl, alkoxy, including C ₁ -C ₆ alkoxy, alkanoyl, including C ₂ -C ₄ alkanoyl, hydroxyC ₁ -C ₄ alkyl, (mono- and dialkylamino)C ₁ -C ₄ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -O-alkyl (C ₃ -C ₇ cycloalkyl), haloalkyl, including C ₁ -C ₆ haloalkyl, and haloalkoxy, including C ₁ -C ₆ haloalkoxy;

or, in an alternative embodiment, each of the above spiro rings may be optionally substituted with an aryl ring;

or R ¹ and R ² are taken together to form a 3-membered carbocyclic ring, a 4- to 6-membered carbocyclic or aryl ring, or a 4- to 6-membered heterocyclic or heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, O and S;

or R ² and R ³ are taken together to form a 3- to 6-membered carbocyclic or aryl ring or a 3- to 6-membered heterocyclic or heteroaryl ring;

where each of these fused R ¹ and R ² or R ² and R ³ rings, or, as a rule, R ¹ , R ² , R ³ , R ^1' , R ^2' or R ^3' , is optionally substituted with 1 or more substituents , independently selected from R ²⁰¹ , halogen (and in particular F), hydroxyl, cyano, -COOH, alkyl, including C ₁ -C ₄ alkyl (and in particular methyl), alkenyl, including C ₂ -C ₄ alkenyl, alkynyl, including C ₂ -C ₄ alkynyl, alkoxy, including C ₁ -C ₄ alkoxy, alkanoyl, including C ₂ -C ₄ alkanoyl, hydroxyC ₁ -C ₄ alkyl, (mono- and dialkylamino)C ₀ -C ₄ alkyl, alkyl (C ₃ -C ₇ cycloalkyl), including -C ₁ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -O-(C ₃ -C ₇ cycloalkyl), haloalkyl, including C ₁ -C ₆ haloalkyl , and haloalkoxy, including C ₁ -C ₆ haloalkoxy;

or R ¹ and R ^1' are taken together to form a carbonyl group;

or R ² and R ^2' are taken together to form a carbonyl group;

or R ³ and R ^3' are taken together to form a carbonyl group;

or R ¹ and R ² are taken together to form a carbon-carbon double bond;

or R ² and R ³ are taken together to form a carbon-carbon double bond;

R and R' are independently selected from H, R ²⁰¹ , alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;

or, in an alternative embodiment, R, R' and R'' are independently selected from R ³⁰¹ , heteroalkyl, H, R ²⁰¹ , alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, and a heteroaliphatic moiety;

R ⁹ and R ¹⁰ are independently selected from hydrogen, alkyl, including C ₁ -C ₆ alkyl, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl) , and -O-C ₀ -C ₄ alkyl(C ₃ -C ₇ cycloalkyl);

C2 is selected from:

q is 0, 1, 2, or 3;

r is 1, 2, or 3;

R ⁴⁴ , R ^44' , R ⁴⁵ , R ^45' are independently selected in each case, if necessary and only in the case of the formation of a stable compound, from hydrogen, R ²⁰¹ , halogen (and in particular fluorine, chlorine, bromine), hydroxyl , nitro, cyano, amino, alkyl, including C ₁ -C ₆ alkyl, alkenyl, including C ₂ -C ₆ alkenyl, alkynyl, including C ₂ -C ₆ alkynyl, alkoxy, including C ₁ -C ₆ alkoxy, alkanoyl, including C ₂ -C ₆ alkanoyl, thioalkyl, including C ₁ -C ₆ alkylthio, hydroxyC ₁ -C ₆ alkyl, aminoC ₁ -C ₆ alkyl, -C ₀ -C ₄ alkylNR ⁹ R ¹⁰ , -C(O)OR ⁹ , -OC(O)R ⁹ , -NR ⁹ C(O)R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ , -NR ⁹ C(O)OR ¹⁰ , haloalkyl, including C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ haloalkoxy;

or R ⁴⁴ and R ^44' or R ⁴⁵ and R ^45' or two R ⁴⁷ groups are taken together to form a carbonyl group;

or R ⁴⁴ and R ^44' or R ⁴⁵ and R ^45' are substituted with a 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, or S;

where each of the above spiro rings may be optionally substituted with 1 or more substituents independently selected from R ²⁰¹ , halogen (and in particular F), hydroxyl, cyano, -COOH; alkyl, including (C ₁ -C ₄ alkyl (and in particular methyl), alkenyl, including C ₂ -C ₄ alkenyl, alkynyl, including C ₂ -C ₄ alkynyl, alkoxy, including C ₁ -C ₆ alkoxy, alkanoyl , including C ₂ -C ₄ alkanoyl, hydroxyC ₁ -C ₄ alkyl, (mono- and dialkylamino) C ₁ -C ₄ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -O-alkyl ( C ₃ -C ₇ cycloalkyl), haloalkyl, including C ₁ -C ₆ haloalkyl, and haloalkoxy, including C ₁ -C ₆ haloalkoxy;

or R ⁴⁴ and R ⁴⁵ or R ^44' and R ^45' are taken together to form a 4 to 6 membered carbocyclic or aryl ring or a 4 to 6 membered heterocyclic or heteroaryl ring; each of which may be optionally substituted with 1 or more substituents;

each of the fused rings or typically R ⁴⁴ , R ^44' , R ⁴⁵ or R ^45' is optionally substituted with 1 or more substituents independently selected from R ²⁰¹ , halogen (and in particular F), hydroxyl, cyano, -COOH, alkyl, including C ₁ -C ₄ alkyl (and in particular methyl), alkenyl, including C ₂ -C ₄ alkenyl, alkynyl, including C ₂ -C ₄ alkynyl, alkoxy, including C ₁ -C ₄ alkoxy, alkanoyl, including C ₂ -C ₄ alkanoyl, hydroxyC ₁ -C ₄ alkyl, (mono- and dialkylamino)C ₀ -C ₄ alkyl, alkyl (C ₃ -C ₇ cycloalkyl), including -C ₁ -C ₄ alkyl (C ₃ - C ₇ cycloalkyl), -O-(C ₃ -C ₇ cycloalkyl), haloalkyl, including C ₁ -C ₆ haloalkyl, and haloalkoxy, including C ₁ -C ₆ haloalkoxy;

C3 is selected from:

X ³ is C(R ¹ R ^1' );

X ⁴ is N or CH;

X ^4a is N, CH or CZ;

X ⁵ and X ⁶ are C(R ¹ R ^1' );

or X ⁴ and X ⁵ or X ⁵ and X ⁶ together represent C=C;

X ⁷ is SO or SO ₂ ;

X ⁸ is C(R ¹ R ^1' ) or N(R ⁴³ );

X ^5a is independently selected from C(R ¹ R ^1' )HO;

Q ⁴ is N or CH;

Q ⁵ is N(R ⁴⁷ ) or C(R ⁴⁶ R ^46' );

Q ^5a is independently selected from C(R ⁴⁷ R ⁴⁷ ), N(R ⁴⁷ ), O, S, SO and SO ₂ ;

Q ⁶ is N(R ⁴⁷ ), C(R ⁴⁶ R ^46' ), S or O;

Q ⁷ is C(R ⁴⁶ R ^46' ), S or N(R ⁴⁷ );

Q ⁸ , Q ⁹ , Q ¹⁰ , Q ¹¹ and Q ¹² are independently C(R ² R ^2' ), S, SO, SO ₂ , O, N(R ² ), B(R ⁵⁰ ) or Si(R ⁴⁹ ) ₂ ;

R ⁴⁰ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, where each group may be optionally substituted;

R ⁴² is halo, hydroxy, alkoxy including C ₁ -C ₆ alkoxy, haloalkoxy including C ₁ -C ₆ haloalkoxy, -SH or -S(C ₁ -C ₆ alkyl);

R ⁴³ is hydrogen, acyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, where each group may be optionally substituted;

R ⁴⁶ and R ^46' independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, where each group may be optionally substituted;

or R ⁴⁶ and R ^46' are taken together to form an optionally substituted 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, or S;

R ⁴⁷ is hydrogen, acyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, where each group may be optionally substituted;

or two R ⁴⁷ groups are taken together to form a carbonyl group;

R ⁴⁹ is halo, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, where each group may be optionally substituted;

R ⁵⁰ is hydroxy or C ₁ -C ₆ alkoxy;

or X ¹ and Q ⁸ or Q ⁸ and Q ⁹ or Q ⁹ and Q ¹⁰ or Q ¹⁰ and Q ¹¹ or Q ¹¹ and Q ¹² or Q ¹² and X ² may form a carbon-carbon double bond;

or two Q ^5a groups or X ^4a and Q ^5a groups may form a carbon-carbon double bond;

and if any of these groups may be further optionally substituted, as that term is defined in the Terminology section below, if desired, a stable compound is obtained to achieve the desired effect, which has a chemical sense to the skilled person, and the group is not redundant (i.e., as known in the art, alkyl substituted with alkyl is in excess; however, for example, alkoxy substituted with alkoxy is not;

or the C3 central core fragment is a small beta-turn mimetic such as a benzodiazepine, Friedinger's lactam, 2-oxo-1,3-oxazolidine-4-carboxylate, or a β-D-glucose backbone. See De Marco, R. et al., "In-peptide synthesis of di-oxazolidinone and dehydroamino acid-oxazolidinone motifs as β-turn inducers", J. Org. Biomol. Chem., 2013, 11, 4316-4326, Hirschmann, R.F. et al., The β-D-Glucose Scaffold as a β-Turn Mimetic, Accounts Chem. Res., 2009, 42, 1511-1520 and Smith, A.B., et al., Accounts of Chem. Res., 2011, 44, 180-193. In another embodiment, the central core fragment C may contain a reverse-rotation mimetic, which may include, but is not limited to; a non-peptide residue, a metal chelate mimetic, or a foldamer. See Nair, R.V. et al., "Synthetic turn mimetics and hairpin nucleators: Quo Vadimus?", Chem. Comm., 2014, 50, 13874-13884. In other embodiments, the central core fragment C may comprise a cyclic amino acid with limited conformational freedom, including, but not limited to, a derivative of (S)- or (R)-α-trifluoromethylpyroglutamic acid. See Chaume, G. et al., "Concise access to enantiopure (S)- or (R)-α-trifluoromethyl pyroglutamic acids from ethyl trifluoropyruvate-base chiral CF3-oxazolidines (Fox)", J. Fluor. Chem., 2008, 129, 1104-1109 and Andre, C. et al., "(S)-ABOC: A Rigid Bicyclic β-Amino Acid as Turn Inducer", Org. Lett., 2012, 14, 960-963. In other embodiments, the central core fragment C may contain a foldamer monomeric unit such as, but not limited to, oxazolidin-2-one. See Tomasii, C., Angelicim G. and Castellucci, N., "Foldamers Based on Oxazolidin-2-ones", Eur. J. Org. Chem., 2011, 3648-3669;

C4 selected from:

or C4 is selected from:

or C4 is selected from:

is a single or double bond;

C5 is selected from:

A1 selected from:

or A1 is selected from:

A2 is selected from:

A3 selected from:

or A3 is selected from:

or A3 is selected from:

or A3 is selected from:

or A3 is selected from:

or A3 is selected from:

or A3 is selected from:

X ⁵¹ , X ⁵² and X ⁵³ are independently selected from N, CR ³¹ and CR ²⁰¹ ;

where at least one of X ⁵¹ , X ⁵² and X ⁵³ is selected from CR ²⁰¹ ;

X ⁵⁴ , X ⁵⁵ and X ⁵⁶ are independently selected from N, CR ³¹ and CR ²⁰¹ ;

R ¹⁰⁴ is selected from R ²⁰¹ , C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, deuterium, -CO ₂ H, CO ₂ R ⁹ , heteroaryl, F, Cl, Br and cyano;

R ²⁰¹ is selected from aminoalkyl-, alkylaminoalkyl-, heterocycloalkyl- and hydroxyalkyl; -alkyl-O-alkyl, including -CH ₂ OCH ₃ , -alkyl-S-alkyl, -alkyl-N(alkyl)-alkyl, -alkyl-NH-alkyl, -aliphatic moiety-O-aliphatic moiety, -aliphatic moiety -S-aliphatic moiety, -aliphatic moiety-N(aliphatic moiety)-aliphatic moiety, -aliphatic moiety-NH-aliphatic moiety, -aliphatic moiety-O-heterocycle, -aliphatic moiety-S-heterocycle, -aliphatic moiety-N( aliphatic fragment)-heterocycle, -aliphatic fragment-NH-heterocycle, -alkyl-NHC(O)haloalkyl, -alkyl-NR ⁹ C(O)haloalkyl, -alkyl-C(O)NHhaloalkyl, -alkyl-C(O) NR ⁹ haloalkyl, -alkyl-NHC(O) haloalkyl, -alkyl-NR ⁹ C(O)aliphatic moiety, -alkyl-C(O)NH-aliphatic moiety, -alkyl-NR ⁹ C(O)-aliphatic moiety, -alkyl-NHC(O)-aliphatic fragment, -substituted alkyl-N(R ⁹ )-substituted alkyl, alkyl-heteroaryl, -alkyl-O-haloalkyl, heteroaryl, heterocycle, alkyl-heterocycle, -N(aliphatic fragment) ₂ ; and where each R ²⁰¹ may be optionally substituted as defined in the terminology section below, and where R ²⁰¹ may be optionally substituted with R ³⁰¹ which may be directly linked to R ²⁰¹ or may be linked to R ²⁰¹ via amino, hydroxyl, thio, a carboxylic acid, phosphate, phosphonate or sulfonate bond;

In an alternative embodiment, R ²⁰¹ is selected from R ³⁰¹ , -alkyl-CN, -alkyl-NR ⁹ C(O)alkenyl, -alkyl-SO ₂ -alkyl, and -alkyl-S(O)NR ⁹ -alkyl;

In an alternative embodiment, R ²⁰¹ is substituted with oxime and —C(O)O alkyl;

R ²⁰² is selected from aryl, heteroaryl and heterocycle, where the aryl, heteroaryl or heterocyclic ring is substituted with R ²⁰¹ ;

R ³⁰¹ selected from the following:

i. fatty acid residue. Examples are short chain fatty acids with 3, 4 or 5 carbon atoms in the aliphatic moieties, medium chain fatty acids with aliphatic tails of 6, 7, 8, 9, 10, 11 or 12 carbon atoms, long chain fatty acids which contain aliphatic tails of 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 carbon atoms, or a very long fatty acid that contains 22, 23, 24, 25, 26, 27, or 28 or more carbon atoms in aliphatic moieties. The chain of the aliphatic moiety can be saturated, monounsaturated, diunsaturated, triunsaturated, polyunsaturated or alkynyl.

ii. Unsaturated fatty acids can be used in cis or trans configuration and include, but are not limited to, oleic acid, ω6 fatty acid such as linoleic acid, ω3 fatty acid such as α-linolenic acid, docosahexaenoic acid, stearidonic acid, eicosapentaenoic acid , docosapentaenoic acid, eicosatetraenoic acid, myristolenic acid, palmitoleic acid, sapienic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, nervonic acid, eicosadienoic acid, docosadienoic acid, linolenic acid, t-linolenic acid, pinolene oic acid, eleostearic acid , β-eleostearic acid, midic acid, eicosatric acid, linoleic acid, linoelaidic acid, α-linolenic acid, arachidonic acid, erucic acid, and docosahexaenoic acid. Non-limiting examples of saturated fatty acids that can be used to prepare the prodrugs of the present invention are caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, and cerotic acid.

iii. An amino acid residue that occurs naturally or is synthetic and includes, for example, α, β γ or δ amino acids. Naturally occurring amino acids include those found in proteins, such as glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine, and histidine. . In some embodiments, the implementation of the amino acid is in the L-configuration. Alternatively, the amino acid may be used in the D-configuration or in a mixture of the L- and D- configurations. Alternatively, the amino acid may be a derivative of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β- alanila , β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β -asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl or β-histidinyl. Additional amino acids include selenocysteine, pyrrolysine, N-formylmethionine, γ-aminobutyric acid (GABA), δ-aminolevulinic acid, aminobenzoic acid (including 4-aminobenzoic acid), aminoisobutyric acid, dehydroalanine, cystathionine, lanthionine, diencolic acid, diaminopimelic acid, norvaline , alloisoleucine, t-leucine, α-aminoheptanoic acid, pipecolic acid, α, β-diaminopropionic acid, α,γ-diaminobutyric acid, ornithine, glutamic acid, allothreonine, homocysteine, β-aminobutyric acid, α-aminoisobutyric acid, isovaline, sarcosine, N-ethylglycine, N-propylglycine, N-isopropylglycine, N-methylalanine, N-ethylalanine, N-methyl-β-alanine, isoserine, norleucine, homoserine, O-methylhomoserine, O-ethylhomoserine, homonorleucine, carboxyglutamic acid, hydroxyproline , hypusine, pyroglutamic acid and α-hydroxy-γ-aminobutyric acid.

iv. An extended unnatural amino acid residue between the amino group and the carboxylic acid, which can be used either alone or as a linker to another prodrug moiety. Examples include amino acids where the amino acid and carboxylic acid are separated by an aliphatic or heteroaliphatic moiety (a non-limiting example is 8-amino-3,6-dioxaoctanoic acid), e.g., alkyl, alkenyl, alkynyl, ethylene glycol, propylene glycol, alkylene glycol, or the like, a moiety, e.g. , with 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more straight, branched, or cyclic atoms or moieties (eg, alkylene glycol moieties) to provide the desired properties, if desired. In some embodiments, the amino acid contains one or more internal amine, carbonyl, carboxyl, oxo, thio, phosphate, or phosphonate moieties in the chain of the heteroaliphatic moiety.

v. A residue of one or more amino acids linked to a terminal fatty acid or to a terminal moiety such as hydrogen or alkyl. In one non-limiting example, 8-amino-3,6-dioxaoctanoic acid (one or more in sequence) is covalently linked to a selected complement factor D inhibitor of the present invention through a functional group such as a carboxylic acid, sulfonyl, hydroxyl, or amino group. See, in general, Lau, et al., "Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semiglutide", J. Med. Chem., 2015, 58, 7370-7380. 8-Amino-3,6-dioxaoctanoic acid is covalently bonded to an aliphatic acid including but not limited to C16, C18, C20 aliphatic acid or dicarboxylic acid including but not limited to C8, C10, C12, C14, C16 , C18 or C20 diacid. One or more amino acids may also be used in the selected configuration to add length or functionality.

R ⁴ , R ⁵ and R ⁶ are selected from hydrogen, -JCHO, -JC(O)NH ₂ , -JC ₂ -C ₆ alkanoyl, -JC(O)NH(CH ₃ ), -J-COOH, -JP( O)(OR ⁹ ) ₂ , -JOC(O)R ⁹ , -JC(O)OR ⁹ , -JC(O)N(CH ₂ CH ₂ R ⁹ )(R ¹⁰ ), -JNR ⁹ C(O) R ¹⁰ , -JSO ₂ NH ₂ , -JS(O)NH ₂ , -JC(CH ₂ ) ₂ F, -JCH(CF ₃ )NH ₂ , -JC(O)C ₀ -C ₂ alkyl (C ₃ - C ₇ cycloalkyl), -JNR ⁹ (C ₂ -C ₆ alkanoyl), -JNR ⁹ C(O)NR ⁹ R ¹⁰ , -JSO ₂ (C ₁ -C ₆ alkyl), -JSO ₂ (C ₁ -C ₆ haloalkyl), -JSO ₂ NR ⁷ R ⁷ , -JSO=NH(C ₁ -C ₆ alkyl), -J-nitro, -J-halogen, -J-hydroxyl, -J-phenyl, 5- to 6- membered heteroaryl, -J-cyano, -J-cyanoimino, -J-amino, -J-imino, -C ₁ -C ₆ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ heterocycloalkyl), -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl),

each of R ⁴ , R ⁵ and R ⁶ other than hydrogen, nitro, halogen, cyano, cyanoimino or -CHO is optionally substituted with one or more amino, imino, halogen, hydroxyl, cyano, cyanoimino, alkyl, including C ₁ -C ₆ alkyl, alkoxy, including C ₁ -C ₆ alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C ₁ -C ₄ alkylamino), -C ₁ -C ₆ haloalkyl and haloalkoxy, including C ₁ -C ₆ haloalkoxy;

J is independently selected from a covalent bond, alkylene including C ₁ -C ₄ alkylene, O-alkylene including -OC ₁ -C ₄ alkylene, alkenylene including C ₂ -C ₄ alkenylene, and alkynylene including C ₂ -C ₄ alkynylene ;

R ^6' represents hydrogen, halogen, hydroxyl, C ₁ -C ₄ alkyl, -C ₀ -C ₄ alkyl(C ₃ -C ₇ cycloalkyl) or C ₁ -C ₄ alkoxy;

or R ⁶ and R ^6' may be taken together to form an oxo, vinyl or imino group;

R ⁷ represents hydrogen, alkyl, including C ₁ -C ₆ alkyl or -C ₀ -C ₄ alkyl(C ₃ -C ₇ cycloalkyl);

R ⁸ and R ^8' are selected from hydrogen, halogen, hydroxyl, alkyl, including C ₁ -C ₆ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), alkoxy, including C ₁ -C ₆ alkoxy, and (C ₁ -C ₄ alkylamino)C ₀ -C ₂ alkyl;

or R ⁸ and R ^8' are taken together to form an oxo group;

or R ⁸ and R ^8' are taken together with the carbon atom to which they are attached to form a 3-membered carbocyclic ring;

R ¹⁶ is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, -C ₁ -C ₆ alkyl, alkenyl, including C ₂ -C ₆ alkenyl, alkanoyl, including C ₂ -C ₆ alkanoyl, alkoxy, including C ₁ -C ₆ alkoxy, -C ₀ -C ₄ alkyl (mono- and di-C ₁ -C ₆ alkylamino), -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), haloalkyl, including C ₁ -C ₆ haloalkyl, and haloalkoxy, including C ₁ -C ₆ haloalkoxy;

R ¹⁹ is hydrogen, alkyl including C ₁ -C ₆ alkyl, alkenyl including C ₂ -C ₆ alkenyl, alkanoyl including C ₂ -C ₆ alkanoyl, -SO ₂ C ₁ -C ₆ alkyl, (mono- and di-C ₁ -C ₆ alkylamino)C ₁ -C ₄ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -C ₀ -C ₄ alkyl (C ₃ -C ₇ heterocycloalkyl), -C ₀ -C ₄ alkyl(aryl) or C ₀ -C ₄ alkyl(heteroaryl), where each R ¹⁹ other than hydrogen is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, amino, -COOH and -C( O)OC ₁ -C ₄ alkyl;

X ¹¹ is N or CR ¹¹ ;

X ¹² is N or CR ¹² ;

X ¹³ is N or CR ¹³ ;

X ¹⁴ is N or CR ¹⁴ ;

where no more than 2 of X ¹¹ , X ¹² , X ¹³ and X ¹⁴ are N;

where one of R ¹² and R ¹³ is R ³² and the other is R ³¹ or R ³² ;

and where in the absence of R ¹³ and R ³² on ring A, then R ¹² is R ³² ;

and where in the absence of R ¹² and R ³² on ring A, then R ¹³ is R ³² ;

R ³¹ is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, -COOH, haloalkyl, including C ₁ -C ₆ haloalkyl, haloalkoxy, including C ₁ -C ₆ haloalkoxy, alkyl, including C ₁ -C ₆ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), alkenyl, including C ₂ -C ₆ alkenyl, alkanoyl, including C ₂ -C ₆ alkanoyl, alkoxy, including C ₁ -C ₆ alkoxy, alkenyloxy, including C ₂ -C ₆ alkenyloxy, -C(O)OR ⁹ , thioalkyl, including C ₁ -C ₆ thioalkyl, -C ₀ -C ₄ alkylNR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO ₂ R ⁹ , -SO ₂ NR ⁹ R ¹⁰ , -OC(O)R ⁹ , and -C(NR ⁹ )NR ⁹ R ¹⁰ , each of R ³¹ other than hydrogen, halogen, hydroxyl, nitro, cyano, haloalkyl, including C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy, optionally substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, -COOH, -C(O)NR ⁹ R ¹⁰ , haloalkyl, including C ₁ -C ₆ haloalkyl, haloalkoxy, including C ₁ -C ₆ haloalkoxy, phenyl and 4- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S; each phenyl or 4- to 7-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, alkyl, including C ₁ -C ₆ alkyl, alkenyl, including C ₂ -C ₆ alkenyl, alkanoyl , including C ₂ -C ₆ alkanoyl, alkoxy, including C ₁ -C ₆ alkoxy, (mono- and di-C ₁ -C ₆ alkylamino)C ₀ -C ₄ alkyl, alkyl ether including C ₁ -C ₆ alkyl ether, (- C ₀ -C ₄ alkyl)(C ₃ -C ₇ cycloalkyl), C ₁ -C ₆ haloalkyl and haloalkoxy, including C ₁ -C ₆ haloalkoxy;

R ³² is selected from aryl, heteroaryl and heterocycle, where aryl, heteroaryl or heterocyclic ring may be optionally substituted;

in one embodiment, R ³² is substituted with R ³⁰¹ , -CH ₂ -R ³⁰¹ or R ²⁰¹ ;

R ¹¹ , R ¹⁴ and R ¹⁵ are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, -O(PO)(OR ⁹ ) ₂ , -(PO)(OR ⁹ ) ₂ , alkyl including C ₁ -C ₆ alkyl, alkenyl, including C ₂ -C ₆ alkenyl, alkynyl, including C ₂ -C ₆ alkynyl, C ₂ -C ₆ alkenyl (aryl), C ₂ -C ₆ alkenyl (cycloalkyl), C ₂ -C ₆ alkenyl (heterocycle ), C ₂ -C ₆ alkenyl (heteroaryl), C ₂ -C ₆ alkynyl (aryl), C ₂ -C ₆ alkynyl (cycloalkyl), C ₂ -C ₆ alkynyl (heterocycle), C ₂ -C ₆ alkynyl (heteroaryl ), alkanoyl, including C ₂ -C ₆ alkanoyl, alkoxy, including C ₁ -C ₆ alkoxy, thioalkyl, including C ₁ -C ₆ thioalkyl, -C ₀ -C ₄ alkyl (mono- and di-C ₁ -C ₆ alkylamino), -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -C ₀ -C ₄ alkoxy (C ₃ -C ₇ cycloalkyl), haloalkyl, including C ₁ -C ₆ haloalkyl, and haloalkoxy, including C ₁ -C ₆ haloalkoxy;

X ¹⁵ represents NH, O or S;

X ¹⁶ is CR ¹² ;

X ¹⁷ is N or CR ¹³ ;

X ¹⁸ is CR ¹² ;

X ¹⁹ is N or CR ¹³ ;

X ²⁰ is NH or O;

X ²¹ is N or CR ¹⁴ ;

X ²² is N or CR ¹³ ;

X ²³ is CR ¹² ;

X ²⁴ is O or S;

X ²⁶ is N or CR ⁴¹ ;

X ²⁷ is CR ¹² , NH, or O;

X ²⁸ is N or CH;

X ³⁰ is N or CR ⁵ ;

X ³¹ is N, C(R ⁵⁴ ) ₂ , or CR ⁵⁴ ;

X ³² is NH, C(R ⁵⁴ ) ₂ or CR ⁵⁴ ;

X ³³ represents -CO-, -SO- or -SO ₂ -;

X ³⁴ is CHR ¹³ , NH, O or S;

where no more than 2 of X ²⁸ are N;

R ⁴¹ represents hydrogen, alkyl, including C ₁ -C ₆ alkyl, or -(C ₀ -C ₂ alkyl)(C ₃ -C ₅ cycloalkyl);

R ⁴⁸ and R ^48a are selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, alkyl, including C ₁ -C ₆ alkyl, haloalkyl, including C ₁ -C ₆ haloalkyl, alkenyl, including C ₂ -C ₆ alkenyl, alkynyl , including C ₂ -C ₆ alkynyl, thioalkyl, including C ₁ -C ₆ thioalkyl, alkoxy, including C ₁ -C ₆ alkoxy, -JC ₃ -C ₇ cycloalkyl, -B(OH) ₂ , -JC(O)NR ⁹ R ²³ , -JOSO ₂ OR ²¹ , -C(O)(CH ₂ ) _1-4 S(O)R ²¹ , -O(CH ₂ ) _1-4 S(O)NR ²¹ R ²² , -JOP( O)(OR ²¹ )(OR ²² ), -JP(O)(OR ²¹ )(OR ²² ), -JOP(O)(OR ²¹ )R ²² , -JP(O)(OR ²¹ )R ²² , - JOP(O)R ²¹ R ²² , -JP(O)R ²¹ R ²² , -JSP(O)(OR ²¹ )(OR ²² ), -JSP(O)(OR ²¹ )(R ²² ), -JSP( O)(R ²¹ )(R ²² ), -JNR ⁹ P(O)(NHR ²¹ )(NHR ²² ), -JNR ⁹ P(O)(OR ²¹ )(NHR ²² ), -JNR ⁹ P(O) (OR ²¹ )(OR ²² ), -JC(S)R ²¹ , -JNR ²¹ SO ₂ R ²² , -JNR ⁹ S(O)NR ¹⁰ R ²² , -JNR ⁹ SO ₂ NR ¹⁰ R ²² , -JSO ₂ NR ⁹ COR ²² , -JSO ₂ NR ⁹ CONR ²¹ R ²² , -JNR ²¹ SO ₂ R ²² , -JC(O)NR ²¹ SO ₂ R ²² , -JC(NH ₂ )-NR ²² , -JCH(NH ₂ )NR ⁹ S(O) ₂ R ²² , -JOC(O)NR ²¹ R ²² , -JNR ²¹ C(O)OR ²² , -JNR ²¹ OC(O)R ²² , -(CH ₂ ) _1-4 C (O)NR ²¹ R ²² , -JC(O)NR ²⁴ R ³⁰ , -JNR ⁹ C(O)R ²¹ , -JC(O)R ²¹ , -JNR ⁹ C(O)NR ¹⁰ R ²² , -CCR ²¹ , -(CH ₂ ) _1-4 OC(O)R ²¹ , -JC(O)OR ²³ and R ¹⁰³ ; each R ⁴⁸ may be optionally substituted with one or more substituents selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) ₂ , -Si(CH ₃ ) ₃ , -COOH, -CONR ⁹ R ¹⁰ , -P(O)(OH) ₂ , alkyl, including C ₁ -C ₆ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₆ alkoxy, -C ₀ -C ₄ alkyl (mono- and di-C ₁ -C ₄ alkylNR ⁹ R ¹⁰ ), alkyl ether, including C ₁ -C ₆ alkyl ether, C ₁ -C ₄ alkylamino, C ₁ -C ₄ hydroxylalkyl, haloalkyl, including C ₁ -C ₆ haloalkyl, -OC(O)R ⁹ , -NR ⁹ C(O)R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ , -NR ⁹ C(O)OR ¹⁰ , haloalkyl including C ₁ -C ₆ haloalkyl, S(O)=NHR ²¹ , SF ₅ , JC(R ⁹ )=NR ²¹ , SO ₂ OR ²¹ and haloalkoxy including C ₁ -C ₆ haloalkoxy

R ¹⁰³ is independently C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, fluorine, chlorine, or bromine;

R ⁵⁴ is hydrogen, alkyl including C ₁ -C ₆ alkyl, alkenyl including C ₂ -C ₆ alkenyl, alkynyl including C ₂ -C ₆ alkynyl, alkoxy including C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkynyl, alkanoyl, including C ₂ -C ₆ alkanoyl, thioalkyl, including C ₁ -C ₆ thioalkyl, hydroxyC ₁ -C ₆ alkyl, aminoC ₁ -C ₆ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), (phenyl)C ₀ -C ₄ alkyl-, (heterocycloalkyl)C ₀ -C ₄ alkyl or (heteroaryl)C ₀ -C ₄ alkyl, where each R ⁵⁴ is optionally substituted;

s is 1 or 2;

L is selected from L1 and L2;

L1 is a bond,

R ¹⁷ represents hydrogen, alkyl, including C ₁ -C ₆ alkyl or -C ₀ -C ₄ alkyl(C ₃ -C ₇ cycloalkyl);

R ¹⁸ and R ^18' are independently selected from hydrogen, halogen, hydroxymethyl and methyl;

m is 0, 1, 2, or 3;

L2 is selected from:

or L2 is selected from an optionally substituted monocyclic or bicyclic carbocyclic moiety; an optionally substituted monocyclic or bicyclic carbocyclic hydroxy group; optionally substituted monocyclic or bicyclic heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and from 4 to 7 ring atoms per ring, optionally substituted with -(C ₀ -c ₄ alkyl)( aryl); optionally substituted -(C ₀ -C ₄ alkyl)(5-membered heteroaryl); optionally substituted -(C ₀ -C ₄ alkyl)(6-membered heteroaryl); optionally substituted -(C ₀ -C ₄ alkyl)(8-membered heteroaryl); optionally substituted -(C ₀ -C ₄ alkyl)(9-membered heteroaryl); and -(C ₀ -C ₄ alkyl)(10-membered heteroaryl);

q is 1, 2, or 3;

R ⁵¹ represents CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ;

R ⁵³ is cyano, nitro, hydroxyl or alkoxy, including C ₁ -C ₆ alkoxy;

X ²⁹ may be O or S;

L3 is -C(O)-, -C(S), -P(O)OH-, -S(O)-, -S(O) ₂ - or -C(R ⁵² ) ₂ -;

each R ⁵² is independently selected from halo, hydrogen, or optionally substituted alkyl, including C ₁ -C ₆ alkyl;

or two R ⁵² groups are taken together to form a 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, or S;

B1 is heteroaryl; aryl; biphenyl, monocyclic or bicyclic carbocycle; a monocyclic or bicyclic carbocyclic hydroxy group; a monocyclic, bicyclic or tricyclic heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from boron, Si, N, O and S and from 4 to 8 ring atoms per ring; alkenyl, including C ₂ -C ₆ alkenyl; or alkynyl, including C ₂ -C ₆ alkynyl; each of B1 is optionally substituted with one or more substituents independently selected from R ³³ , R ³⁴ , R ³⁵ and R ³⁶ ;

R ³³ is independently selected from halo, hydroxyl, -COOH, cyano, alkyl including C ₁ -C ₆ alkyl, alkanoyl including C ₂ -C ₆ alkanoyl, alkoxy including C ₁ -C ₆ alkoxy, -C ₀ -C ₄ alkylNR ⁹ R ¹⁰ , -SO ₂ R ⁹ , haloalkyl including C ₁ -C ₆ haloalkyl, S(O)=NHR ²¹ , SF ₅ , and JC(R ⁹ )=NR ²¹ , and haloalkoxy including C ₁ -C ₆ haloalkoxy;

R ³⁴ is independently selected from nitro, alkenyl including C ₂ -C ₆ alkenyl, alkynyl including C ₂ -C ₆ alkynyl, thioalkyl including C ₁ -C ₆ thioalkyl, -JC ₃ -C ₇ cycloalkyl, -JB(OH) ₂ , -JC(O)NR ⁹ R ²³ , -JOSO ₂ OR ²¹ , -JC(O)(CH ₂ ) _1-4 S(O)R ²¹ , -O(CH ₂ ) _1-4 S(O) NR ²¹ R ²² , -JOP(O)(OR ²¹ )(OR ²² ), -JP(O)(OR ²¹ )(OR ²² ), -JOP(O)(OR ²¹ )R ²² , -JP(O) (OR ²¹ )R ²² , -JOP(O)R ²¹ R ²² , -JP(O)R ²¹ R ²² , -JSP(O)(OR ²¹ )(OR ²² ), -JSP(O)(OR ²¹ ) (R ²² ), -JSP(O)(R ²¹ )(R ²² ), -JNR ⁹ P(O)(NHR ²¹ )(NHR ²² ), -JNR ⁹ P(O)(OR ²¹ )(NHR ²² ) , -JNR ⁹ P(O)(OR ²¹ )(OR ²² ), -JC(S)R ²¹ , -JNR ²¹ SO ₂ R ²² , -JNR ⁹ S(O)NR ¹⁰ R ²² , -JNR ⁹ SO ₂ NR ¹⁰ R ²² , -JSO ₂ NR ⁹ COR ²² , -JSO ₂ NR ⁹ CONR ²¹ R ²² , -JNR ²¹ SO ₂ R ²² , -JC(O)NR ²¹ SO ₂ R ²² , -JC(NH ₂ )= NR ²² , -JCH(NH ₂ )NR ⁹ S(O) ₂ R ²² , -JOC(O)NR ²¹ R ²² , -JNR ²¹ C(O)OR ²² , -JNR ²¹ OC(O)R ²² , - (CH ₂ ) _1-4 C(O)NR ²¹ R ²² , -JC(O)R ²⁴ R ³⁰ , -JNR ⁹ C(O)R ²¹ , -JC(O)R ²¹ , -JNR ⁹ C(O )NR ¹⁰ R ²² , -CCR ²¹ , -(CH ₂ ) _1-4 OC(O)R ²¹ , -S(O) ₂ OR ²¹ , and -JC(O)OR ²³ ; where each R ³⁴ may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) ₂ , -Si(CH ₃ ) ₃ , -COOH, -CONR ⁹ R ¹⁰ , -P(O)(OH) ₂ , C ₁ -C ₆ alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), alkoxy, including C ₁ -C ₆ alkoxy, -C ₀ - C ₂ alkyl (mono- and di-C ₁ -C ₄ alkylamino), C ₁ -C ₆ alkyl ether, C ₁ -C ₄ alkylamino, C ₁ -C ₄ hydroxylalkyl, haloalkyl, including C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ haloalkoxy;

R ³⁵ is independently selected from naphthyl, naphthyloxy, indanyl, (4- to 7-membered heterocycloalkyl)C ₀ -C ₄ alkyl containing 1 or 2 heteroatoms selected from N, O and S, and a bicyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and containing from 4 to 8 ring atoms in each ring; where each R ³⁵ is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ alkyl, alkenyl, including C ₂ -C ₆ alkenyl, alkanoyl, including C ₂ -C ₆ alkanoyl, alkoxy , including C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl ether, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -SO ₂ R ⁹ , haloalkyl, including C ₁ -C ₆ haloalkyl, and haloalkoxy , including C ₁ -C ₆ haloalkoxy;

R ³⁶ is independently selected from tetrazolyl, (phenyl)C ₀ -C ₂ alkyl, (phenyl)C ₁ -C ₆ alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N , O, boron, Si and S, where each R ³⁶ is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, alkyl, including C ₁ -C ₆ alkyl, alkenyl, including C ₂ -C ₆ alkenyl , alkanoyl, including C ₂ -C ₆ alkanoyl, alkoxy, including C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl ether, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -SO ₂ R ⁹ , -OSi(CH ₃ ) ₂ C(CH ₃ ) ₃ , -Si(CH ₃ ) ₂ C(CH ₃ ) ₃ , haloalkyl, including C ₁ -C ₆ haloalkyl, and haloalkoxy, including C ₁ -C ₆ haloalkoxy;

in an alternative embodiment, R ³⁶ is a bicyclic heteroaryl such as 9-membered heteroaryl;

R ²¹ and R ²² are independently selected from hydrogen, hydroxyl, cyano, amino, C ₁ -C ₆ alkyl, haloalkyl, including C ₁ -C ₆ haloalkyl, alkoxy, including C ₁ -C ₆ alkoxy, (C ₃ -C ₇ cycloalkyl )C ₀ -C ₄ alkyl, (phenyl) C ₀ -C ₄ alkyl, -C ₁ -C ₄ alkylOC (O)OC ₁ -C ₆ alkyl, -C ₁ -C ₄ alkylOC (O)C ₁ -C ₆ alkyl, -C ₁ -C ₄ alkylC(O)OC ₁ -C ₆ alkyl, (4- to 8-membered heterocycloalkyl)C ₀ -C ₄ alkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C ₀ -C ₄ alkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and each R ²¹ and R ²² may optionally be replaced;

or R ²¹ and R ²² may be taken together to form a carbocyclic or heterocyclic ring;

R ²³ is independently selected at each occurrence from alkyl, including C ₁ -C ₆ alkyl, haloalkyl, including C ₁ -C ₆ haloalkyl, (aryl)C ₀ -C ₄ alkyl, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl, (phenyl)C ₀ -C ₄ alkyl, (4- to 8-membered heterocycle)C ₀ -C ₄ alkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5 - or 6-membered unsaturated or aromatic heterocycle)C ₀ -C ₄ alkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, where each R ²³ may be optionally substituted;

R ²⁴ and R ³⁰ are taken together with the nitrogen atom to which they are attached to form a 4- to 7-membered monocyclic heterocycle, or a 6- to 10-membered bicyclic heterocyclic group containing fused, spiro, or bridged rings, where each the ring may be optionally substituted;

B2 is selected from:

a. a 4-membered carbocycle fused to a 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; where the 4-5 or 4-6 ring system may be optionally substituteda;

b. (optionally substituted alkyl)-(optionally substituted cycloalkyl), (optionally substituted alkenyl)-(optionally substituted cycloalkyl), or (optionally substituted alkynyl)-(optionally substituted cycloalkyl);

c. a 4-membered carbocycle fused to a 6-membered aryl ring, where the 4-6 ring system may be optionally substituted;

d (cycloalkyl)-(optionally substituted aryl), (cycloalkyl)-(optionally substituted heteroaryl), (cycloalkyl)-(optionally substituted heterocycle), (alkyl)-alkenyl), cycloalkyl-alkenyl;

e. alkyl, alkyl(alkynyl), where each may be optionally substituted;

where B2 may be further substituted 1, 2, 3 or 4 times or more substituents independently selected from R ³³ , R ³⁴ , R ³⁵ , R ³⁶ and R ⁴⁸ ;

B3 is a monocyclic or bicyclic carbocycle; a monocyclic or bicyclic carbocyclic hydroxy group; a monocyclic, bicyclic or tricyclic heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from boron, Si, N, O and S and from 4 to 8 ring atoms per ring; alkenyl, including C ₂ -C ₆ alkenyl; alkynyl, including C ₂ -C ₆ alkynyl; -(C ₀ -C ₄ alkyl)(aryl); -(C ₀ -C ₄ alkyl)(heteroaryl); or -(C ₀ -C ₄ alkyl)(biphenyl), where each B3 is substituted with at least one R ²⁰¹ and optionally substituted with one or more substituents independently selected from R ³³ , R ³⁴ , R ³⁵ and R ³⁶ ;

B4 is a six-membered heteroaryl ring with at least two substituents selected from R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ ;

or B4 is a six-membered heteroaryl ring with at least three substituents selected from R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ ;

or B4 is pyridine with at least two substituents selected from R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ ;

or B4 is selected from:

R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ are independently selected from halogen, hydroxyl, nitro, cyano, alkyl, including C ₁ -C ₆ alkyl, alkenyl, including C ₂ -C ₆ alkenyl, alkanoyl, including C ₂ -C ₆ alkanoyl, alkoxy, including C ₁ -C ₆ alkoxy, thioalkyl, including C ₁ -C ₆ thioalkyl, (mono- and di-C ₁ -C ₆ alkylamino)C ₀ -C ₄ alkyl, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, (aryl)C ₀ -C ₄ alkyl-, (heteroaryl)C ₀ -C ₄ alkyl-, and -C ₀ -C ₄ alkoxy(C ₃ -C ₇ cycloalkyl); where each R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, alkoxy, including C ₁ - C ₆ alkoxy, haloalkyl, including C ₁ -C ₆ haloalkyl, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl-, and haloalkoxy, including C ₁ -C ₆ haloalkoxy;

or R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ are independently selected from tetrazole, halogen, hydroxyl, nitro, cyano, alkyl, including C ₁ -C ₆ alkyl, alkenyl, including C ₂ -C ₆ alkenyl, alkanoyl, including C ₂ -C ₆ alkanoyl, alkoxy, including C ₁ -C ₆ alkoxy, thioalkyl, including C ₁ -C ₆ thioalkyl, (mono- and di-C ₁ -C ₆ alkylamino)C ₀ -C ₄ alkyl, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl, (aryl)C ₀ -C ₄ alkyl-, (heteroaryl)C ₀ -C ₄ alkyl-, and -C ₀ -C ₄ alkoxy(C ₃ -C ₇ cycloalkyl); where each R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, alkoxy, including C ₁ - C ₆ alkoxy, haloalkyl, including C ₁ -C ₆ haloalkyl, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl-, and haloalkoxy, including C ₁ -C ₆ haloalkoxy;

and where any of these groups may be further optionally substituted in the manner that term is defined in the terminology section below, if desired, to achieve the desired effect, resulting in a stable compound that is chemically meaningful to the skilled artisan and the group is not redundant (i.e., as is known in the art, alkyl substituted with alkyl is in excess; however, for example, alkoxy substituted with alkoxy is not in excess); And

where any of the structures shown here, for example, A1, A2, A3, B1, B2, B3, B4, C1, C2, C3, C4, C5, L, L3, or any of the R moieties, may optionally be independently substituted with 0 , 1, 2, 3 or 4, if necessary, R ⁴⁸ substituents.

In another aspect, the invention relates to a compound of Formula IV:

or a pharmaceutically acceptable salt, isotopic analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

Where:

R ³² group on ring A is selected from

and where all other variables have the meanings defined herein.

In another aspect, the invention relates to a compound of Formula V:

or a pharmaceutically acceptable salt, isotopic analog, prodrug, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

Where:

B is as defined above.

C is as defined above.

L is as defined above.

L3 is as defined above.

A4 selected from:

where all other variables have the meanings defined in this document.

Also disclosed are pharmaceutical compositions containing a compound or salt of Formula I, Formula II, Formula III, Formula IV or Formula V together with a pharmaceutically acceptable carrier.

The present invention thus includes at least the following features:

a. a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition,

b. a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition, for use in the treatment or prevention of a disorder, including, but without limitation, the development of fatty liver disease and conditions associated with fatty liver, such as non-alcoholic steatohepatitis (NASH), inflammation of the liver, cirrhosis or liver failure; dermatomyasitis; amyotrophic lateral sclerosis; cytokine or inflammatory reactions in response to biotherapeutic agents (eg, CAR T-cell therapy); paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid arthritis, multiple sclerosis, age-related macular degeneration (AMD), retinal degeneration, other ophthalmic diseases (eg, geographic atrophy), respiratory disease, or cardiovascular disease;

c. a pharmaceutically acceptable composition of a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, in a pharmaceutically acceptable carrier;

d. a compound selected from Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition, for use in the treatment or prevention of a disorder mediated by complement activation and, for example, the Factor D cascade;

e. using a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V as described herein, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition, when the manufacture of a medicinal product for the treatment or prevention of a disorder, including, but not limited to, the development of fatty liver disease and conditions associated with fatty liver, such as non-alcoholic steatohepatitis (NASH), inflammation of the liver, cirrhosis, liver failure; dermatomyasitis; amyotrophic lateral sclerosis; cytokine or inflammatory reactions in response to biotherapeutic agents (eg, CAR T-cell therapy); paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid arthritis, multiple sclerosis, age-related macular degeneration (AMD), retinal degeneration, other ophthalmic disorders (eg, geographic atrophy), respiratory disease, or cardiovascular disease;

f. a process for the manufacture of a medicament intended for therapeutic use in the treatment or prevention of a disorder, or generally in the treatment or prevention of disorders mediated by the Complement Factor D cascade, characterized in that the compound selected from Formula I, Formula II, Formula III, Formula IV or Formula V or an embodiment of this active compound is used in the manufacture;

g. a compound selected from Formula I, Formula II, Formula III, Formula IV, or Formula V, or a salt thereof, as described herein, in substantially pure form (e.g., at least 90% or 95%):

h. a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V as described herein, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a carrier, to form a pharmaceutically acceptable composition for use in the treatment of a medical disorder that is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade), a disorder or pathological change in a cell that adversely affects the cell's ability to participate in or respond to normal complement activity, or an unwanted complement-mediated response to medical treatment, such as surgery or other medical procedure, or administration of medicinal or biopharmaceuticals, blood transfusion, or administration of other allogeneic tissue or fluid.

i. For each of (a)-(i) above and otherwise herein, each group of moieties in the Figures and each active compound or use thereof derived therefrom are contemplated and considered to be specifically and individually disclosed as such description is provided for convenience of arrangement only. and is not intended to describe only a genus or even a subgenus for such display.

BRIEF DESCRIPTION OF THE FIGURES

On FIG. 1 shows a six-step process for the synthesis of the intermediate tert-butyl (1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexane- 2-carboxylate.

On FIG. 2 shows a two-step process for the synthesis of the 2-bromo-3-fluoro-5-methylpyridine 1-oxide intermediate (Compound 3 in FIG. 2).

On FIG. 3 shows a three-step process for the synthesis of the tert-butyl 2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate intermediate.

On FIG. 4 shows a seven-step process for the synthesis of the intermediate 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid.

On FIG. 5 shows a two-step process for the synthesis of the tert-butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate intermediate.

On FIG. 6 shows a six-step process for the synthesis of the intermediate (S)-3-fluoro-4-methylpent-3-en-2-amine salt of hydrochloric acid.

On FIG. 7 shows a six-step process for the synthesis of hydrochloric acid intermediate (R)-1-((R)-2,2-dichlorocyclopropyl)ethane-1-amine salt.

On FIG. 8 shows an extended eight step synthesis of Compound 208 shown in Scheme 153.

On FIG. 9 shows an eight-step process for the synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-methyl-5-(2-(oxetan-3-yl)pyrimidin-5-yl)-1H-indazol- 1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide.

On FIG. 10 shows a four-step process for the synthesis of (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-(2-(7-methyl-5-(2-methylpyrimidin- 5-yl)-3-(oxetan-3-yl)-1H-indazol-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide.

On FIG. 11 shows a three-step method for the synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl )acetyl)-N-((S)-3-fluoro-4-methylpent-3-en-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide.

On FIG. 12 shows a seven-step process for the synthesis of Compound 100.

On FIG. 13 shows a three-step synthesis of Compound 50 which is an alternative to the synthesis shown in Scheme 45.

On FIG. 14 is an extended six-step process for the synthesis of Compound 107 shown in Scheme 80.

On FIG. 15A shows an eight-step process for the synthesis of the intermediate 2-(3-acetyl-7-methyl-5-(2-(3-((trimethylsilyl)oxy)oxetan-3-yl)pyrimidin-5-yl)-1H-indazol-1- yl) acetic acid.

On FIG. 15B shows two final steps in the synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-(3-hydroxyoxetan-3-yl)pyrimidin-5-yl)-7-methyl-1H -indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide from the intermediate shown in FIG. . 18A.

On FIG. 16 shows an eight-step process for the synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-(3-fluoroxetan-3-yl)pyrimidin-5-yl)-7-methyl-1H- indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide.

On FIG. 17 schematically shows various potential attachment points for R ³⁰¹ functionality on an A-ring, B-ring, C-ring, or heteroaryl-containing R ₃₂ group. X ₉ used in FIG. 17 is selected from -CH ₂ -, -O-, -NH- and -Nalkyl-.

On FIG. 18A, 18B, 18C, 18D, 18E, 18F, 18G, 18H, 18I, 18J, 18K, 18L, 18M, 18N, 18O, 18P, 18Q, 18R, 18S, 18T, 18U, and 18V are examples of compounds that illustrate Formula I, Formula II or Formula III.

On FIG. 19 shows Formula I, Formula II and Formula III.

DETAILED DESCRIPTION

Terminology

Compounds are described using standard nomenclature. Unless otherwise indicated, all technical and scientific terms used in this document have the same meaning as generally understood by a person skilled in the art to which this invention pertains.

Compounds in any of the Formulas described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates, and other isomers, such as rotamers, as if each were specifically described unless otherwise noted or otherwise excluded by context.

The term "or" means "and/or". The indication of ranges of values is only intended to serve as a concise way of referring independently to each individual value falling within that range, unless otherwise noted here, and each individual value is included in the description as if it were separately specified here. The endpoints of all ranges are included in the range and can be independently combined. All methods described herein can be performed in an appropriate order, unless otherwise specified herein or otherwise contrary to the context. The use of examples or introductory words (eg, "such as") is only intended to better illustrate the invention and does not limit the scope of the invention unless otherwise stated. Unless otherwise indicated, the technical and scientific terms used herein have the same meaning as generally understood by a person skilled in the art to which this invention pertains.

The present invention includes compounds of Formula I, Formula II, Formula III, Formula IV or Formula V with at least one desired isotopic substitution of an atom in excess of the natural abundance of the isotope, that is, enriched. Isotopes are atoms that have the same atomic number but different mass numbers, that is, the same number of protons but a different number of neutrons.

Examples of isotopes that may be included in the compounds of the invention 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, ¹⁸ F ³¹ R, ³² R, ³⁵ S, ³⁶ CI, ¹²⁵ I, respectively. In one embodiment, isotopically labeled compounds can be used in metabolic studies (with ¹⁴ C), reaction kinetics studies (for example, with ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including studies of the distribution of drugs or substrate in tissues, or in the radioactive treatment of patients. In particular, a compound labeled with ¹⁸ F may be particularly desirable for PET or SPECT studies. The isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by following the procedures described in the Schemes or in the examples and preparations described below by replacing a readily available isotopically labeled reagent with a non-isotopically labeled reagent.

As a general example and without limitation, isotopes of hydrogen, such as deuterium ( ² H) and tritium ( ³ H), can optionally be used anywhere in the described structures, which allows you to achieve the desired result. Alternatively or in addition, isotopes of carbon, such as ¹³ C and ¹⁴ C, can be used. In one embodiment, isotopic substitution is the replacement of hydrogen with deuterium at one or more locations on a molecule to improve drug performance, e.g., pharmacodynamics, pharmacokinetics , biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, deuterium can be bonded to carbon at the site of the bond break during metabolism (α-deuterium kinetic isotope effect) or near or near the bond break point (β-deuterium kinetic isotope effect). Isotopic substitutions, such as deuterium, may be partial or complete. Partial substitution by deuterium means that at least one hydrogen atom is replaced by deuterium. In some embodiments, the isotope is 80%, 85%, 90%, 95%, or 99% or more enriched in the isotope at any location of interest. In one embodiment, the deuterium is enriched to 80%, 85%, 90%, 95%, or 99% at any point of interest. Unless otherwise indicated, enrichment at any point exceeds natural abundance, and in one embodiment, it is sufficient to change the detectable property of the drug in humans.

In one embodiment, the substitution of a hydrogen atom for a deuterium atom can be carried out in any of A1, A1', A2, B1, B1', B2, B3, B4, C1, C1', C2, C3, C4, L1, L1', L2 , L2', L4 or L5. In one embodiment, the replacement of a hydrogen atom by a deuterium atom occurs within any R group. In one embodiment, the R group is selected from any of R ¹ , R ^1' , R ² , R ^2' , R ³ , R ^3' , R ⁴ , R ^4' , R ⁵ , R ⁶ , R ^6' , R ⁷ , R ⁸ , R ^8' , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R 14 , R ¹⁵ , ^{R 16 ,} R ¹⁷ , R ¹⁸ , R ^18' , R ¹⁹ , R ²¹ , R ²² , R ²³ , R ²⁵ , R ²⁶ , R 27 , R ²⁸ , R ³⁰ , R ³¹ , R ³² , ^{R 33 ,} R ³⁴ , R ³⁵ , R ³⁶ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R 44 ^' , R ⁴⁵ , R ^45' , R ⁴⁶ , R ^46' , R ⁴⁷ , R ⁴⁸ , R ^48a , R ⁴⁹ , R ⁵⁰ , R ⁵¹ , R ⁵² , R ⁵³ , R ⁵⁴ , R ¹⁰³ , R ¹⁰⁴ , R ²⁰¹ , R ²⁰² and R ³⁰¹ . For example, when any of the R groups are or contain, for example, when substituted with methyl, ethyl, or methoxy, the alkyl moiety can be deuterated (in non-limiting embodiments, CD ₃ , CH ₂ CD ₃ , CD ₂ CD ₃ , CDH ₂ , CD ₂ H, CD ₃ , CHDCH ₂ D, CH ₂ CD ₃ , CHDCHD ₂ , OCDH ₂ , OCD ₂ H or OCD ₃ , etc.). In some other embodiments, the R group has the designation "'" or "a", which in one embodiment may be deuterated. In some other embodiments, when two central ring substituents combine to form a cyclopropyl ring, the unsubstituted methylene carbon may be deuterated. The compound of the present invention can form a solvate with solvents (including water). Therefore, in one embodiment, the invention includes a solvated form of the active compound. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salt) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex containing a compound of the invention and water. Pharmaceutically acceptable solvates in accordance with the invention include those in which the solvent of crystallization can be isotopically substituted, for example, D ₂ O, d ₆ -acetone, d ₆ - DMSO. The solvate may be in liquid or solid form.

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

As used herein, the term "substituted" means that any one or more hydrogen atoms in the specified atom or group is replaced by a fragment selected from the specified group, provided that the normal valency of the specified atom is not exceeded, and the resulting compound is stable. For example, when a substituent is oxo (ie, ═O), then two hydrogens on that atom are substituted. For example, a pyridyl group substituted with oxo is pyridone. Combinations of substituents and/or variables are allowed only if such combinations result in the formation of stable compounds or useful synthetic intermediates.

A stable active compound refers to a compound that can be isolated and put into dosage form with a shelf life of at least one month. A stable manufacturing intermediate or active compound precursor is stable if it does not degrade within the time required for the reaction or other use. A stable moiety or substituent group is a group that does not decompose, react or disintegrate within the period required for use. Non-limiting examples of unstable moieties are those that combine a heteroatom in an unstable arrangement, as commonly known and identified by those skilled in the art.

Any suitable group may be present at the "substituted" or "optionally substituted" position, which forms a stable molecule and is consistent with the desired object of the invention, and includes, but is not limited to, for example, halogen (which may independently be F, Cl, Br, or I) ; cyano; hydroxyl; nitro; azido; alkanoyl (such as a C ₂ -C ₆ alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl, including one or more thioether bonds; alkylsulfinyl; alkylsulfonyl groups, including those containing one or more sulfonyl bonds; aminoalkyl groups, including groups containing more than one N atom; aryl (eg phenyl, biphenyl, naphthyl or the like, each ring is either substituted or unsubstituted); arylalkyl containing, for example, from 1 to 3 separate or fused rings and from 6 to about 14 or 18 ring carbon atoms, the benzyl group being an example of an arylalkyl group; arylalkoxy, for example containing from 1 to 3 separate or fused rings, benzyloxy being an example of an arylalkoxy group; or a saturated or partially unsaturated heterocycle containing from 1 to 3 separate or fused rings with one or more N, O or S atoms, or a heteroaryl containing from 1 to 3 separate or fused rings with one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl , piperazinil, and pyrrolidinyl . Such groups may be further substituted with, for example, hydroxy, alkyl, alkoxy, halogen and amino. In some embodiments, "optionally substituted" includes one or more substituents independently selected from halo, hydroxyl, amino, cyano, -CHO, -COOH, -CONH ₂ , alkyl, including C ₁ -C ₆ alkyl, alkenyl, including C ₂ -C ₆ alkenyl, alkynyl, including C ₂ -C ₆ alkynyl, -C ₁ -C ₆ alkoxy, alkanoyl, including C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkyl ether, (mono- and di-C ₁ -C ₆ alkylamino)C ₀ -C ₂ alkyl, haloalkyl, including C ₁ -C ₆ haloalkyl, hydroxyC ₁ -C ₆ alkyl, ester, carbamate, urea, sulfonamide, -C ₁ -C ₆ alkyl (heterocyclo), C ₁ - C ₆ alkyl (heteroaryl), -C ₁ -C ₆ alkyl (C ₃ -C ₇ cycloalkyl), O-C ₁ -C ₆ alkyl (C ₃ -C ₇ cycloalkyl), B (OH) ₂ , phosphate, phosphonate and haloalkoxy, including C ₁ -C ₆ haloalkoxy.

"Alkyl" is a saturated aliphatic hydrocarbon group with a branched or linear chain. In one embodiment, the alkyl contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms. In one embodiment, alkyl contains from 1 to about 8 carbon atoms. In some embodiments, alkyl is C ₁ -C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , C ₁ -C ₅ , or C ₁ -C ₆ . The indicated ranges used in this description denote an alkyl group in which each member of the range is described as an independent group. For example, the term C ₁ -C ₆ alkyl as used herein means a straight or branched alkyl group containing 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each is described as an independent group. . For example, the term C ₁ -C ₄ alkyl as used herein denotes a straight or branched alkyl group containing 1, 2, 3, or 4 carbon atoms and is intended to mean that each is described as an independent group. When C ₀ -C _n alkyl is used here together with another group, for example, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl or -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl, the specified group, in in this case cycloalkyl, either directly linked by a single covalent bond (C ₀ alkyl), or attached by an alkyl chain in this case with 1, 2, 3 or 4 carbon atoms Alkyls can also be attached through other groups such as a heteroatom, as in - O-C ₀ -C ₄ alkyl(C ₃ -C ₇ cycloalkyl) Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, t-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane and hexyl In one embodiment, the alkyl groups are optionally substituted as above In one embodiment, trimethylsilyl can be used instead of tert-butyl.

"Aliphatic" refers to a saturated or unsaturated, straight, branched or cyclic hydrocarbon. "Aliphatic" is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus includes each of these definitions. In one embodiment, "aliphatic" is used to refer to those aliphatic groups that contain 1-20 carbon atoms. The aliphatic chain may be, for example, monounsaturated, diunsaturated, triunsaturated, polyunsaturated or alkynyl. Unsaturated aliphatic groups may be in the cis or trans configuration. In one embodiment, the aliphatic group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms. In one embodiment, the aliphatic group contains from 1 to about 8 carbon atoms. In some embodiments, the aliphatic group is C ₁ -C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , C ₁ -C ₅ , or C ₁ -C ₆ . The indicated ranges used herein denote an aliphatic group in which each member of the range is described as an independent group. For example, the term "C ₁ -C ₆ aliphatic" as used herein means a straight or branched alkyl, alkenyl, or alkynyl group containing from 1, 2, 3, 4, 5, or 6 carbon atoms, and is intended to notation that each of them is described as an independent group. For example, the term "C ₁ -C ₄ aliphatic" as used herein means a straight or branched alkyl, alkenyl or alkynyl group containing from 1, 2, 3 or 4 carbon atoms, and is intended to mean that each of they are described as an independent group. In one embodiment, the aliphatic group is substituted with one or more functional groups, resulting in a stable moiety.

The term "heteroaliphatic" refers to an aliphatic moiety that contains at least one heteroatom in the chain, such as an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron in place of a carbon atom. In one embodiment, the only heteroatom is a nitrogen atom. In one embodiment, the only heteroatom is an oxygen atom. In one embodiment, the only heteroatom is a sulfur atom. The term "heteroaliphatic" is intended to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment, "heteroaliphatic" is used to refer to a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) containing 1-20 carbon atoms. In one embodiment, if the heteroaliphatic group is optionally substituted, a stable moiety is formed. Non-limiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocyclo-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc. In one embodiment, when when a term is used that includes "alk", it is to be understood that "cycloalkyl" or "carbocyclic" may be considered part of the definition, unless the context expressly excludes this. For example and without limitation, the terms alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenoxy, haloalkyl, aminoalkyl, alkylene, alkenylene, alkynylene, etc. may be considered as including cyclic forms of alkyl, unless this is clearly excluded from the context.

"Alkenyl" is a branched or straight chain aliphatic hydrocarbon group containing one or more carbon-carbon double bonds that may occur at a stable point along the chain. Non-limiting examples are C ₂ -C ₈ alkenyl, C ₂ -C ₇ alkenyl, C ₂ -C ₆ alkenyl, C ₂ -C ₅ alkenyl and C ₂ -C ₄ alkenyl. The indicated ranges used in this description denote an alkenyl group in which each member of the range is described as an independent group, as described above for the alkyl fragment. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. In one embodiment, the alkenyl group is optionally substituted as described above.

"Alkynyl" is a branched or straight chain aliphatic hydrocarbon group containing one or more carbon-carbon triple bonds that can occur at any stable point along the chain, for example, C ₂ -C ₈ alkynyl or C ₂ -C ₆ alkynyl. The specified ranges used in this description, denote alkynyl group containing each group of the range, described as an independent group, as described above for the alkyl fragment. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3 -hexynyl, 4-hexynyl and 5-hexynyl. In one embodiment, the alkynyl group is optionally substituted as described above.

"Alkylene" is a divalent saturated hydrocarbon. Alkylenes, for example, can be 1, 2, 3, 4, 5, 6, 7-8 carbon moiety, 1 to 6 carbon moiety or with the specified number of carbon atoms, for example, C ₁ -C ₂ alkylene, C ₁ - C ₃ alkylene, C ₁ -C ₄ alkylene, C ₁ -C ₅ alkylene, or C ₁ -C ₆ alkylene.

"Alkenylene" is a divalent hydrocarbon containing at least one carbon-carbon double bond. Alkenylenes, for example, can be a 2-8 carbon moiety, a 2-6 carbon moiety, or the specified number of carbon atoms, for example, C ₂ -C ₄ alkenylene.

"Alkynylene" is a divalent hydrocarbon containing at least one carbon-carbon triple bond. Alkynylenes, for example, may be a fragment with from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or with the specified number of carbon atoms, for example, C ₂ -C ₄ alkynylene.

"Alkoxy" is an alkyl group, as defined above, covalently linked through an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy , 2-hexoxy, 3-hexoxy and 3-methylpentoxy. Similarly, an "alkylthio" or "thioalkyl" group is an alkyl group, as defined above, with the indicated number of carbon atoms covalently bonded through a sulfur bridge (-S-). In one embodiment, the alkoxy group is optionally substituted as described above.

"Alkenyloxy" is an alkenyl group, as defined above, covalently linked to the group it replaces with an oxygen bridge (-O-).

"Alkanoyl" is an alkyl group, as defined above, covalently linked through a carbonyl bridge (C=O). Carbonyl carbon is one of the carbon atoms, that is, Cgalkanoyl is a CH ₃ (C=O) - group. In one embodiment, the alkanoyl group is optionally substituted as described above.

"Alkylether" is an alkyl group, as defined herein, covalently linked through an ester bond. The ester bond may be in any position, for example, a group of formula -O(C=O)alkyl or a group of formula -(C=O)Oalkyl.

"Amide" or "carboxamide" is -C(O)NR ^a R ^b , where R ^a and R ^b are independently selected from hydrogen, alkyl, eg alkyl, including C ₁ -C ₆ alkyl, alkenyl, eg C ₂ -C ₆ alkenyl, alkynyl, for example, C ₂ -C ₆ alkynyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), -C ₀ -C ₄ alkyl (C ₃ -C ₇ heterocycloalkyl), -C ₀ -C ₄ alkyl(aryl) and -C ₀ -C ₄ alkyl(heteroaryl); or together with the nitrogen atom to which they are bonded, R ^a and R ^b may form a C ₃ -C ₇ heterocyclic ring. In one embodiment, the R ^a and R ^b groups are independently optionally substituted as described herein.

"Carbocyclic group", "carbocyclic ring" or "cycloalkyl" is a saturated or partially unsaturated (ie, non-aromatic) group containing all carbon atoms of the ring. The carbocyclic group usually contains 1 ring of 3-7 carbon atoms or 2 fused rings each containing 3 to 7 carbon atoms. Cycloalkyl substituents may be pendant from a substituted nitrogen or carbon atom, or a substituted carbon atom that may have two substituents may contain a cycloalkyl group that is attached as a spiro group. Examples of carbocyclic rings include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl and cyclopropyl rings. In one embodiment, the carbocyclic ring is optionally substituted as described above. In one embodiment, cycloalkyl is a partially unsaturated (ie, non-aromatic) group containing all carbon ring atoms. In another embodiment, cycloalkyl is a saturated group containing all carbon atoms of the ring.

A "carbocyclic hydroxy group" is a monocyclic carbocyclic ring or a mono- or bicyclic carbocyclic group, as defined above, attached to the group it replaces via an oxygen, -O-, linker.

"Haloalkyl" refers to both branched and straight chain alkyl groups substituted with 1 or more halogen atoms, up to the maximum number of halogen atoms allowed. Examples of haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.

"Haloalkoxy" means a haloalkyl group, as defined herein, attached via an oxygen bridge (the oxygen of the alcohol radical).

"Hydroxyalkyl" is an alkyl group, as previously described, substituted with at least one hydroxyl substituent.

"Aminoalkyl" is an alkyl group, as previously described, substituted with at least one amino substituent.

"Halo" or "halogen" independently means any of the fluorine, chlorine, bromine or iodine atoms.

"Aryl" means an aromatic group containing only carbon in the aromatic ring or rings. In one embodiment, the aryl group contains from 1 to 3 separate or fused rings and is from 6 to about 14 or 18 ring atoms, with no heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon atoms or non-carbon atoms or groups. Such substitution may include condensation with a 4-7 or 5-7 membered saturated or partially unsaturated cyclic group which optionally contains 1, 2 or 3 heteroatoms independently selected from N, O, B, P, Si and/or S, with forming, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, the aryl groups are pendent. An example of a side ring is a phenyl group substituted with a phenyl group. In one embodiment, the aryl group is optionally substituted as described above.

The term "heterocycle" or "heterocyclic ring" as used herein refers to a saturated or partially unsaturated (i.e., containing one or more double and/or triple bonds in the ring without aromaticity) carbocyclic moiety of 3 to about 12, and more typically 3, 4, 5, 6, 7, 8-10 ring atoms, in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, while the remaining ring atoms are is C, where one or more ring atoms are optionally independently substituted with one or more substituents as described above. The heterocycle may be a monocycle containing 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, S, Si and B) or a bicycle containing 6 to 10 ring members. members (from 4 to 9 carbon atoms and from 1 to 6 heteroatoms selected from N, O, P, S, Si and B), for example: bicyclo [4.5], [5.5], [5.6] or [6,6] system. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur, boron, or silicon. Heterocycles are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), in particular sections 1, 3, 4, 6, 7 and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular volumes 13, 14, 16, 19 and 28; and J. Am. Chem. soc. (1960) 82:5566. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, piperidonyl, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl , thiepanil, oxazepinil, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, pyrazolidine imidazolinil, imidazolidinil, 2-oxa-5-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[ 3.1.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H- indolyl, quinolisinyl, N-pyridylureas and pyrrolopyrimidine. Spiro fragments are also included within the scope of this definition. Examples of a heterocyclic group in which 1 or 2 ring carbons are substituted by oxo (=O) moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocyclic groups here are optionally substituted independently with one or more of the substituents described herein, for example 1, 2 or 3 substituents.

A "heterocyclic hydroxy group" is a monocyclic heterocyclic ring or a bicyclic heterocyclic group, as previously described, linked to the group it replaces via an oxygen, -O-, linker.

"Heteroaryl" refers to a stable monocyclic, bicyclic, or polycyclic aromatic ring that contains 1 to 3, or in some embodiments, 1, 2, or 3 heteroatoms selected from N, O, S, B, or P, with the remaining ring atoms, being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7-membered aromatic ring that contains 1 to 3, or in some embodiments, 1 to 2, heteroatoms selected from N, O , S, B or P, with the remaining ring atoms being carbon. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Monocyclic heteroaryl groups usually contain from 5, 6 or 7 ring atoms. In some embodiments, the bicyclic heteroaryl groups are 8-10 membered heteroaryl groups, that is, groups containing 8 or 10 ring atoms in which one 5, 6 or 7 membered aromatic ring is fused to a second aromatic or non-aromatic ring. 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 is not more than 2. In another embodiment, the total number of S and O atoms in the aromatic heterocycle is not more than 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, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indole silt , benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanil, benzofurazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl and furopyridinyl . The heteroaryl groups are optionally substituted independently with one or more of the substituents described herein. "Heteroaryloxy" is a heteroaryl group, as described, linked to the group it replaces via an oxygen, -O-, linker.

"Heterocycloalkyl" is a fully saturated heterocycle as defined herein. For example, it may include 1, 2, 3, or 4 heteroatoms independently selected from N, S, O, Si, and B, while the remaining ring atoms are carbon. In a typical embodiment, nitrogen is a heteroatom. Monocyclic heterocycloalkyl groups typically contain 3 to about 8 ring atoms, or 4 to 6 ring atoms.

The term "mono - and/or dialkylamino" means a secondary or tertiary alkylamino group, where the alkyl groups are independently selected, as defined herein. The point of attachment of the alkylamino group is on the nitrogen atom. Examples of mono- and dialkylamino groups include ethylamino, dimethylamino and methyl-propyl-amino. "Dosage form" means the unit of administration of the active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalation forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like. A "dosage form" may also include an implant, such as an ocular implant. "Pharmaceutical compositions" are compositions containing at least one active agent and at least one other substance, such as a carrier. "Pharmaceutical combinations" are combinations of at least two active agents that may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein.

A "pharmaceutically acceptable salt" is a derivative of a disclosed compound in which the parent compound has been modified by obtaining its inorganic and organic, pharmaceutically acceptable acid or base addition salts. Salts of the present compounds can be synthesized from a parent compound that contains a basic or acid moiety using conventional chemical techniques. Generally, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate, or the like), or by reacting the free base forms of these compounds with a stoichiometric amount of suitable acid. Such reactions are usually carried out in water or in an organic solvent, or in a mixture of the two. Typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical where practicable. Salts of the present compounds further include solvates of the compounds and salts of the compounds.

Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acid residues such as carboxylic acids; etc. Pharmaceutically acceptable salts include salts that are acceptable for human consumption and quaternary ammonium salts of the parent compound derived from, for example, inorganic or organic acids. Examples of such salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesyl, esyl, benzyl, sulfanyl, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, HOOC-(CH ₂ ) _n -COOH, where n is 0-4, and the like, or using another acid that forms the same counterion . Lists of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

The term "carrier" as applied to the pharmaceutical compositions/combinations of the invention refers to the diluent, excipient or vehicle with which the active compound is provided.

A "pharmaceutically acceptable excipient" means an excipient that is useful in formulating a pharmaceutical composition/combination that is generally safe, acceptable for human consumption, and is neither biologically nor otherwise unacceptable for administration to a patient, usually a human. In one embodiment, an excipient is used that is acceptable for veterinary use.

A "patient" or "host" or "subject" is a human or non-human animal in need of treatment or prevention of any of the disorders as specifically described herein, including, but not limited to, modulation of the factor D pathway complement activation or with a condition that is treatable with one of the compounds described herein. Typically, the host is a human. The term "patient" or "host" or "subject" also refers to, for example, a mammal, primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, bird, etc. .P.

"Prodrug" as used herein means a compound that, when administered to a host in vivo, is converted to the parent drug. As used herein, the term "parent drug" means any of the chemical compounds described herein. Prodrugs can be used to achieve any desired effect, including improving the properties of the parent drug or improving the pharmaceutical or pharmacokinetic properties of the parent drug, including increasing the in vivo half-life of the drug. Prodrug strategies provide a choice of modulating conditions for creating the parent drug in vivo. Non-limiting examples of prodrug strategies include covalent attachment of leaving groups or leaving portions of groups, such as, but not limited to, acylation, phosphorylation, phosphonylation, date phosphorus derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation or anhydride, among others. In some embodiments, the prodrug makes the parent compound more lipophilic. In some embodiments, a prodrug may be provided that has multiple prodrug groups in a linear, branched, or cyclic form. For example, non-limiting embodiments include using a divalent linker moiety, such as a dicarboxylic acid, amino acid, diamine, hydroxycarboxylic acid, hydroxyamine, di-hydroxy compound, or other compound that has at least two functional groups that can link the parent molecule to another prodrug moiety, and is generally biodegradable in vivo. In some embodiments, 2, 3, 4 or 5 prodrug biodegradable moieties are covalently linked in series, branched or cyclic form to the parent compound. Non-limiting examples of prodrugs of the present invention are formed with:

i. a carboxylic acid in the parent drug and a hydroxylated prodrug moiety to form an ester;

ii. a carboxylic acid in the parent drug and an amine prodrug to form an amide;

iii. an amine in the parent drug and a prodrug carboxylic acid moiety to form an amide;

iv. an amine in the parent drug and sulfonic acid to form a sulfonamide;

v. sulfonic acid on the parent drug and an amine on the prodrug moiety to form a sulfonamide;

vi. a hydroxyl group in the parent drug and a carboxylic acid in the prodrug moiety to form an ester;

vii. hydroxyl in the parent drug and a hydroxylated prodrug moiety to form an ether;

viii. a phosphonate in the parent drug and a hydroxylated prodrug moiety to form a phosphonate ester;

ix. phosphoric acid in the parent drug and a hydroxylated prodrug moiety to form a phosphate ester;

x. hydroxyl in the parent drug and phosphonate in the prodrug to form a phosphonate ester;

xi. hydroxyl in the parent drug and the phosphate moiety of the prodrug to form a phosphate ester;

xi. carboxylic acid in the parent drug and a prodrug of the structure HO-(CH ₂ ) ₂ -O-(C _2-24 aliphatic group), for example, HO-(CH ₂ ) ₂ -O-(C _2-24 alkyl group), c ester formation;

xiii. carboxylic acid in the parent drug and a prodrug of the structure HO-(CH ₂ ) ₂ -S-(C _2-24 aliphatic group), for example, HO-(CH ₂ ) ₂ -S-(C _2-24 alkyl group), with the formation of thioether;

xiv. hydroxyl in the parent drug and a prodrug of the structure HO-(CH ₂ ) ₂ -O-(C _2-24 aliphatic group), for example, HO-(CH ₂ ) ₂ -O-(C _2-24 alkyl group) to form an ester ;

xv. carboxylic acid in the parent drug and a prodrug of the structure HO-(CH ₂ ) ₂ -S-(C _2-24 aliphatic group), for example, HO-(CH ₂ ) ₂ -S-(C _2-24 alkyl group), with the formation of a thioether; And

xvi. a carboxylic acid, oxime, hydrazide, hydrazone, amine, or hydroxyl in the parent compound and a prodrug moiety that is a biodegradable polymer or oligomer including, but not limited to, polylactic acid, polylactide-co-glycolide, polyglycolide, polyethylene glycol, polyganhydride, polyester , polyamide or peptide. An exemplary synthesis of oxime bonds is presented in an article published by Jin et. al. and entitled "Oxime Linkage: A Robust Tool for the Design of PH-Sensitive Polymeric Drug Carriers" in BioMacromolecules, 2011, 12(10), 3460-3468.

In one embodiment, the prodrug is provided by attaching a naturally occurring or non-naturally occurring amino acid to the appropriate functional moiety in the parent compound, e.g., oxygen, nitrogen, or sulfur, and typically oxygen or nitrogen, usually such that the amino acid can be cleaved in vivo to produce original drug. The amino acid can be used alone or covalently linked (straight, branched, or cyclic) to one or more other prodrug moieties to modify the parent drug to achieve desired characteristics such as increased half-life, lipophilicity, or other drug delivery, or pharmacokinetic properties. The amino acid can be any compound with an amino group and a carboxylic acid, which includes aliphatic amino acids, an alkyl amino acid, an aromatic amino acid, a heteroaliphatic amino acid, a heteroalkyl amino acid, or a heterocyclic amino acid or a heteroaryl amino acid.

"Providing a compound with at least one additional active agent", for example, in one embodiment may mean that the compound and additional active agent(s) are provided simultaneously in a single dosage form, are provided simultaneously in separate dosage forms, or are provided in separate dosage forms for administration. In one embodiment, the administrations of the compounds are separated by some amount of time, which is within the time that both the compound and at least one additional active agent are in the patient's bloodstream. In some embodiments, the compound and the additional active agent must not be administered to the patient by the same healthcare professional. In some embodiments, the implementation of additional active agent or agents do not require appointment. Administration of the compound or at least one additional active agent may be by any suitable route, e.g., oral tablets, oral capsules, oral liquids, inhalation, injection, suppositories, parenteral, sublingual, buccal, intravenous, intra-aortic, transdermal, polymer-controlled system. delivery, non-polymeric controlled delivery system, nano or microparticles, liposomes and/or topical contact. In one embodiment, the instructions for use in the form of combination therapy are provided in the labeling of the medicinal product.

A "therapeutically effective amount" of a pharmaceutical composition/combination of the present invention means an amount effective when administered to a patient to provide a therapeutic benefit, such as reduction in symptoms or reduction or amelioration of the disease itself. In one embodiment, a therapeutically effective amount is an amount sufficient to prevent a significant increase or significantly decrease the detectable level of complement factor D in the blood, serum, or tissues of a patient.

DETAILED DESCRIPTION OF ACTIVE COMPOUNDS

N-OXIDES

In some embodiments, any of the active compounds may be provided in the form of its N-oxide to a patient in need thereof. In one embodiment, the production scheme uses the N-oxide of the active compound or a precursor of the active compound. In yet another embodiment, the N-oxide is an administration metabolite of one of the active compounds provided herein and may have independent activity. The N-oxide can be formed by treating the compound of interest with an oxidizing agent, such as a suitable peroxyacid or peroxide, to form the N-oxide compound. For example, a heteroaryl group, such as a pyridyl group, can be treated with an oxidizing agent such as sodium percarbonate in the presence of a rhenium-based catalyst under mild reaction conditions to form an N-oxide compound. One of skill in the art will appreciate that appropriate protecting groups may be necessary to carry out the chemical reaction. See Jain, SL et al., "Rhenium-Catalyzed Highly Efficient Oxidations of Tretiary Nitrogen Compounds to N-Oxides Using Sodium Percarbonate as Oxygen Source, Synlett, 2261-2663, 2006. In one embodiment, the N-oxide is in the A ring. In one embodiment, the N-oxide is in ring B. In one embodiment, the N-oxide is in the R ³² group.

In other embodiments, any of the active sulfur compounds may be provided in its sulfoxide or sulfone form to a patient in need thereof. In another embodiment, a sulfoxide or sulfone of one of the active compounds, or a precursor of the active compound, is used in a manufacturing scheme. The sulfur atom in the selected compound, as described here, can be oxidized to form a sulfoxide or sulfone using known techniques. For example, the compound 1,3,5-triazo-2,4,6-triphosphorin-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). Oxidation of sulfides with 30% hydrogen peroxide catalyzed by tantalum carbide gives sulfoxides in high yields, see, Kirihara, A., et al., "Tantalum Carbide or Niobium Carbide Catalyzed Oxidation of Sulfides with Hydrogen Peroxide: Highly Efficient and Chemoselective Syntheses of Sulfoxides and Sulfones", Synlett, 1557-1561 (2010). Sulfides can be oxidized to sulfones using e.g. niobium carbide as a catalyst, 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). The adduct of urea and hydrogen peroxide is a stable, inexpensive and easily processed reagent for the oxidation of sulfides to sulfones, see, Varma, RS and Naicker, KP, "The Urea - Hydrogen Peroxide Complex: Solid-State Oxidative Protocols for Hydroxylated Aldehydes and Ketones (Dakin Reaction ), Nitriles, Sulfides, and Nitrogen Heterocycles", Org. Lett., 1, 189-191 (1999). One skilled in the art will appreciate that another heteroatom, such as nitrogen, may need to be protected and then deprotected when the sulfur atom is oxidized to give the desired compound.

Embodiments "alkyl"

In one embodiment, "alkyl" is C ₁ -C ₁₀ alkyl, C ₁ -C ₉ alkyl, C ₁ -C ₈ alkyl, C ₁ -C ₇ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₅ alkyl , C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl or C ₁ -C ₂ alkyl.

In one embodiment, "alkyl" contains one carbon atom.

In one embodiment, "alkyl" contains two carbon atoms.

In one embodiment, "alkyl" contains three carbon atoms.

In one embodiment, "alkyl" contains four carbon atoms.

In one embodiment, "alkyl" contains five carbon atoms.

In one embodiment, "alkyl" contains six carbon atoms.

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

Additional non-limiting examples of "alkyl" include: isopropyl, isobutyl, isopentyl and isohexyl.

Additional non-limiting examples of "alkyl" include: sec-butyl, sec-pentyl and sec-hexyl.

Additional non-limiting examples of "alkyl" include: t-butyl, t-pentyl and t-hexyl.

Additional non-limiting examples of "alkyl" include: neopentyl, 3-pentyl and active pentyl.

In one embodiment, "alkyl" means "substituted alkyl".

In one embodiment, "alkenyl" means "substituted alkenyl".

In one embodiment, "alkynyl" means "substituted alkynyl".

Embodiments "haloalkyl"

In one embodiment, "haloalkyl" is C ₁ -C ₁₀ haloalkyl, C ₁ -C ₉ haloalkyl, C ₁ -C ₈ haloalkyl, C ₁ -C ₇ haloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₅ haloalkyl , C ₁ -C ₄ haloalkyl, C ₁ -C ₃ haloalkyl and C ₁ -C ₂ haloalkyl.

In one embodiment, "haloalkyl" contains one carbon atom.

In one embodiment, "haloalkyl" contains one carbon atom and one halogen atom.

In one embodiment, "haloalkyl" contains one carbon atom and two halogen atoms.

In one embodiment, "haloalkyl" contains one carbon atom and three halogen atoms.

In one embodiment, "haloalkyl" contains two carbon atoms. In one embodiment, "haloalkyl" contains three carbon atoms. In one embodiment, "haloalkyl" contains four carbon atoms. In one embodiment, "haloalkyl" contains five carbon atoms. In one embodiment, "haloalkyl" contains six carbon atoms.

Non-limiting examples of "haloalkyl" include

Additional non-limiting examples of "haloalkyl" include:

Additional non-limiting examples of "haloalkyl" include:

Additional non-limiting examples of "haloalkyl" include:

Embodiments "aryl"

In one embodiment, "aryl" is a 6 carbon aromatic group (phenyl).

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

In one embodiment, "aryl" is "substituted aryl". Embodiments "heteroaryl"

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

Non-limiting examples of 5-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, isoxazole, oxazole, oxadiazole, ochatriazol, isothiazole, thiazole, thiadiazole, and thiatriasol.

Additional non-limiting examples of 5-membered "heteroaryl" groups include:

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

Non-limiting examples of 6-membered "heteroaryl" groups with 1 or 2 nitrogen atoms include:

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

Non-limiting examples of "heteroaryl" groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzoxazole, and benzothiazole. Additional non-limiting examples of "heteroaryl" groups that are bicyclic include:

Additional non-limiting examples of "heteroaryl" groups that are bicyclic include:

Additional non-limiting examples of "heteroaryl" groups that are bicyclic include:

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

Non-limiting examples of "heteroaryl" groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine. Additional non-limiting examples of "heteroaryl" groups that are bicyclic include:

In one embodiment, "heteroaryl" is "substituted heteroaryl".

In an alternative embodiment, the heteroaryl is a tetrazole.

Embodiments "cycloalkyl"

In one embodiment, "cycloalkyl" is C ₃ -C ₈ cycloalkyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₅ cycloalkyl, C ₃ -C ₄ cycloalkyl, C ₄ -C ₈ cycloalkyl , C ₅ -C ₈ cycloalkyl or C ₆ -C ₈ cycloalkyl.

In one embodiment, "cycloalkyl" contains three carbon atoms.

In one embodiment, "cycloalkyl" contains four carbon atoms.

In one embodiment, "cycloalkyl" contains five carbon atoms.

In one embodiment, "cycloalkyl" contains six carbon atoms.

In one embodiment, "cycloalkyl" contains seven carbon atoms.

In one embodiment, "cycloalkyl" contains eight carbon atoms.

In one embodiment, "cycloalkyl" contains nine carbon atoms.

In one embodiment, "cycloalkyl" contains ten carbon atoms.

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

In one embodiment, "cycloalkyl" is "substituted cycloalkyl".

Embodiments "heterocycle"

In one embodiment, the term "heterocycle" refers to a cyclic ring with one nitrogen atom and 3, 4, 5, 6, 7 or 8 carbon atoms.

In one embodiment, the term "heterocycle" refers to a cyclic ring with one nitrogen atom and one oxygen atom and 3, 4, 5, 6, 7 or 8 carbon atoms. In one embodiment, the term "heterocycle" refers to a cyclic ring with two nitrogen atoms and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment, the term "heterocycle" refers to a cyclic ring with one oxygen atom and 3, 4, 5, 6, 7 or 8 carbon atoms.

In one embodiment, the term "heterocycle" refers to a cyclic ring with one sulfur atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

Non-limiting examples of "heterocycle" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane.

Additional non-limiting examples of "heterocycle" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

Additional non-limiting examples of "heterocycle" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

Additional non-limiting examples of "heterocycle" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thian, 1,3-dithian, 1,4-dithian, morpholine, and thiomorpholine.

Non-limiting examples of "heterocycle" also include:

Additional non-limiting examples of "heterocycle" include:

Additional non-limiting examples of "heterocycle" include:

Non-limiting examples of "heterocycle" also include:

Non-limiting examples of "heterocycle" also include:

Additional non-limiting examples of "heterocycle" include:

Additional non-limiting examples of "heterocycle" include:

In one embodiment, "heterocycle" is "substituted heterocycle".

Embodiments R ²⁰¹

In one embodiment, R ²⁰¹ is selected from -(CH ₂ ) _m -O-heterocycle, -(CH ₂ ) _m -NH-heterocycle or -(CH ₂ ) _m -NR ⁹ -heterocycle.

In one embodiment, R ²⁰¹ is selected from -(CH ₂ ) _m -NR ⁹ R ¹⁰ , -(CH ₂ ) _m -CR ⁹ or -(CH ₂ ) _m -heterocycle;

In one embodiment, R ²⁰¹ is selected from -CH ₂ -O-heterocycle, -CH ₂ -NH-heterocycle, or -CH ₂ -NR ⁹ -heterocycle;

In one embodiment, R ²⁰¹ is selected from CH ₂ -NR ⁹ R ¹⁰ , CH ₂ -OR ⁹ or CH ₂ -heterocycle;

In one embodiment, R ²⁰¹ is selected from -(CH ₂ ) _m -NH ₂ , -(CH ₂ ) _m -OH, or -(CH ₂ ) _m -OC ₁ -C ₆ alkyl;

In one embodiment, m is 1, 2, or 3.

In one embodiment, m is 1.

In one embodiment, m is 2.

In one embodiment, m is 3.

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

Embodiments C

In one embodiment, C5 is

In one embodiment, C5 is

In one embodiment, C5 is

In one embodiment, C5 is co6

In one embodiment, C1 is selected from:

In one embodiment, C1 is selected from:

In one embodiment, the methyl group in the structure shown above may be replaced by another alkyl group, as defined here. In another embodiment, the fluorine atoms in the above structures can be replaced by any other halogen. Any of the structures illustrated above or otherwise may be optionally substituted with 0, 1, 2, 3 or 4, optionally and independently, with an R ⁴⁸ substituent.

Examples of beta-turn central core small mimetics, beta-turn inducers, reverse-turn mimetics, and foldamer monomers include:

In one embodiment, C is selected from:

Where:

R ¹⁰¹ is C ₁ -C ₄ alkyl or C ₃ -C ₇ cycloalkyl; And

R ¹⁰² is C ₁ -C ₄ alkyl, fluorine, chlorine or bromine.

In one embodiment, C4 is selected from:

In one embodiment, C4 is selected from:

In one embodiment, C4 is selected from:

In one embodiment, C4 is selected from:

In one embodiment, C is selected from:

In one embodiment, R ¹ is selected from F, Cl, Br and C ₁ -C ₆ alkyl.

In one embodiment, R ¹ is selected from hydroxyl and C ₁ -C ₆ alkoxy.

In one embodiment, R ¹ is selected from C ₂ -C ₆ alkynyl, C ₂ -C ₆ alkanoyl, and C ₁ -C ₆ thioalkyl.

In one embodiment, R ¹ is selected from aminoC ₁ -C ₆ alkyl and -C ₀ -C ₄ alkylNR ⁹ R ¹⁰ .

In an alternative embodiment, C is selected from

Embodiments A

Non-limiting examples of A1 include:

In one embodiment, A1 is selected from:

In one embodiment, A3 is selected from:

In one embodiment, A3 is selected from:

In one embodiment, A3 is selected from:

In one embodiment, A3 is selected from:

In one embodiment, A3 is selected from:

In one embodiment, A3 is selected from:

In one embodiment, A3 is selected from:

In one embodiment, A1 is selected from

In one embodiment, A1 is selected from:

In one embodiment, A1 is selected from:

In one embodiment, A1 is selected from:

In one embodiment, A1 is selected from:

In one embodiment, A1 is selected from:

In the above embodiments and throughout this description, R ¹⁰¹ is C ₁ -C ₄ alkyl or C ₃ -C ₇ cycloalkyl.

In another embodiment, A1 is selected from:

In one embodiment, A4 is selected from:

In one embodiment, A4 is

In one embodiment, A4 is selected from:

In one embodiment, A4 is selected from:

In one embodiment, A4 is selected from:

In one embodiment, A4 is

Embodiments L

In one embodiment, L1 is selected from:

In one embodiment, L1 is selected from:

In one embodiment, L1 is selected from:

In one embodiment, L1 is selected from:

In one embodiment, L1 is selected from:

In one embodiment, the methyl groups in the above structures may be replaced by another alkyl group as defined herein. In one embodiment, L2 is selected from:

Non-limiting examples of L2 include:

Non-limiting examples of L2 include:

Non-limiting examples of L2 include:

Non-limiting examples of L2 include:

Non-limiting examples of L2 include:

In one embodiment, the methyl groups in the above structures may be replaced by another alkyl or acyl as defined herein. In another embodiment, carbocyclic, heterocyclic, aryl or heteroaryl rings may be optionally substituted. As indicated above, any of the structures shown above or below may optionally be replaced by 0, 1, 2, 3 or 4, optionally and independently, with an R ⁴⁸ substituent.

In a specific embodiment, L2 is a bond. In some embodiments, if L2 is heterocyclic or heteroaryl, then B may be hydrogen.

Embodiments B

In one further alternative embodiment, B is selected from:

In another embodiment, B1 is selected from:

In one further alternative embodiment, R ³⁶ is selected from:

In one embodiment, B is selected from:

where R ²⁷ represents hydrogen, methyl or trifluoromethyl; R ²⁸ is hydrogen or halogen; and R ²⁹ is hydrogen, methyl, trifluoromethyl or -Si(CH ₃ ) ₂ C(CH ₃ ) _s

. In one embodiment, B is selected from:

Examples of Fragments B include, but are not limited to:

In one embodiment, B4 is

In one embodiment, B4 is

In one embodiment, B4 is

In one embodiment, B4 is

In one embodiment, B4 is

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

In one embodiment, R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ are independently selected from hydrogen, halogen and C ₁ -C ₆ alkyl.

In another embodiment, B4 is selected from:

In another embodiment, B4 is selected from:

In another embodiment, B4 is selected from:

In another embodiment, B4 is selected from:

In another embodiment, B4 is selected from:

In another embodiment, B4 is selected from:

In an alternative embodiment, B4 is selected from:

In another alternative embodiment, B4 is selected from:

In another alternative embodiment, B4 is -alkyl-Si(alkyl) ₃ or -alkyl-SF ₅ .

In another alternative embodiment, B4 is ring B substituted with oxo. In this embodiment, if ring B is a nitrogen containing a heteroaryl group, then the nitrogen may also be substituted as defined herein. For example: substituted oxo may be selected from the following compounds: and examples include:

In another alternative embodiment, B4 is selected from:

In another alternative embodiment, R ³² is a heteroaryl ring substituted with oxo according to valency. In this embodiment, if the R ³² ring is a nitrogen containing a heteroaryl group, then the nitrogen may also be substituted as defined herein. For example: substituted oxo may be selected from the following compounds: and examples include:

In another alternative embodiment, R ³² is selected from:

In another alternative embodiment, B4 is an alkyl group. In another alternative embodiment, B4 is an alkenyl group.

In another embodiment, C4 is selected from:

In one embodiment, L2 is a spirocyclic linker attached to ring C such that the resulting compound of Formula I is:

In one embodiment, L2 is a spirocyclic linker attached to ring C such that the resulting compound of Formula II is:

In one embodiment, L2 is a spirocyclic linker attached to ring C such that the resulting compound of Formula IIII is:

In one embodiment, a compound of Formula

In one embodiment, R ³² is selected from:

In one embodiment, R ³² is selected from:

In an alternative embodiment, R ³² is selected from:

In an alternative embodiment, R ¹¹ , R ¹² , R ¹³ , R ¹⁴ or R ¹⁵ is alkyl-R ³² or -O-alkyl-R ³² .

In an alternative embodiment, R ¹¹ , R ¹² , R ¹³ , R ¹⁴ or R ¹⁵ is

In one embodiment, R ¹¹ , R ¹² , R ¹⁴ , R ¹⁴ or R ¹⁵ is

In one embodiment, X ³¹ is selected from N and CR ⁵⁴ ;

In another embodiment, X ³¹ is C(R ⁵⁴ ) ₂ ;

In one embodiment, X ²⁵ is O or S;

In one embodiment, R ^4' is selected from -JCHO, -JCONH ₂ , -JCONR ⁹ R ¹⁰ , JC ₂ -C ₆ alkanoyl, -JSO ₂ NH ₂ , -JSO ₂ NR ²¹ R ²² , -JC(CH ₂ ) ₂ F, -JCH(CF ₃ )NH ₂ , -J-haloalkyl-NH ₂ , -J-haloalkyl-NR ⁹ R ¹⁰ , alkyl including C ₁ -C ₆ alkyl, -C ₀ -C ₄ alkyl(C ₃ - C ₇ cycloalkyl), -JC (O) C ₀ -C ₂ alkyl (C ₃ -C ₇ cycloalkyl), -JNR ⁹ (C ₂ -C ₆ alkanoyl), -JNR ⁹ C (O) NR ⁹ R ¹⁰ ,

where each R4' other than -CHO is optionally substituted with one or more amino, imino, halogen, hydroxyl, cyano, cyanoimino, alkyl, including C ₁ -C ₆ alkyl, alkoxy, including C ₁ -C ₆ alkoxy, -C ₀ -C ₂ alkyl (mono - and di-C ₁ -C ₄ alkylamino), haloalkyl, including C ₁ -C ₆ haloalkyl, and haloalkoxy, including C ₁ -C ₆ haloalkoxy.

Additional embodiments of R ³²

In one embodiment, R ³² is

Embodiments B

In one embodiment, B is selected from:

Embodiments R ³⁰¹

Examples of R ³⁰¹ are shown below. In the compounds of the present invention, R ³⁰¹ is monovalently attached to the molecule. The divalent moieties below are provided to illustrate that ^R301 may be attached at any point and may be limited to, for example, H, alkyl, halogen, haloalkyl, aryl, heteroaryl, and heterocycle, where each may be optionally substituted as described Here. In one embodiment, R ³⁰¹ is selected from:

where, if this fragment is presented as a divalent group, it may also be limited to hydrogen, methyl, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, another blocking fragment of another biologically active fragment, or an additional prodrug fragment.

In one embodiment, R ³⁰¹ is selected from:

In one embodiment, R301 is ; where R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ and R ³⁰⁸ are selected from: bond, polyethylene glycol, natural amino acid, non-natural amino acid,

R ³⁰⁹ is selected from: alkyl, hydrogen,

n2 is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20; And

X ³⁰⁰ is selected from the bond, -NH-, -N(alkyl)-, O, -CH ₂ -O-, -CH ₂ -NH- and -CH ₂ -N(alkyl).

In one embodiment, only 1, 2, 3, 4 or 5 R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ and R ³⁰⁸

selected for communication.

In one embodiment, none of R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ and R ³⁰⁸ are selected for communication.

In one embodiment, only 1 of R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ and R ³⁰⁸ is selected for communication.

In one embodiment, only 2 of R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ and R ³⁰⁸ are selected for communication.

In one embodiment, only 3 of R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ and R ³⁰⁸ are selected for communication.

In one embodiment, only 4 of R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ and R ³⁰⁸ are selected for communication.

In one embodiment, only 5 of R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ and R ³⁰⁸ are selected for communication.

Non-limiting examples of compounds of the present invention with an R ³⁰¹ group include:

Non-limiting examples of compounds of the present invention with the group R ³⁰¹ include:

Non-limiting examples of compounds of the present invention with the group R ³⁰¹ include:

Non-limiting examples of compounds of the present invention with the group R ³⁰¹ include:

Non-limiting examples of compounds of the present invention with the group R ³⁰¹ include:

In one embodiment, C is selected from:

In one embodiment, A is selected from: C

In one embodiment, B is selected from:

In one embodiment, R ³² is:

Additional Formulas

In one aspect, the disclosure includes compounds and salts of the Formulas in Table 1 for any use and in any composition described in this application.

In some of the Formulas below, for the sake of convenience and location, R ³² is denoted as however, each R ³² described or illustrated in this application is considered to be independently shown in each of these Formulas.

where R ¹⁰³ represents C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, fluorine, chlorine or bromine.

Claims (31)

1. Connection selected from And , or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, where the compound is , or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, where the compound is , or a pharmaceutically acceptable salt thereof. 4. A pharmaceutical composition for the treatment of a disorder mediated by complement factor D, comprising a therapeutically effective amount of a compound according to any one of paragraphs. 1-3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 5. A method of treating a disorder mediated by complement factor D, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of paragraphs. 1-3 or its pharmaceutical composition according to claim 4 or its pharmaceutically acceptable salt. 6. The method of claim 5, wherein the subject is a human. 7. The method of claim 5 or 6, wherein the disorder is selected from acute respiratory distress syndrome, age-related macular degeneration (AMD), arthritis, asthma, Alzheimer's disease dementia, amyotrophic lateral sclerosis, antibody-mediated transplant rejection, antineutrophil-associated vasculitis cytoplasmic antibodies, antiphospholipid syndrome, atypical or typical hemolytic uremic syndrome, cardiovascular disease, cold agglutinin disease, chronic obstructive pulmonary disease (COPD), cirrhosis, Crohn's disease, C3 glomerulopathy, C3 glomerulonephritis, diabetic retinopathy, dense sediment disease, dermatomyositis, dermatitis, epidermolysis bullosa acquired, fatty liver, focal segmental glomerulosclerosis, geographic atrophy, glomerulonephritis, graft-versus-host disease, Guillain-Barré syndrome, hemolytic anemia, hydradenitis suppurativa, IgA nephropathy, ischemic/reperfusion injury, liver full-time insufficiency , inflammation of the liver, lupus nephritis, membranoproliferative glomerulonephritis, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, optomyelitis, non-alcoholic steatohepatitis (NASH), ophthalmic disease, pancreatitis, paroxysmal nocturnal hemoglobinuria, pemphigoid, pemphigus vulgaris, preeclampsia, decreased glomerular filtration rate, renovascular disorders, respiratory disease, retinal degeneration, retinal detachment, rheumatoid arthritis, scleroderma, E. coli Shiga toxin-associated sepsis, hemolytic uremic syndrome, spinal cord injury, sickle cell disease, traumatic brain injury, and ulcerative colitis. 8. The method of claim 7 wherein the disorder is age-related macular degeneration (AMD). 9. The method of claim 7, wherein the disorder is retinal degeneration, ophthalmic disease, multiple sclerosis, arthritis, or COPD. 10. The method of claim 7 wherein the disorder is an ophthalmic disease. 11. The method of claim 7 wherein the disorder is paroxysmal nocturnal hemoglobinuria (PNH). 12. The method of claim 7 wherein the disorder is a respiratory disease. 13. The method of claim 7 wherein the disorder is cardiovascular disease. 14. The method of claim 7 wherein the disorder is atypical or typical hemolytic uremic syndrome. 15. The method of claim 7 wherein the disorder is rheumatoid arthritis. 16. The method of claim 7 wherein the disorder is C3 glomerulopathy. 17. The method of claim 7 wherein the disorder is C3 glomerulonephritis or hard sediment disease. 18. The method of claim 7 wherein the disorder is IgA nephropathy. 19. The method of claim 7 wherein the disorder is geographic atrophy. 20. The method of claim 7 wherein the disorder is lupus nephritis. 21. The method of claim 7, wherein the disorder is a decrease in glomerular filtration rate. 22. The method of claim 7 wherein the disorder is a renovascular disorder. 23. The method of claim 7 wherein the disorder is sickle cell disease. 24. The method of claim 7 wherein the disorder is myasthenia gravis. 25. The method of claim 7 wherein the disorder is myelitis optica.